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Dietary polyacetylene falcarinol upregulated intestinal heme oxygenase-1 and modified plasma cytokine profile in late phase lipopolysaccharide (LPS)-induced acute inflammation in CB57BL/6 mice

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Abstract

Unlike polyphenols which are widely available in the diet, polyacetylenes are available only from the Apiaceae family vegetables, including carrot, parsnip, fennel, celery and many herbs (parsley, lovage etc). The aim of this study was to investigate the hypothesis that polyacetylene falcarinol reduces intestinal inflammation and examine its similarity of effect to isothiocyanate R-sulforaphane, during the late phase of acute inflammation. To this end, three month old male CB57BL/6 mice were fed twice daily for one week with 5 mg/kg of either FA, SF or vehicle before receiving an intraperitoneal injection of 5 mg/kg endotoxin (lipopolysaccharide) to induce modest acute inflammation. The expression of intestinal and hepatic heme oxygenase-1 at the mRNA and protein levels, circulating cytokines, as well as intestinal and mesenteric n-6 and n-3 fatty acid lipid mediators were compared 24 hours after LPS administration to examine their effects on the late phase of inflammation. Intestinal Nrf2 target enzyme heme oxygenase-1 was upregulated 8.42-fold at the mRNA level and 10.7-fold at the protein level by falcarinol supplemented diet. However, the falcarinol-supplemented diet produced a unique type-2 plasma cytokine skew after LPS treatment. Plasma cytokines IL-4, IL-13, IL-9 and IL-10 were upregulated, reflecting the cytokine profile of reduced type-1 inflammation. A detailed lipidomic analysis of n-6 and n-3 fatty acid pro- and anti-inflammatory pathways in the mesentery and intestinal mucosa showed that falcarinol diet was more similar to the control groups than to other LPS treated groups. In this study we demonstrated that falcarinol-supplemented diet produced a unique immunomodulatory effect not observed with sulforaphane in late phases of inflammation. These results support the hypothesis that falcarinol may have role as a dietary immunosuppressant in patients with inflammatory gastrointestinal as well as other inflammatory disorders that may be alleviated by increasing carrot consumption or other falcarinol-containing food sources.

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... Immunosuppressive activities have also been reported in drumsticks (Tang et al., 2018) and purple sweet potato (Mahajan & Mehta, 2010). Similarly, polyacetylene, falcarinol, which is exclusively found in vegetable crops of Umbelliferae family, has shown immunosuppressive activities by reducing intestinal inflammation (Stefanson & Bakovic, 2020). Besides fresh vegetables, processed or derived products have also been found to strengthen immune system. ...
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Reorientation of life style becomes necessary for staying healthy, especially during the challenging times as it is prevailing at present. Consumption of ample plant-based foods like vegetables could be an important step towards it. However, certain vegetables hold more significance as they boost immunity. Daily intake of vegetables with immunomodulation properties (modification of the immune response or the functioning of the immune system) seems promising. The immunomodulatory properties of these vegetables are attributed to the presence of certain phytoconstituents like polysachharides (e.g. RG-I in bell pepper; CMDP-4b in pumpkin; MOP-3 in drumstick), lectins (ASA I & ASA II in garlic; BOL in cauliflower), isothiocynates (Sulforaphane in broccoli), unsaturated fatty acids (pumpkin seeds), bryonolic acid (acorn squash), ribosomes inactivating protein (Lagenin in bottle gourd), glycoprotein (Luffaculin in ridge gourd), trypsin inhibitor (MoFTI in drumsticks) etc. The aim of this review is to highlight results of work done on immunomodulatory activity of vegetables. The roles of various vegetables and their phytoconstituents, which are accountable for immunomodulation and reduction in the risk of infectious as well as non-communicable diseases, have been discussed. Such information may be encouraging for researchers to carry out further advanced research on vegetables with potential immunomodulatory properties.
... Indeed, n-3 PUFAs had demonstrated antioxidant effects in optic epithelial cells, through the activation of the nuclear factor erythroid 2-related factor (NRF2) antioxidant pathways [170]. Nrf2 is a master regulator for a series of antioxidant proteins such as the superoxide dismutase (SOD), the heme oxygenase (HO-1), the glutathione disulfide reductase (GSR), sulfiredoxin (Srx), thioredoxin (Trx), which participate in the antioxidant defense [171,172]. Actions of Nrf2 against neurodegeneration had also been implicated by the reduced Nrf2 levels in ALS and PD-like mouse models; this is more detailed reviewed in [171]. Furthermore, post-mortem analysis of the brains of human ALS patients showed decreased levels of Nrf2 with elevated the Kelch-like ECH-associated protein 1 (KEAP1) [173]. ...
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... Recently, the bioactive polyacetylenes isolated from apiaceous vegetables (including carrots, celery, celeriac, fennel, parsley, and parsnip) have been attracted increasing attention (Zidorn et al., 2005;Kramer et al., 2011). Among them, falcarinol and FAD, are both found to mediate biological processes, such as neural stem cell homeostasis , inflammatory response (Stefanson and Bakovic, 2020), lipid peroxidation (Ohnuma et al., 2011), granulocytic differentiation (Tsolmon et al., 2009), and cytotoxic activity (Cheung et al., 2019). Besides, several studies have found that FAD exerts tumor-suppressive effects by activating endoplasmic reticulum stress (Jin et al., 2012;Lu et al., 2017). ...
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This study assessed the concentrations of three falcarinol-type polyacetylenes (falcarinol, falcarindiol, falcarindiol-3-acetate) in carrots and the correlations between these and different soil traits. A total of 144 carrot samples, from three different harvests taken a single season, were analysed in terms of their polyacetylene concentrations and root development. On one of the harvesting occasions, 48 soil samples were also taken and analysed. The chemical composition of the soil was found to influence the concentrations of falcarinol-type polyacetylenes in carrots. When the total soil potassium level was 200 mg/100 g soil, the concentration of falcarindiol (FaDOH) in the carrot samples was 630 μg/g DW, but when carrots were grown in soil with a total potassium level of 300 mg/100 g soil, the FaDOH concentration in the carrots fell to 445 μg/g DW. Carrots grown in soils generally low in available phosphorus exhibited higher levels of falcarindiol if the soil was also low in available magnesium and calcium. The concentrations of polyacetylenes in carrots were positively correlated with total soil phosphorus level, but negatively correlated with total soil potassium level. Of the three polyacetylenes analysed, FaDOH concentrations were influenced most by changes in soil chemical composition.
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The ratio of ω-6 to ω-3 polyunsaturated fatty acids (PUFAs) appears to be critical in the regulation of various pathophysiological processes and to maintain cellular homeostasis. While a high proportion of dietary intake of ω-6 PUFAs is associated with various inflammatory disorders, higher intake of ω-3 PUFAs is known to offer protection. It is now well established that beneficial effects of ω-3 PUFAs are mediated in part by their oxygenated metabolites mainly via the lipoxygenase (LOX) and cyclooxygenase (COX) pathways. However, the down-stream signaling pathways that are involved in these anti-inflammatory effects of ω-3 PUFAs have not been elucidated. The present study evaluates the effects of 15-LOX metabolites of α-linolenic acid (ALA, ω-3 PUFA) on lipopolysaccharide (LPS) induced inflammation in RAW 264.7 cells and peritoneal macrophages. Further, the effect of these metabolites on the survival of BALB/c mice in LPS mediated septic shock and also polymicrobial sepsis in Cecal Ligation and Puncture (CLP) mouse model was studied. These studies reveal the anti-inflammatory effects of 13-(S)-hydroperoxyoctadecatrienoic acid [13-(S)-HPOTrE] and 13-(S)- hydroxyoctadecatrienoic acid [13-(S)-HOTrE] by inactivating NLRP3 inflammasome complex through the PPAR-γ pathway. Additionally, both metabolites also deactivated autophagy and induced apoptosis. In mediating all these effects 13-(S)-HPOTrE was more potent than 13-(S)-HOTrE.
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Oxidative stress plays a critical role in the pathogenesis of intestinal ischemia reperfusion (IIR) injury. Enhancement in endogenous Lipoxin A4 (LXA4), a potent antioxidant and mediator, is associated with attenuation of IIR. However, the effects of LXA4 on IIR injury and the potential mechanisms are unknown. In a rat IIR (ischemia 45 minutes and subsequent reperfusion 6 hours) model, IIR caused intestinal injury, evidenced by increased serum diamine oxidase, D-lactic acid, intestinal-type fatty acid-binding protein, and the oxidative stress marker 15-F2t-Isoprostane. LXA4 treatment significantly attenuated IIR injury by reducing mucosal 15-F2t-Isoprostane and elevating endogenous antioxidant superoxide dismutase activity, accompanied with Keap1/Nrf2 pathway activation. Meanwhile, LXA4 receptor antagonist Boc-2 reversed the protective effects of LXA4 on intestinal injury but failed to affect the oxidative stress and the related Nrf2 pathway. Furthermore, Nrf2 antagonist brusatol reversed the antioxidant effects conferred by LXA4 and led to exacerbation of intestinal epithelium cells oxidative stress and apoptosis, finally resulting in a decrease of survival rate of rat. Meanwhile, LXA4 pretreatment upregulated nuclear Nrf2 level and reduced hypoxia/reoxygenation-induced IEC-6 cell damage and Nrf2 siRNA reversed this protective effect of LXA4 in vitro . In conclusion, these findings suggest that LXA4 ameliorates IIR injury by activating Keap1/Nrf2 pathway in a LXA4 receptor independent manner.
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The profile of global health today presents a striking reciprocal distribution between parasitic diseases in many of the world’s lower-income countries, and ever-increasing levels of inflammatory disorders such as allergy, autoimmunity and inflammatory bowel diseases in the more affluent societies. Attention is particularly focused on helminth worm parasites, which are associated with protection from allergy and inflammation in both epidemiological and laboratory settings. One mechanistic explanation of this is that helminths drive the regulatory arm of the immune system, abrogating the ability of the host to expel the parasites, while also dampening reactivity to many “bystander” specificities. Interest has therefore heightened into whether helminth parasites, or their products, hold therapeutic potential for immunological disorders of the developed world. In this narrative review, progress across a range of trials is discussed, together with prospects for isolating individual molecular mediators from helminths that may offer defined new therapies for inflammatory conditions.
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Within the secreted phospholipase A2 (sPLA2) family, group X sPLA2 (sPLA2-X) has the highest capacity to hydrolyze cellular membranes and has long been thought to promote inflammation by releasing arachidonic acid (AA), a precursor of pro-inflammatory eicosanoids. Unexpectedly, we found that transgenic mice globally overexpressing human sPLA2-X (PLA2G10-Tg) displayed striking immunosuppressive and lean phenotypes with lymphopenia and increased M2-like macrophages, accompanied by marked elevation of free ω-3 polyunsaturated fatty acids (PUFAs) and their metabolites. Studies using Pla2g10-deficient mice revealed that endogenous sPLA2-X, which is highly expressed in the colon epithelium and spermatozoa, mobilized ωPUFAs or their metabolites to protect against dextran sulfate-induced colitis and to promote fertilization, respectively. In colitis, sPLA2-X deficiency increased colorectal expression of Th17 cytokines, and ω3 PUFAs attenuated their production by lamina propria cells partly through the fatty acid receptor GPR120. In comparison, cytosolic phospholipase A2 (cPLA2α) protects from colitis by mobilizing ω-6 AA metabolites including prostaglandin E2. Thus, our results underscore a previously unrecognized role of sPLA2-X as an ω3 PUFA mobilizer in vivo, segregated mobilization of ω-3 and ω-6 PUFA metabolites by sPLA2-X and cPLA2α, respectively, in protection against colitis, and the novel role of a particular sPLA2-X-driven PUFA in fertilization.
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The inflammatory process seen in inflammatory bowel disease (IBD) is due to excess production of pro-inflammatory cytokines interleukin-1 (IL-1), IL-6, tumor necrosis factor-α (TNF-α), interferons (IFNs), macrophage migration inhibitory factor (MIF), HMGB1 (high mobility group B1) and possibly, a reduction in anti-inflammatory cytokines IL-10, IL-4, and transforming growth factor-β (TGF-β). These pro-inflammatory molecules lead to increased production of reactive oxygen species (ROS) including nitric oxide resulting in target tissue damage. I propose that inadequate production of inflammation resolving molecules lipoxins, resolvins, protectins, maresins and nitrolipids that suppress inflammation, ROS production, enhance wound healing and have cytoprotective properties results in inappropriate inflammation, delay in healing/repair process and so target tissue/organ damage continues in IBD. Hence, suggested therapeutic approach could include administration of stable synthetic analogues of lipoxins, resolvins, protectins, maresins and nitrolipids. This implies that measuring urine, stool and plasma levels of lipoxins, resolvins, protectins, maresins and nitrolipids may be used to detect the onset, progression and response to treatment of IBD.
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The recognition that food-derived nonnutrient molecules can modulate gene expression to influence intracellular molecular mechanisms has seen the emergence of the fields of nutrigenomics and nutrigenetics. The aim of this review is to describe the properties of nutrigenomic activators of transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2), comparing the potential for sulforaphane and other phytochemicals to demonstrate clinical efficacy as complementary medicines. Broccoli-derived sulforaphane emerges as a phytochemical with this capability, with oral doses capable of favourably modifying genes associated with chemoprevention. Compared with widely used phytochemical-based supplements like curcumin, silymarin, and resveratrol, sulforaphane more potently activates Nrf2 to induce the expression of a battery of cytoprotective genes. By virtue of its lipophilic nature and low molecular weight, sulforaphane displays significantly higher bioavailability than the polyphenol-based dietary supplements that also activate Nrf2. Nrf2 activation induces cytoprotective genes such as those playing key roles in cellular defense mechanisms including redox status and detoxification. Both its high bioavailability and significant Nrf2 inducer capacity contribute to the therapeutic potential of sulforaphane-yielding supplements.
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Background: The metabolic syndrome (MetS) is associated with a chronic low-grade inflammatory state and may be affected by the ability to resolve inflammation, which is an active process that involves specialized proresolving lipid mediators (SPMs) derived from n-3 (ω-3) fatty acids. Objective: We compared plasma concentrations of SPMs in men and women with features of the MetS and in healthy matched control subjects in response to intakes of n-3 fatty acids and aspirin. Design: MetS volunteers (n = 22) and healthy, matched controls (n = 21) were studied in parallel for 4 wk. Both groups took n-3 fatty acids (2.4 g/d) for 4 wk with the addition of aspirin (300 mg/d) during the last 7 d. Blood was collected at baseline and at 3 and 4 wk. Plasma SPMs were measured with the use of liquid chromatography-tandem mass spectrometry and included 18-hydroxyeicosapentaenoic acid (18-HEPE), E-series resolvins, 17-hydroxydocosahexaenoic acid (17-HDHA), D-series resolvins, 14-hydroxydocosahexaenoic acid (14-HDHA), and maresin-1. Results: Baseline SPMs did not differ between groups. There was an increase in the SPM precursors 18-HEPE, 17-HDHA, and 14-HDHA after n-3 fatty acid supplementation that was significantly attenuated in the MetS (P < 0.05). However, the E-series resolvins increased to a similar extent in the groups after n-3 fatty acid supplementation, and the D-series resolvins were not different from those at baseline. The addition of aspirin to n-3 fatty acids did not alter any SPMs in either group. Conclusions: Volunteers with MetS had reduced plasma concentrations of the precursors of the E- and D- series resolvins as well as of 14-HDHA in response to n-3 fatty acid supplementation. However, plasma E-series resolvins were increased to a similar extent after n-3 fatty acid supplementation in both groups, and the addition of aspirin to n-3 fatty acid supplementation did not alter any of the plasma SPMs in MetS and control subjects. Additional studies in the MetS are required to determine whether SPMs affect the ability to mount an appropriate response to infection. This trial was registered at the Australian New Zealand Clinical Trials Registry as ACTRN12610000708055.
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Infection with helminth parasites and treatment with worm extracts can suppress inflammatory disease, including colitis. Postulating that dendritic cells (DCs) participated in the suppression of inflammation and seeking to move beyond the use of helminths per se, we tested the ability of Hymenolepis diminuta antigen-pulsed DCs to suppress colitis as a novel cell-based immunotherapy. Bone-marrow derived DCs pulsed with H. diminuta antigen (HD-DCs), or PBS-, BSA- or LPS-DCs as controls, were transferred into wild-type (WT), interleukin-10 (IL-10) knock-out (KO), and RAG-1 KO mice, and the impact on dinitrobenzene sulphonic acid (DNBS)-induced colitis and splenic cytokine production assessed 72 h later. Mice receiving HD-DCs were significantly protected from DNBS-induced colitis and of the experimental groups only these mice displayed increased Th2 cytokines and IL-10 production. Adoptive transfer of HD-DCs protected neither RAG-1 nor IL-10 KO mice from DNBS-colitis. Furthermore, the transfer of CD4(+) splenocytes from recipients of HD-DCs protected naïve mice against DNBS-colitis, in an IL-10 dependent manner. Thus, HD-DCs are a novel anti-colitic immunotherapy that can educate anti-colitic CD4(+) T cells: mechanistically, the anti-colitic effect of HD-DCs requires that the host has an adaptive immune response and the ability to mobilize IL-10. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
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BackgroundNEC, an intestinal inflammatory disease affecting premature infants, is associated with low regulatory T (Treg) to effector T (Teff) cell ratios. We recently demonstrated that heme oxygenase-1 (HO-1) deficiency leads to increased NEC development. Here, we investigated the effects of HO-1 on T cell proportions in a murine NEC-like injury model.Methods Intestinal injury was induced in 7d-old WT or HO-1 heterozygous (Het) pups by p.o. formula-feeding every 4h for 24-78h and exposures to 5%O2. Controls remained breastfed. HO-1 was induced in WT pups by administering heme pre-injury induction. Lamina propria T cells were identified by flow cytometry. For adoptive transfer studies, WT splenic/thymic Tregs were injected i.p. into Het pups 12-24h pre-induction.ResultsHet mice showed increased intestinal injury and decreased Treg/Teff ratios. Genes for pattern recognition (TLR4, C-reactive protein, MyD88) and neutrophil recruitment increased in Het pups after NEC induction. Inducing intestinal HO-1 decreased NEC scores and incidence, and increased Treg/Teff ratios. Moreover, adoptive transfer of Tregs from WT to Het pps decreased NEC scores and incidence and restored Treg/Teff ratios.ConclusionsHO-1 can change Treg proportions in the lamina propria of young mice under inflammatory conditions, which might, in part, confer partial intestinal protection.Pediatric Research (2015); doi:10.1038/pr.2015.22.
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It has become increasingly evident that chronic inflammation underpins the development of many chronic diseases including cancer, cardiovascular disease and type 2 diabetes. Oxidative stress is inherently a biochemical dysregulation of the redox status of the intracellular environment, which under homeostatic conditions is a reducing environment, whereas inflammation is the biological response to oxidative stress in that the cell initiates the production of proteins, enzymes, and other compounds to restore homeostasis. At the center of the day-to-day biological response to oxidative stress is the Keap1/Nrf2/ARE pathway, which regulates the transcription of many antioxidant genes that preserve cellular homeostasis and detoxification genes that process and eliminate carcinogens and toxins before they can cause damage. The Keap1/Nrf2/ARE pathway plays a major role in health resilience and can be made more robust and responsive by certain dietary factors. Transient activation of Nrf2 by dietary electrophilic phytochemicals can upregulate antioxidant and chemopreventive enzymes in the absence of actual oxidative stress inducers. Priming the Keap1/Nrf2/ARE pathway by upregulating these enzymes prior to oxidative stress or xenobiotic encounter increases cellular fitness to respond more robustly to oxidative assaults without activating more intense inflammatory NFκB-mediated responses.
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Toosendanin (TSN), a triterpenoid extracted from the bark of fruit of Melia toosendan Sieb et Zucc, has been proven to have various biological activities including anti-inflammatory activity. But its effects on experimental colitis remain unreported. Herein, we investigated the role and potential mechanisms of TSN in dextran sulfate sodium (DSS) induced colitis in mice. The results showed that, TSN reduced colitis-associated disease activity index (DAI), shortened colon length, and weakened the pathological damage of the colon tissues in murine colitis models. Further studies disclosed that, TSN inhibited the secretion of proinflammatory cytokines and oxidative stress, and suppressed M1 macrophage polarization and the activation of NLR family pyrin domain containing 3 (NLRP3) inflammasome, but upregulated HO-1/Nrf2 expression in murine colitis. In addition, TSN maintained intestinal barrier by regulating zonula occludens-1 (ZO-1) and occludin expression. In conclusion, our findings demonstrated that, TSN alleviates DSS-induced experimental colitis by inhibiting M1 macrophage polarization and regulating NLRP3 inflammasome and Nrf2/HO-1 signaling, and may provide a novel Chinese patent medicine for the treatment of murine colitis.
Article
BACKGROUND The aim of the study was to investigate the effects of variety (Nantes and Imperator), soil fertility status (high and low), and agronomic treatments on yield and quality traits of carrot composition and sensory factors. The treatments compared synthetic nitrogen at conventionally recommended amounts with compost‐sourced nitrogen (high and low rates) and a range of amendments (compost, compost tea, micronutrients and foliar treatments). Additionally, we intended to identify factors affecting polyacetylene accumulation in carrots, due to the growing interest in their health effects and paucity of agronomic information on their bioaccumulation in carrots. RESULTS Imperator accumulated more minerals, produced more phytochemicals and had higher antioxidant capacity than Nantes, which had more carotenoids. However, consumers preferred the flavour of Nantes over Imperator. High fertility soil produced carrots of superior nutritional quality, than did low fertility soil, regardless of year‐of‐application amendments, the effects of which were often variety‐dependent. High soil biological activity was able to overcome low fertility status and stimulate greater yield. Carrot phosphorus was correlated with falcarindiol biosynthesis. Chlorogenic acid and falcarindiol were correlated with antioxidant capacity, but not falcarinol or total phenolic compounds. CONCLUSION Carrots were not strongly affected by agronomic treatments in terms of yield or phytochemical status, however soil biological activity overcame a soil nutrient deficit in terms of yield. Phenolic compounds and antioxidant status were generally higher in the high fertility site, whereas polyacetylenes were variety‐dependent. Chlorogenic acid and falcarindiol were associated with antioxidant capacity, but not total phenolic compounds and carotenoids. This article is protected by copyright. All rights reserved.
Article
Rheum rhabarbarum has been widely used as a herbal medicine and food in China. The objective of this study was to investigate the cytoprotective action and underlying mechanisms of rhein, one active ingredient isolated from R. rhabarbarum, on H2O2-challenged rat small intestine epithelial cells (IEC-6 cells). H2O2-challenged IEC-6 cells were incubated in the pretreatment with or without rhein or LY294002, a PI3K/Akt inhibitor. The cell viability, apoptosis, intracellular reactive oxygen species (ROS), and antioxidants were measured. The expressions of heme oxygenase 1 (HO-1), nuclear factor erythroid 2-related factor (Nrf2), Akt, and p-Akt were evaluated by western blotting. Meanwhile, LY294002 was also used to investigate the role of PI3K/Akt in the rhein-induced cytoprotective role. The results showed that pretreatment of rhein could reverse the inhibition of cell viability and suppress the apoptosis, caspase-3 activity, and intracellular ROS induced by H2O2. Rhein also supported SOD activity catalase activity, glutathione S-transferase activity, and glutathione content. Furthermore, rhein induced the protein expression of HO-1 together with its upstream mediator Nrf2 and activated the phosphorylation of Akt in IEC-6 cells. LY294002 inhibited increased cell viability, upregulated the lowered apoptotic rate, and enhanced the weakened ROS levels. Although the inhibition of PI3K/Akt did not inhibit the Nrf2 nuclear level under 4 μM rhein, LY294002 inhibited the Nrf2 nuclear level under 2 μM rhein and blocked HO-1 expression. These data demonstrated that rhein protected IEC-6 cells against oxidative damage partly via PI3K/Akt and Nrf2/HO-1 pathways.
Article
Alteration in the expression pattern of Nrf-2 and NFκB has been reported in ulcerative colitis (UC) in which functional crosstalk between these two critical pathways has been suggested. The ameliorative potential of the AT1R blocker olmesartan (OLM) on oxidative stress and inflammatory cytokines has received considerable attention in recent years. Acetic acid (AA)-induced UC demonstrates close resemblance to human UC regarding histopathological features and cytokine profile and is associated with local intense immune response, oxidative stress and release of inflammatory cytokines. Therefore, The effect of OLM (1, 5 and 10 mg/kg) administered orally to rats subjected to intra-rectal instillation of 2 ml of 3% AA in saline solution is investigated. The study revealed that OLM ameliorated colon injury and inflammatory signs as visualized by histopathological examination. Levels of colon IL-6, TNF-α IL-1β TGF-β and serum CRP were down-regulated, while the level of colon IL-10 was up-regulated. In a dose-dependent manner, OLM suppressed AA-induced neutrophils accumulation and improved colon anti-oxidant defense machinery. Also, OLM repressed the Bax:BCL-2 ratio and caspase3 expression. The mechanism of these protective effects was found to lay behind its ability to down-regulate gene expression and inhibit phosphorylation and nuclear translocation of p65 subunits. On the other hand, OLM up-regulated gene expression of Nrf-2 and HO-1. In conclusion, our data show that OLM is an Nrf2 activator, NFkB inhibitor and apoptosis inhibitor in an experimental model of ulcerative colitis. Overall, the study indicates that OLM shows promise as a potential therapy for the treatment of human inflammatory bowel diseases.
Article
Scope Gut microbiota imbalance, inflammation and gut barrier deficiency play an important role in carcinogenesis. Sulforaphane (SFN), an isothiocyanate found in cruciferous vegetables, has been proven to be highly effective in inhibiting cancer. The objective of this study is to investigate the potential roles of the gut microbiota in the inhibition of BBN‐induced bladder cancer by SFN. Methods and Results N‐butyl‐N‐(4‐hydroxybutyl) ‐nitrosamine was used to induce bladder cancer in male C57BL/6 mice, with or without SFN for 23 weeks. SFN ameliorated the histological changes characteristic of bladder cancer, resulting in fewer submucosal capillaries. SFN normalized gut microbiota dysbiosis in mice with BBN‐induced bladder cancer with a significant increase in Bacteroides fragilis and Clostridium cluster I. SFN also increased butyric acid levels in the mouse colon, and repaired the injury to the mucosal epithelium of the colon and cecum through the upregulation of the expression of tight junction proteins and GLP2. SFN greatly decreased the release of cytokines (IL‐6) and secretory immunoglobulin A in the mice with bladder cancer. Conclusion These results suggest that SFN protects against chemical‐induced bladder cancer through normalizing the composition of gut microbiota and repairing the physiological destruction of gut barrier, as well as decreasing inflammation and the immune response. This article is protected by copyright. All rights reserved
Article
Type 2 diabetes mellitus (DM) has reached pandemic proportions and effective prevention strategies are wanted. Its onset is accompanied by cellular distress, the nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor boosting cytoprotective responses, and many phytochemicals activate Nrf2 signaling. Thus, Nrf2 activation by natural products could presumably alleviate DM. We summarize function, regulation and exogenous activation of Nrf2, as well as diabetes-linked and Nrf2-susceptible forms of cellular stress. The reported amelioration of insulin resistance, β-cell dysfunction and diabetic complications by activated Nrf2 as well as the status quo of Nrf2 in precision medicine for DM are reviewed.
MetaboAnalyst (http://www.metaboanalyst.ca) is a comprehensive Web application for metabolomic data analysis and interpretation. MetaboAnalyst handles most of the common metabolomic data types from most kinds of metabolomics platforms (MS and NMR) for most kinds of metabolomics experiments (targeted, untargeted, quantitative). In addition to providing a variety of data processing and normalization procedures, MetaboAnalyst also supports a number of data analysis and data visualization tasks using a range of univariate, multivariate methods such as PCA (principal component analysis), PLS-DA (partial least squares discriminant analysis), heatmap clustering and machine learning methods. MetaboAnalyst also offers a variety of tools for metabolomic data interpretation including MSEA (metabolite set enrichment analysis), MetPA (metabolite pathway analysis), and biomarker selection via ROC (receiver operating characteristic) curve analysis, as well as time series and power analysis. This unit provides an overview of the main functional modules and the general workflow of the latest version of MetaboAnalyst (MetaboAnalyst 3.0), followed by eight detailed protocols.
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Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that regulate gene transcription in response to peroxisome proliferators and fatty acids. PPARs also play an important role in the regulation of adipocyte differentiation. It is unclear, however, what naturally occurring compounds activate each of the PPAR subtypes. To address this issue, a screening assay was established using heterologous fusions of the bacterial tetracycline repressor to several members of the peroxisome proliferator-activated receptor (PPAR) family. This assay was employed to compare the activation of PPAR family members by known PPAR activators including peroxisome proliferators and fatty acids. Interestingly, the activation of PPARs by fatty acids was partially inhibited by the cyclooxygenase inhibitor indomethacin, which prevents prostaglandin synthesis. Indeed, prostaglandins PGA1 and 2, PGD1 and 2, and PGJ2-activated PPARs, while a number of other prostaglandins had no effect. We also screened a variety of hydroxyeicosatetraenoic acids (HETEs) for the ability to activate PPARs. 8(S)-HETE, but not other (S)-HETEs, was a strong activator of PPAR alpha. Remarkably, PPAR activation by 8(S)-HETE was stereoselective. In addition, 8(S)-HETE was able to induce differentiation of 3T3-L1 preadipocytes. These results indicate that PPARs are differentially activated by naturally occurring eicosanoids and related molecules.
Article
The eating quality of carrots (Daucus carota L.) was investigated to evaluate the impact of cropping systems (one conventional and three organic systems) and growing years (2007, 2008, and 2009) on root size, chemical composition, and sensory quality. The content of dry matter, sugars, polyacetylenes, and terpenes as well as the sensory quality and root size were related to the climate during the three growing years. A higher global radiation and a higher temperature sum in 2009 as compared to 2007 and 2008 resulted in larger roots, higher contents of dry matter, sucrose, total sugars, and total polyacetylenes, and lower contents of terpenes, fructose, and glucose. No differences were found between conventional and organic carrots with regard to the investigated parameters. This result shows that organically grown carrots have the same eating quality as conventionally grown carrots, while being produced in a more sustainable way.
Article
C17-polyacetylenes are a prominent group of oxylipins and are primarily produced by plants of the families Apiaceae, Araliaceae, and Asteraceae, respectively. Recent studies on the biological activity of PAs have indicated their potential to improve human health due to anticancer, antifungal, antibacterial, anti-inflammatory, and serotogenic effects. Out of the twelve known C17-PAs in carrots falcarinol and falcarindiol have been identified as the major oxylipins and were demonstrated to inhibit the cancer cell growth in in vitro and in vivo studies. These findings suggest targeting vegetables with elevated levels of bisacetylenic oxylipins, such as, e.g. falcarinol by breeding studies. Due to the abundant availability, high diversity of cultivars, world-wide experience and its high agricultural yields, in particular, carrot (Daucus carota L.) genotypes are a very promising target vegetable. Whereas higher concentrations of PAs in Apiaceae vegetables are detrimental for palatability due to their bitter off-taste, the content of PAs in carrots to be used for pharmaceutical purposes need to be high enough to allow for a cost-efficient drug production. Breeding specific carrot chemotypes might efficiently enhance the commercial production of the pharmaceutically relevant PAs, since the direct usage of wild carrot relatives rich for the wanted PAs is recently neither practicable nor economical. For breeding experiments including future approaches of targeted gene editing, the knowledge on the inheritance, molecular bases of the genes involved, and structure and function of enzymes involved in biosynthesis of PAs like falcarinol need to be widened. This article provides a review on falcarinol-type C17-polyacetylenes in carrots and a perspective on their potential as a future contributor to improving human health.
Article
Polyacetylenes are a class of highly bioactive compounds which may negatively affect the sensory properties of Apiaceous plants such as carrots and parsnips. In the present study, the effects of organic nitrogen fertilisation, water supply, and cold storage on the contents of falcarinol (FaOH), falcarindiol (FaDOH), and falcarindiol-3-acetate (FaDOAc) were investigated in four carrot (Daucus carota L.) and two parsnip (Pastinaca sativa L.) cultivars. Relatively high contents of polyacetylenes were observed at an early developmental stage of the roots of both carrot and parsnip, decreasing to a transient minimum approx. 1 month prior to harvest maturity. The supply of super-optimal levels of nitrogen (50 or 100 kg N ha -1) using organic fertiliser did not significantly affect the polyacetylene contents of carrot or parsnip at harvest (except FaDOH contents in 'Rodelika' carrot). Different levels of water supply to pot-grown carrots in climate chambers induced complex, cultivar-dependent, and apparently development-dependent patterns of change in polyacetylene contents and profiles. Cold storage of field-grown 'Bolero F 1' and 'Rodelika' carrot significantly increased the levels of individual polyacetylenes in both cultivars. However, carrots previously supplied with super-optimal amounts of nitrogen fertiliser (50 or 100 kg N ha -1) either showed a transient increase ('Bolero F 1') or a transient decline ('Rodelika') in polyacetylene contents during cold storage. The results suggest active pre- and post-harvest synthesis and metabolism of polyacetylenes in carrot and parsnip. This may affect the sensory and bio-functional properties of these crops.
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Resolution of acute inflammation is an active process coordinated by proresolving lipid mediators (SPMs) such as lipoxins (LXs) and resolvins (Rvs), which are formed by the concerted action of 2 lipoxygenases (LOs). Because the exact molecular mechanisms of SPM biosynthesis are not completely understood, we aimed to investigate LX and D-type Rv formation in human leukocytes and HEK293T cells overexpressing leukotriene (LT) pathway enzymes. Activity assays in precursor (15-hydroxyeicosatetraenoic acids, 17-HDoHE)-treated granulocytes [polymorphonuclear leukocyte (PMNL)] showed a strict dependence of LXA4/RvD1 biosynthesis on cell integrity, and incubation with recombinant human 5-LO did not lead to LX or Rv formation. Pharmacologic inhibition of 5-LO activating protein (FLAP) by MK-886 inhibited LXA4/RvD1 biosynthesis in precursor-treated PMNL (drug concentration causing 50% inhibition ∼0.3/0.2 µM), as did knockdown of the enzyme in MM6 cells, and precursor-treated HEK293T overexpressing 5-LO produced high amounts of LXA4 only in the presence of FLAP. In addition, inhibition of cytosolic phospholipase A2α (cPLA2α) interfered with LXA4/RvD1 formation from exogenous precursors in PMNL. Furthermore, inhibition of the LT synthases LTA4 hydrolase and LTC4 synthase in PMNL/platelet coincubations augmented LXA4 levels. These findings show that several enzymes known to be involved in the biosynthesis of proinflammatory LTs such as FLAP and cPLA2α also contribute to LX and Rv formation.-Lehmann, C., Homann, J., Ball, A., Blöcher, R., Kleinschmidt, T. K., Basavarajappa, D., Angioni, C., Ferreirós, N., Häfner, A., Rådmark, O., Proschak, E., Haeggström, J. Z., Geisslinger, G., Parnham, M. J., Steinhilber, D., Kahnt, A. S. Lipoxin and resolvin biosynthesis is dependent on 5-lipoxygenase activating protein. © FASEB.
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American ginseng is capable of ameliorating cardiac dysfunction and activating Nrf2, a master regulator of antioxidant defense, in the heart. This study was designed to isolate compounds from American ginseng and to determine those responsible for the Nrf2-mediated resolution of inflamed macrophage-induced cardiomyocyte hypertrophy. A standardized crude extract of American ginseng was supplied by the National Research Council of Canada, Institute for National Measurement Standards. A bioassay-based fractionization of American ginseng was performed to identify the putative substances which could activate Nrf2-mediated suppression of pro-inflammatory cytokine expression in macrophages and macrophage-mediated pro-hypertrophic growth in cardiomyocytes. A hexane fraction of an anti-inflammatory crude extract of American ginseng was found to be most effective in suppressing the inflammatory responses in macrophages. Preparative, reverse-phase HPLC and a comparative analysis by analytical scale LC-UV/MS revealed the hexane fraction contains predominantly C17 polyacetylenes and linolenic acid. Panaxynol, one of the major polyacetylenes, was found to be a potent Nrf2 activator. Panaxynol posttranscriptionally activated Nrf2 by inhibiting Kelch-like ECH-associated protein (Keap) 1-mediated degradation without affecting the binding of Keap1 and Nrf2. Moreover, panaxynol suppressed a selected set of cytokine expression via the activation of Nrf2 while minimally regulating nuclear factor-kappa B (NF-κB)-mediated cytokine expression in macrophages. It also dramatically inhibited the inflamed macrophage-mediated cardiomyocyte death and hypertrophy by activating Nrf2 in macrophages. These results demonstrate that American ginseng-derived panaxynol is a specific Nrf2 activator and panaxynol-activated Nrf2 signaling is at least partly responsible for American ginseng-induced health benefit in the heart. Copyright © 2015. Published by Elsevier Ireland Ltd.
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Heme oxygenase-1 (HO-1) catalyzes the first and rate-limiting enzymatic step of heme degradation and produces carbon monoxide, free iron, and biliverdin. HO-1, a stress-inducible protein, is induced by various oxidative and inflammatory signals. Consequently, HO-1 expression has been regarded as an adaptive cellular response against inflammatory response and oxidative injury. Although several transcriptional factors and signaling cascades are involved in HO-1 regulation, the two main pathways of Nrf2/Bach1 system and IL-10/HO-1 axis exist in monocyte/macrophage. Macrophages are broadly divisible into two groups: pro-inflammatory M1 macrophages and anti-inflammatory M2 macrophages. More recently, several novel macrophage subsets have been identified including Mhem, Mox, and M4 macrophages. Of these, M2 macrophages, Mhem, and Mox are HO-1 highly expressing macrophages. HO-1 has been recognized as having major immunomodulatory and anti-inflammatory properties, which have been demonstrated in HO-1 deficient mice and human cases of genetic HO-1 deficiency. However, the mechanism underlying the immunomodulatory actions of HO-1 remains poorly defined. This review specifically addresses macrophage polarization. The present current evidence indicates that HO-1 induction mediated by multiple pathways can drive the phenotypic shift to M2 macrophages and suggests that HO-1 induction in macrophages is a potential therapeutic approach to immunomodulation in widely diverse human diseases.