Metabolomics revealed decreased level of omega‐3 PUFA‐derived protective eicosanoids in pregnant women with pre‐eclampsia

Pre‐eclampsia (PE) is considered a leading cause of mortality and morbidity in pregnant women worldwide. Eicosanoids derived from polyunsaturated fatty acids (PUFAs) might play an important role in the occurrence and development of PE. Omega‐3 PUFAs are nutrients that are popular supplements for pregnant women and can reduce blood pressure. However, the levels of eicosanoids derived from omega‐3 PUFAs in women with PE is not clear. The purpose of this study was to investigate the eicosanoid metabolic signature of PE. We performed a case–control study using data for pregnant women (n = 10) with PE and normotensive pregnant women (n = 10). We investigated the difference in eicosanoid profile between the groups by LC‐MS/MS‐based metabolomics. The plasma levels of arachidonic acid metabolites and some of the lipoxygenase metabolites of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) showed an increasing trend, and those of the cytochrome P450 metabolites of EPA and DHA were decreased in women with PE. Levels of leukotriene B4, 14,15‐dihydroxy‐eicosatetraenoate, 16‐hydroxydocosahexaenoic acid and 8,9‐epoxy eicosatetraenoic acid were significantly correlated with PE occurrence. These eicosanoids might take part in the progression of PE in pregnant women.     

Investigation of long chain omega‐3 PUFAs on arterial blood pressure,vascular reactivity and survival in angiotensin II‐infused Apolipoprotein E‐knockout mice

Abdominal aortic aneurysm (AAA) is an inflammatory vascular disease. Long chain omega‐3 polyunsaturated fatty acids (LC n‐3 PUFAs) decrease inflammation and oxidative stress in an angiotensin II‐infused apolipoprotein E‐knockout (ApoE^?/?) mouse model of AAA. This study investigated the effects of LC n‐3 PUFAs on blood pressure and vascular reactivity in fourteen angiotensin II‐infused ApoE^?/? male mice. Blood pressure was obtained using a non‐invasive tail cuff method and whole blood was collected by cardiac puncture. Vascular reactivity of the thoracic aorta was assessed using wire myography and activation of endothelial nitric oxide synthase (eNOS) was determined by immunohistochemistry. A high LC n‐3 PUFA diet increased the omega‐3 index and reduced the n‐6 to n‐3 PUFA ratio. At day 10 post‐infusion with angiotensin II, there was no difference in systolic blood pressure or diastolic blood pressure in mice fed the high or low n‐3 PUFA diets. The high LC n‐3 PUFA diet resulted in a non‐significant trend for delay in time to death from abdominal aortic rupture. Vascular reactivity and eNOS activation remained unchanged in mice fed the high compared to the low LC n‐3 PUFA diet. This study argues against direct improvement in vascular reactivity in ApoE^?/? mice that were supplemented with n‐3 PUFA for 8 weeks prior to infusion with angiotensin II.     

Omega‐3 fatty acids in coronary heart disease: Recent updates and future perspectives

Incidence of coronary heart disease (CHD) increases worldwide with varying etiological factors. In addition to the control of risk factors, dietary modification has been recommended to reduce the prevalence. Omega‐3 (ω‐3) fatty acids (FAs), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), of fish oil are beneficial for the prevention of CHD. The effect can be ascribed to anti‐inflammatory, vasodilating, antiarrhythmic, antihypertensive activities and lowering of triacyl glycerol level. The American Heart Association advises two fish meals per week in subjects without CHD or supplementation of 1 g of EPA plus DHA per day in subjects with CHD. Despite the beneficial effects of EPA/DHA reported in some of the clinical trials, results of many others were inconsistent that can be ascribed to short duration of studies, low doses of ω‐3 FAs, variations in the EPA:DHA ratio, selection of patients with different risk factors or interaction of ω‐3 FAs with drugs used in the therapy. Therefore, well designed clinical trials in various populations are warranted. This article discusses the current situation and future prospective of ω‐3 FAs in CHD.     

Protective effect of curcumin against formaldehyde‐induced genotoxicity in A549 Cell Lines

Formaldehyde is ubiquitous in the environment. It is known to be a genotoxic substance. We hypothesized that reactive oxygen species (ROS) and lipid peroxidation are involved in formaldehyde‐induced genotoxicity in human lung cancer cell lines A549. To test this hypothesis, we investigated the effects of antioxidant on formaldehyde‐induced genotoxicity in A549 Cell Lines. Formaldehyde exposure caused induction of DNA–protein cross‐links (DPCs). Curcumin is an important antioxidant. Formaldehyde significantly increased malondialdehyde (MDA) levels, and decreased superoxide dismutase (SOD) and glutathione peroxidase (GSH‐Px) activity. In addition, the activation of NF‐κB and AP‐1 were induced by formaldehyde treatment. Pretreatment with curcumin counteracted formaldehyde‐induced oxidative stress, ameliorated DPCs and attenuated activation of NF‐κB and AP‐1 in A549 Cell Lines. These results, taken together, suggest that formaldehyde induced genotoxicity through its ROS and lipid peroxidase activity and caused DPCs effects in A549 cells. Copyright © 2012 John Wiley & Sons, Ltd.     

Acrolein-induced oxidative stress and genotoxicity in rats: protective effects of whey protein and conjugated linoleic acid

Acrolein (AC), a highly reactive hazardous pollutant, poses serious threats to human health. Whey protein (WP) and conjugated linoleic acid (CLA) have beneficial health implications. We investigated the protective effects of WP and CLA against AC-induced toxicity in rats. The animals were orally gavaged with CLA (200?mg/kg/day), WP (200?mg/kg/day), AC (5?mg/kg/day), CLA?+?AC (200?+?5?mg/kg/day), and WP?+?AC (200?+?5?mg/kg/day) six days per week for 30?days. The oral administration of AC significantly induced oxidative stress by increasing thiobarbituric acid reactive substances (TBARS) and protein carbonyls (PCOs) levels and decreasing glutathione (GSH) level in the spleen, thymus, and polymorphonuclear leukocytes (PMNs). It also increased the frequencies of micronucleus (MN) and megakaryocytic emperipolesis (ME) and decreased the ratio of polychromatic erythrocytes (PCEs) in bone marrow. Slight alterations in urinary 8-hydroxydeoxyguanosine (8-OHdG) levels were not significant. Co-treatment with CLA?+?AC or WP?+?AC ameliorated the values of oxidative stress, MN, PCE, and ME. These data suggest that CLA and WP can improve the antioxidant defenses and preclude the formation of genetic damage and ME.     

(‐)‐Epigallocatechin‐3‐gallate and atorvastatin treatment down‐regulates liver fibrosis‐related genes in non‐alcoholic fatty liver disease

Non‐alcoholic fatty liver disease (NAFLD) and associated advanced liver diseases have become prevalent conditions in many countries and are associated with increased mortality. Gene expression profiles in NAFLD have been examined recently but changes in expression elicited by chemical compound treatments have not been investigated. Since (‐)‐Epigallocatechin‐3‐gallate (EGCG) and atorvastatin (ATST) exhibit similar efficacy in NAFLD models, we reasoned that some common key genes might alter after treatment of EGCG and ATST. Accordingly, we applied integrated bioinformatics analyses of RNA microarray data from EGCG and ATST treatment groups compared to controls in a NAFLD phenotypic mouse model. Using differential expression (DE) analysis, Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway analysis, Gene Set Enrichment Analysis (GSEA) and ClueGO enrichment, shared EGCG and ATST down‐regulated pathways were identified which included extracellular matrix (ECM)‐receptor interaction and protein processing in endoplasmic reticulum (ER). To refine key genes associated with liver fibrosis, a human NAFLD signature derived from patients of different fibrosis stages was analyzed. The results showed that fibrosis‐related genes Col1a1, Col1a2, Col3a1 and Col6a3 were significantly down‐regulated. These four genes were further validated as down‐regulated in an independent mouse NAFLD dataset. We conclude that EGCG and ATST treatment results in the significant down‐regulation of genes related to liver fibrosis.     

Cadmium inhibits the ovary δ‐aminolevulinate dehydratase activity in vitro and ex vivo: protective role of seleno‐furanoside

Cadmium (Cd) toxicity is a concern to the tobacco‐smoking sub‐population which includes millions of people worldwide. Although this metal may cause severe damage to embryos and the reproductive organs, the precise mechanisms underlying its toxicity remain unclear. In the present study, the Cd effect on ovary δ‐aminolevulinate dehydratase (δ‐ALA‐D) activity was investigated in vitro and ex vivo. We observed that low concentrations of Cd inhibited cow ovary δ‐ALA‐D activity in vitro and the IC₅₀ value obtained was 19.17 μM. Furthermore, the protective effect of a novel organic selenium compound (seleno‐furanoside) in restoring enzyme activity was evaluated. Seleno‐furanoside (10, 50, 100, 200, 400 and 1000 μM) did not reverse the Cd toxicity in bovine ovarian tissue in vitro. According to the in vitro reults, acute Cd exposure (2.5 and 5 mg kg^–1) caused a significant inhibition in ovary δ‐ALA‐D activity in mice (around 27% and 34%, respectively). Therapy with seleno‐furanoside (100 µmol kg^–1) was able to restore enzyme activity. Thus, we demonstrated for the first time that δ‐ALA‐D activity from ovary is inhibited by Cd both in vitro and ex vivo. Additionally, seleno‐furanoside therapy was effective in restoring ovarian enzyme activity inhibited by Cd exposure in mice, but it did not reverse the in vitro metal effect. This study detected a new toxicity marker of Cd toxicity on ovarian tissue as well as the beneficial effect of a new compound to manage the metal effect after acute exposure. Copyright © 2012 John Wiley & Sons, Ltd.     

Toxic effects of 4‐methylthio‐3‐butenyl isothiocyanate (Raphasatin) in the rat urinary bladder without genotoxicity

We recently reported that 4‐methylthio‐3‐butenyl isothiocyanate (MTBITC) exerts chemopreventive effects on the rat esophageal carcinogenesis model at a low dose of 80 ppm in a diet. In contrast, some isothiocyanates (ITCs) have been reported to cause toxic effects, promotion activity, and/or carcinogenic potential in the urinary bladder of rats. In the present study, we investigated whether MTBITC had toxic effects in the urinary bladder similar to other ITCs, such as phenethyl ITC (PEITC). First, to examine the early toxicity of MTBITC, rats were fed a diet supplemented with 100, 300 or 1000 ppm MTBITC for 14 days. Treatment with 1000 ppm MTBITC caused increased organ weights and histopathological changes in the urinary bladder, producing lesions similar to those of 1000 ppm PEITC. In contrast, rats treated with 100 or 300 ppm MTBITC showed no signs of toxicity. Additionally, we performed in vivo genotoxicity studies to clarify whether MTBITC may exhibit a carcinogenic potential through a genotoxic mechanism in rats. Rats were treated with MTBITC for 3 days at doses of 10, 30 or 90 mg kg⁻¹ body weight by gavage, and comet assays in the urinary bladder and micronucleus assays in the bone marrow were performed. No genotoxic changes were observed after treatment with MTBITC at all doses. Overall, these results suggested that the effects of MTBITC in the rat urinary bladder are less than those of PEITC, but that MTBITC could have toxic effects through a nongenotoxic mechanism in the urinary bladder of rats at high doses. Copyright © 2016 John Wiley & Sons, Ltd.     

3‐Acetyl‐11‐keto‐β‐boswellic acid loaded‐polymeric nanomicelles for topical anti‐inflammatory and anti‐arthritic activity

Objectives The aim of this study was to develop 3‐acetyl‐11‐keto‐β‐boswellic acid (AKBA)‐loaded polymeric nanomicelles for topical anti‐inflammatory and anti‐arthritic activity. Methods Polymeric nanomicelles of AKBA were developed by a radical polymerization method using N‐isopropylacrylamide, vinylpyrrolidone and acrylic acid. The polymeric nanomicelles obtained were characterized by Fourier transform infrared (FTIR), transmission electron microscopy (TEM) and dynamic light scattering (DLS). In‐vitro and in‐vivo evaluations of AKBA polymeric nanomicelles gel were carried out for enhanced skin permeability and anti‐inflammatory and anti‐arthritic activity. Key findings TEM and DLS results demonstrated that polymeric nanomicelles were spherical with a mean diameter approximately 45 nm. FTIR data indicated a weak interaction between polymer and AKBA in the encapsulated system. The release of drug in aqueous buffer (pH 7.4) from the polymeric nanomicelles was 23 and 55% after 2 and 8 h, respectively, indicating sustained release. In‐vitro skin permeation studies through excised abdominal skin indicated a threefold increase in skin permeability compared with AKBA gel containing the same amount of AKBA as the AKBA polymeric nanomicelles gel. The AKBA polymeric nanomicelle gel showed significantly enhanced anti‐inflammatory and anti‐arthritic activity compared with the AKBA gel. Conclusions This study suggested that AKBA polymeric nanomicelle gel significantly enhanced skin permeability, and anti‐inflammatory and anti‐arthritic activity.     

Cyanidin‐3‐glucoside inhibits inflammatory activities in human fibroblast‐like synoviocytes and in mice with collagen‐induced arthritis

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by joint tissue inflammation. Cyanidin‐3‐glucoside (C3G) is a major component in the flavonoid family and has shown anti‐inflammatory, anti‐oxidant and anti‐tumour activity. In this study, we investigated the effects of C3G on lipopolysaccharides (LPS)‐induced inflammation on human rheumatoid fibroblast‐like synoviocytes (FLS) and on collagen‐induced arthritis (CIA) mice model. We treated FLS with C3G followed by LPS induction, the expressions of tumour necrosis factor alpha (TNF‐α), interleukin 1 beta (IL‐1β) and IL‐6 and the activation of nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐κB) and mitogen‐activated protein kinase (MAPK) signalling pathway were analyzed. CIA was induced in mice and the arthritic mice were treated with C3G for 3 weeks. The disease severity was compared between control and C3G treated mice. The serum levels of TNF‐α, IL‐1β and IL‐6 were analyzed by ELISA. C3G inhibited LPS‐induced TNF‐α, IL‐1β and IL‐6 expression in FLS. Moreover, C3G inhibited LPS‐induced p65 production and IκBa, p38, ERK and JNK phosphorylation. Administration of C3G significantly attenuated disease in mice with CIA and decreased the serum level of TNF‐α, IL‐1β and IL‐6. C3G inhibited LPS‐induced inflammation in human FLS by inhibiting activation of NF‐κB and MAPK signalling pathway. C3G exhibited therapeutic effects in mice with CIA.     

丹酚酸B通过介导SIRT3/FOXO1信号通路减轻非酒精性脂肪肝的氧化应激反应（英文）

丹酚酸B (Salvianolic acid B, Sal B)是一种多酚类抗氧化剂,已被证明在多种疾病中具有抗脂质积累、抗炎和清除氧自由基的活性。我们旨在研究Sal B是否可以改善非酒精性脂肪性肝病(Non-alcoholic fatty liver disease, NAFLD)的疾病进展并探索其可能的机制。通过油酸诱导Hep G2细胞建立NAFLD模型组细胞,SalB干预模型细胞建立治疗组细胞,进行生化分析及油红O染色检测各组细胞内脂质含量,通过免疫荧光及流式细胞仪检测细胞内活性氧(reactiveoxygen species, ROS)含量;试剂盒及酶标仪定量细胞内脂氧化物丙二醛(Malonydialdehyde, MDA)的含量;通过蛋白质印迹分析、RT-q PCR和免疫沉淀(Immunoprecipitation, IP)检测参与氧化应激的信号通路蛋白,包括SIRT3、SOD2和FOXO1通路蛋白。研究发现,油酸(Oleicacid,OA)可以诱导细胞内脂质、过氧化物及脂氧化物的积累,降低SIRT3的表达,并促进FOXO1乙酰化。然而Sal B治疗后显著扭转了这些趋势。进一...     

l‐Carnitine protects against 1,4‐benzoquinone‐induced apoptosis and DNA damage by suppressing oxidative stress and promoting fatty acid oxidation in K562 cells

Widespread occupational and environmental exposure to benzene is unavoidable and poses a public health threat. Studies of potential interventions to prevent or relieve benzene toxicity are, thus, essential. Research has shown l ‐carnitine (LC) has beneficial effects against various pathological processes and diseases. LC possesses antioxidant activities and participates in fatty acid oxidation (FAO). In this study, we investigated whether 1,4‐benzoquinone (1,4‐BQ) affects LC levels and the FAO pathway, as well as analyzed the influence of LC on the cytotoxic effects of 1,4‐BQ. We found that 1,4‐BQ significantly decreased LC levels and downregulated Cpt1a, Cpt2, Crat, Hadha, Acaa2, and Acadvl mRNA expression in K562 cells. Subsequent assays confirmed that 1,4‐BQ decreased cell viability and increased apoptosis and caspase‐3, ‐8, and ‐9 activities. It also induced obvious oxidative stress and DNA damage, including an increase in the levels of reactive oxygen species and malondialdehyde, tail DNA%, and olive tail moment. Additionally, the mitochondrial membrane potential was significantly reduced. Cotreatment with LC (500 μmol/L) relieved these alterations by reducing oxidative stress and increasing the protein expression levels of Cpt1a and Hadha, particularly in the 20 μmol/L 1,4‐BQ group. Thus, our results demonstrate that 1,4‐BQ causes cytotoxicity, reduces LC levels, and downregulates the FAO genes. In contrast, LC exhibits protective effects against 1,4‐BQ‐induced apoptosis and DNA damage by decreasing oxidative stress and promoting the FAO pathway.     

Synthesis and bio evaluation of a new fatty acid derivative labelled with technetium‐99m

¹²³I‐iodophenylpentadecanoic acid (IPPA) and ¹²³I‐beta‐methyliodophenylpentadecanoic acid (BMIPP) are radiolabelled fatty acid derivatives used for assessment of myocardial viability. Because of limited accessibility of ¹²³I in the clinical scenario, a 99m‐technetium‐based agent would be more advantageous. In this context, a xanthate derivative of 15‐hydroxypentadecanoic acid (HPDA) was synthesized for radiolabelling with [^99mTcN]²⁺ intermediate. Direct reaction of the HPDA with carbon disulphide in presence of crushed sodium hydroxide in dry tetrahydrofuran resulted in moderate yield of the desired xanthate product. The prepared ligand was radiolabelled with [^99mTcN]²⁺ intermediate and the resultant complex was characterized by paper electrophoresis and HPLC. The labelled preparation was assessed for its myocardial extraction and retention characteristics using Swiss mice model. The HPDA xanthate derivative was obtained in a low yield of ～30%. Labelling via the [^99mTcN]²⁺intermediate gave more than 95% complexation. During in vivo studies with the [TcN]²⁺ labelled complex maximum heart uptake observed was 3.10%ID/g at 5 min p.i., which cleared out rapidly, with retention of 0.79%ID/g of the activity at 60 min p.i. The ^99mTcN‐HPDA xanthate derivative showed some uptake in the heart but rapid wash out and substantial uptake in the background organs (blood, liver and lungs) led to unfavourable critical ratios at all the time points of study. Copyright © 2006 John Wiley & Sons, Ltd.     

Protective effect of isochlorogenic acid B on liver fibrosis in non‐alcoholic steatohepatitis of mice

Liver fibrosis is a common symptom of non‐alcoholic steatohepatitis (NASH) and a worldwide clinical issue. The miR‐122/HIF‐1α signalling pathway is believed to play an important role in the genesis of progressive fibrosis. Isochlorogenic acid B (ICAB), naturally isolated from Laggera alata, is verified to have antioxidative and hepatoprotective properties. The aim of this study was to investigate the effect of ICAB on liver fibrosis in NASH and its potential protective mechanisms. NASH was induced in a mouse model with a methionine‐ and choline‐deficient (MCD) diet for 4 weeks, and ICAB was orally administered every day at three doses (5, 10 and 20 mg/kg). Pathological results indicated that ICAB significantly improved the pathological lesions of liver fibrosis. The levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and hepatic hydroxyproline (Hyp), cholesterol (CHO) and triglyceride (TG) were also significantly decreased by ICAB. In addition, ICAB inhibited hepatic stellate cells (HSCs) activation and the expressions of hepatic genes involved in liver fibrosis including LOX, TGF‐β1, MCP‐1, COL1α1 and TIMP‐1. ICAB also attenuated liver oxidative stress through Nrf2 signalling pathway. What is more, the decreased levels of miR‐122 and over‐expression of hepatic HIF‐1α could be reversed by ICAB treatment. These results simultaneously confirmed that ICAB had a significant protective effect on fibrosis in NASH by inhibiting oxidative stress via Nrf2 and suppressing multiple profibrogenic factors through miR‐122/HIF‐1α signalling pathway.