PMID: 

Arch Pharm Res. 2011 May ;34(5):853-9. Epub 2011 Jun 9. PMID: 21656372

Abstract Title: 

Antiarthritic effect of lonicerin on Candida albicans arthritis in mice.

Abstract: 

Fungal arthritis is a potentially serious disease resulting in rapid destruction of the joint. Among the various Candida species, Candida albicans is the most commonly associated with fungal arthritis. In the present study, we examined the effect of lonicerin, a flavonoid isolated from Lonicerae Flos, on an arthritis caused by C. albicans cell wall (CACW) in mice. To examine the effect, an emulsified mixture of CACW and complete Freund's adjuvant (CACW/CFA) was injected into BALB/c mice via hind footpad route on days -3, -2, and -1. On Day 0, mice with the swollen footpad received lonicerin at 1 or 2 mg/dose/time intraperitoneally 3 times every other day. The footpad-swelling was measured for 20 days. Results showed that the lonicerin treatment reduced the edema at all dose levels, and, furthermore, there was app. 54% edema reduction in animals given the 2 mg-dose at the peak (day 10) of septic arthritis (p

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PMID: 

Biochim Biophys Acta. 2015 Apr ;1851(4):446-55. Epub 2014 Nov 14. PMID: 25463478

Abstract Title: 

Non-enzymatic cyclic oxygenated metabolites of adrenic, docosahexaenoic, eicosapentaenoic andα-linolenic acids; bioactivities and potential use as biomarkers.

Abstract: 

Cyclic oxygenated metabolites are formed in vivo through non-enzymatic free radical reaction of n-6 and n-3 polyunsaturated fatty acids (PUFAs) such as arachidonic (ARA C20:4 n-6), adrenic (AdA 22:4 n-6),α-linolenic (ALA 18:3 n-3), eicosapentaenoic (EPA 20:5 n-3) and docosahexaenoic (DHA 22:6 n-3) acids. These cyclic compounds are known as isoprostanes, neuroprostanes, dihomo-isoprostanes and phytoprostanes. Evidence has emerged for their use as biomarkers of oxidative stress and, more recently, the n-3PUFA-derived compounds have been shown to mediate bioactivities as secondary messengers. Accordingly, this review will focus on the cyclic oxygenated metabolites generated from AdA, ALA, EPA and DHA. This article is part of a Special Issue entitled"Oxygenated metabolism of PUFA: analysis and biological relevance".

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PMID: 

PLoS One. 2014 ;9(2):e89393. Epub 2014 Feb 18. PMID: 24558496

Abstract Title: 

Lipid profiling following intake of the omega 3 fatty acid DHA identifies the peroxidized metabolites F4-neuroprostanes as the best predictors of atherosclerosis prevention.

Abstract: 

The anti-atherogenic effects of omega 3 fatty acids, namely eicosapentaenoic (EPA) and docosahexaenoic acids (DHA) are well recognized but the impact of dietary intake on bioactive lipid mediator profiles remains unclear. Such a profiling effort may offer novel targets for future studies into the mechanism of action of omega 3 fatty acids. The present study aimed to determine the impact of DHA supplementation on the profiles of polyunsaturated fatty acids (PUFA) oxygenated metabolites and to investigate their contribution to atherosclerosis prevention. A special emphasis was given to the non-enzymatic metabolites knowing the high susceptibility of DHA to free radical-mediated peroxidation and the increased oxidative stress associated with plaque formation. Atherosclerosis prone mice (LDLR(-/-)) received increasing doses of DHA (0, 0.1, 1 or 2% of energy) during 20 weeks leading to a dose-dependent reduction of atherosclerosis (R(2) = 0.97, p = 0.02), triglyceridemia (R(2) = 0.97, p = 0.01) and cholesterolemia (R(2) = 0.96, p

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PMID: 

PLoS One. 2013 ;8(7):e69415. Epub 2013 Jul 23. PMID: 23936010

Abstract Title: 

4-Hydroxy hexenal derived from docosahexaenoic acid protects endothelial cells via Nrf2 activation.

Abstract: 

Recent studies have proposed that n-3 polyunsaturated fatty acids (n-3 PUFAs) have direct antioxidant and anti-inflammatory effects in vascular tissue, explaining their cardioprotective effects. However, the molecular mechanisms are not yet fully understood. We tested whether n-3 PUFAs showed antioxidant activity through the activation of nuclear factor erythroid 2-related factor 2 (Nrf2), a master transcriptional factor for antioxidant genes. C57BL/6 or Nrf2(-/-) mice were fed a fish-oil diet for 3 weeks. Fish-oil diet significantly increased the expression of heme oxygenase-1 (HO-1), and endothelium-dependent vasodilation in the aorta of C57BL/6 mice, but not in the Nrf2(-/-) mice. Furthermore, we observed that 4-hydroxy hexenal (4-HHE), an end-product of n-3 PUFA peroxidation, was significantly increased in the aorta of C57BL/6 mice, accompanied by intra-aortic predominant increase in docosahexaenoic acid (DHA) rather than that in eicosapentaenoic acid (EPA). Human umbilical vein endothelial cells were incubated with DHA or EPA. We found that DHA, but not EPA, markedly increased intracellular 4-HHE, and nuclear expression and DNA binding of Nrf2. Both DHA and 4-HHE also increased the expressions of Nrf2 target genes including HO-1, and the siRNA of Nrf2 abolished these effects. Furthermore, DHA prevented oxidant-induced cellular damage or reactive oxygen species production, and these effects were disappeared by an HO-1 inhibitor or the siRNA of Nrf2. Thus, we found protective effects of DHA through Nrf2 activation in vascular tissue, accompanied by intra-vascular increases in 4-HHE, which may explain the mechanism of the cardioprotective effects of DHA.

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PMID: 

Free Radic Biol Med. 2015 Sep ;86:269-78. Epub 2015 Apr 21. PMID: 25911196

Abstract Title: 

Nonenzymatic lipid mediators, neuroprostanes, exert the antiarrhythmic properties of docosahexaenoic acid.

Abstract: 

Neuroprostanes are lipid mediators produced by nonenzymatic free radical peroxidation of docosahexaenoic acid (DHA). DHA is associated with a lower atherosclerosis risk, suggesting a beneficial role in cardiovascular diseases. The aim of this study was to investigate the influence of DHA peroxidation on its potentially antiarrhythmic properties (AAP) in isolated ventricular cardiomyocytes and in vivo in post-myocardial infarcted mice. Calcium imaging and biochemical experiments indicate that cardiac arrhythmias induced by isoproterenol are associated with Ca(2+) leak from the sarcoplasmic reticulum after oxidation and phosphorylation of the type 2 ryanodine receptor (RyR2) leading to dissociation of the FKBP12.6/RyR2 complex. Both oxidized DHA and 4(RS)-4-F4t-NeuroP prevented cellular arrhythmias and posttranslational modifications of the RyR2 leading to a stabilized FKBP12.6/RyR2 complex. DHA per se did not have AAP. The AAP of 4(RS)-4-F4t-NeuroP was also observed in vivo. In this study, we challenged the paradigm that spontaneously formed oxygenated metabolites of lipids are undesirable as they are unconditionally toxic. This study reveals that the lipid mediator 4(RS)-4-F4t-neuroprostane derived from nonenzymatic peroxidation of docosahexaenoic acid can counteract such deleterious effects through cardiac antiarrhythmic properties. Our findings demonstrate 4(RS)-4-F4t-NeuroP as a mediator of the cardioprotective AAP of DHA. This discovery opens new perspectives for products of nonenzymatic oxidizedω3 polyunsaturated fatty acids as potent mediators in diseases that involve ryanodine complex destabilization such as ischemic events.

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PMID: 

Free Radic Biol Med. 2017 01 ;102:229-239. Epub 2016 Dec 5. PMID: 27932075

Abstract Title: 

Non-enzymatic oxidized metabolite of DHA, 4(RS)-4-F-neuroprostane protects the heart against reperfusion injury.

Abstract: 

Acute myocardial infarction leads to an increase in oxidative stress and lipid peroxidation. 4(RS)-4-F-Neuroprostane (4-F-NeuroP) is a mediator produced by non-enzymatic free radical peroxidation of the cardioprotective polyunsaturated fatty acid, docosahexaenoic acid (DHA). In this study, we investigated whether intra-cardiac delivery of 4-F-NeuroP (0.03mg/kg) prior to occlusion (ischemia) prevents and protects rat myocardium from reperfusion damages. Using a rat model of ischemic-reperfusion (I/R), we showed that intra-cardiac infusion of 4-F-NeuroP significantly decreased infarct size following reperfusion (-27%) and also reduced ventricular arrhythmia score considerably during reperfusion (-41%). Most notably, 4-F-NeuroP decreased ventricular tachycardia and post-reperfusion lengthening of QT interval. The evaluation of the mitochondrial homeostasis indicates a limitation of mitochondrial swelling in response to Caby decreasing the mitochondrial permeability transition pore opening and increasing mitochondria membrane potential. On the other hand, mitochondrial respiration measured by oxygraphy, and mitochondrial ROS production measured with MitoSox red® were unchanged. We found decreased cytochrome c release and caspase 3 activity, indicating that 4-F-NeuroP prevented reperfusion damages and reduced apoptosis. In conclusion, 4-F-NeuroP derived from DHA was able to protect I/R cardiac injuries by regulating the mitochondrial homeostasis.

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PMID: 

J Clin Endocrinol Metab. 2016 09 ;101(9):3264-71. Epub 2016 May 18. PMID: 27192695

Abstract Title: 

Increased F3-Isoprostanes in the Canadian Inuit Population Could Be Cardioprotective by Limiting F2-Isoprostane Production.

Abstract: 

CONTEXT: F3-isoprostanes (F3-IsoPs), derived from peroxidation of eicosapentaenoic acid (C20:5n-3), could be cardioprotective by limiting production of F2-isoprostanes (F2-IsoPs), a cardiovascular disease risk factor.OBJECTIVE: The objective of the study was to determine whether the n-3-polyunsaturated (PUFA)-rich Inuit diet is associated with a lower plasma ratio of F2-IsoPs to F3-IsoPs.DESIGN: This was a cross-sectional observational study.SETTING: The study was conducted in 36 Canadian Arctic Inuit communities.PARTICIPANTS: Participants included a random subset (n = 233) of Inuit adults taken from a population-based survey.MAIN OUTCOME MEASURES: Plasma F2-IsoPs and F3-IsoPs, cardiometabolic risk factors (blood lipids, C-reactive protein, blood pressure, fasting glucose) and markers of dietary exposure (erythrocyte n-3 and n-6 PUFA, blood levels of Se, mercury, polychlorinated biphenyls) were measured.RESULTS: Inuit aged 40 years old and older vs younger Inuit showed higher concentrations of plasma F3-IsoPs and erythrocyte n-3 PUFA and lower plasma F2-IsoPs concentrations despite having higher blood lipids, fasting glucose, systolic blood pressure, and percentage body fat. Plasma F3-IsoPs were not associated with any cardiometabolic measures. When subjects were categorized into tertiles according to total n-3 PUFA erythrocyte concentrations, F3-IsoPs increased with increasing tertiles, whereas the F2-IsoP to F3-IsoP ratio was lowest at the highest n-3 tertile. The F2-IsoP to F3-IsoP ratio was significantly predicted by C20:5n-3 (β= -.365, P = .002); C20:4n-6:C20:5n-3 (β = .056, P = .006), blood mercury (β = -.812, P =.015), blood Se (β = -1.95, P = .015), and smoking (β = .745, P = .025).CONCLUSIONS: Plasma F3-IsoPs were not associated with cardiometabolic risk factors previously seen with F2-IsoPs. Higher n-3 fatty acid status was associated with lower plasma F2-IsoPs and higher plasma F3-IsoPs, which provides partial explanation to the cardioprotective effects of the n-3 PUFA-rich Inuit diet.

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PMID: 

J Ethnopharmacol. 2011 Oct 31 ;138(1):1-21. Epub 2011 Aug 16. PMID: 21864666

Abstract Title: 

Lonicera japonica Thunb.: ethnopharmacology, phytochemistry and pharmacology of an important traditional Chinese medicine.

Abstract: 

ETHNOPHARMACOLOGICAL RELEVANCE: Lonicera japonica Thunb. (Caprifoliaceae), a widely used traditional Chinese medicine, was known as Jin Yin Hua (Chinese: ), Ren Dong and Japanese honeysuckle. It was taken to treat the exopathogenic wind-heat, epidemic febrile diseases, sores, carbuncles and some infectious diseases. At the same time, Lonicera japonica could be used as healthy food, cosmetics, ornamental groundcover, and so on.AIM OF THE REVIEW: The present paper reviewed the ethnopharmacology, the biological activities, toxicology and phytochemistry of Lonicera japonica.MATERIALS AND METHODS: Information on Lonicera japonica was gathered via the Internet (using Google Scholar, Baidu Scholar, Elsevier, ACS, Medline Plus, CNKI and Web of Science) and libraries. Additionally, information also was obtained from some local books and brilliant scholars on ethnopharmacology.RESULTS: More than 140 chemical compounds have been isolated, and the main compositions are essential oils, organic acids and flavones, etc. Lonicera japonica and its active principles possess wide pharmacological actions, such as anti-inflammatory, antibacterial, antiviral, antioxidative and hepatoprotective activities.CONCLUSIONS: As an important traditional Chinese medicine, further studies on Lonicera japonica can lead to the development of new drugs and therapeutics for various diseases, and how to utilize it better should be paid more attentions.

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PMID: 

Food Chem Toxicol. 2012 Mar ;50(3-4):797-807. Epub 2011 Dec 28. PMID: 22227216

Abstract Title: 

Lonicera japonica THUNB. protects 6-hydroxydopamine-induced neurotoxicity by inhibiting activation of MAPKs, PI3K/Akt, and NF-κB in SH-SY5Y cells.

Abstract: 

In this study, we investigated the neuroprotective effects of Lonicera japonica THUNB. extract (LJ) on 6-hydroxydopamine (6-OHDA)-induced neurotoxicity in SH-SY5Y cells. We found that LJ significantly increased cell viability decrease, lactate dehydrogenase release (LDH), morphological changes, nuclear condensation, fragmentation, and reactive oxygen species (ROS) production induced by 6-OHDA in SH-SY5Y cells. The cytoprotection afforded by pretreatment with LJ was associated with increases of the glutathione (GSH) level, superoxide dismutase (SOD) activity, and catalase (CAT) activity in 6-OHDA-induced SH-SY5Y cells. In addition, LJ strikingly inhibited 6-OHDA-induced mitochondrial dysfunctions including reduction of mitochondria membrane potential (MMP) and activation of cleaved poly-ADP-ribose polymerase (PARP), cleaved caspase-3, cleaved caspase-9, increased Bax, as well as decreased Bcl-2 and Bcl-xL. Additionally, LJ dramatically attenuated 6-OHDA-induced phosphorylation of c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase 1/2 (ERK 1/2), and phosphoinositide 3-kinase (PI3K)/Akt. Meanwhile, LJ counteracted nuclear factor-κB (NF-κB) activation by blocking its translocation to the nucleus. These findings suggest that LJ has a potent anti-parkinsonism; this effect was mediated, at least in part, by inhibition of neurotoxicity, apoptotic cascade events, and oxidative stress via activation of MAPKs, PI3K/Akt, and NF-κB.

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PMID: 

Pharmacogn Mag. 2011 Oct ;7(28):284-8. PMID: 22262930

Abstract Title: 

Neuroprotective activity of the methanolic extract of Lonicera japonica in glutamate-injured primary rat cortical cells.

Abstract: 

BACKGROUND: We previously reported that the extracts of several Korean medicinal plants showed neuroprotective activity in glutamate-injured primary culutres of rat cortical cells.OBJECTIVE: Among them, the effect of the methanolic extract of Lonicera japonica flower on the glutamate-induced neuronal cell death and its potential mechanism of action was investigated.RESULTS: Treatment by the methanolic extract of L. japonica flower significantly protected neuronal cells against glutamate-induced excitotoxicity. It decreased the calcium influx that accompanies the glutamate induced excitotoxicity of neuronal cells, and inhibited the subsequent overproduction of nitric oxide, reactive oxygen species and peroxide to the level of control cells. In addition, it preserved cellular activity of superoxide dismutase, an antioxidative enzyme reduced by glutamate insult.CONCLUSIONS: According to this data, the methanolic extract of L. japonica flower significantly protected neuronal cells against glutamate excitotoxicity via antioxidative activity.

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