Oxidation Of Arachidonic Acid Research Articles

Low back pain: justification of treatment standards (literature review)

Low back pain: justification of treatment standards (literature review)

Anti-bacterial and anti-biofilm activities of arachidonic acid against the cariogenic bacterium Streptococcus mutans.

Streptococcus mutans is a Gram-positive, facultative anaerobic bacterium, which causes dental caries after forming biofilms on the tooth surface while producing organic acids that demineralize enamel and dentin. We observed that the polyunsaturated arachidonic acid (AA) (ω-6; 20:4) had an anti-bacterial activity against S. mutans, which prompted us to investigate its mechanism of action. The minimum inhibitory concentration (MIC) of AA on S. mutans was 25 μg/ml in the presence of 5% CO2, while it was reduced to 6.25-12.5 μg/ml in the absence of CO2 supplementation. The anti-bacterial action was due to a combination of bactericidal and bacteriostatic effects. The minimum biofilm inhibitory concentration (MBIC) was the same as the MIC, suggesting that part of the anti-biofilm effect was due to the anti-bacterial activity. Gene expression studies showed decreased expression of biofilm-related genes, suggesting that AA also has a specific anti-biofilm effect. Flow cytometric analyses using potentiometric DiOC2(3) dye, fluorescent efflux pump substrates, and live/dead SYTO 9/propidium iodide staining showed that AA leads to immediate membrane hyperpolarization, altered membrane transport and efflux pump activities, and increased membrane permeability with subsequent membrane perforation. High-resolution scanning electron microscopy (HR-SEM) showed remnants of burst bacteria. Furthermore, flow cytometric analysis using the redox probe 2',7'-dichlorofluorescein diacetate (DCFHDA) showed that AA acts as an antioxidant in a dose-dependent manner. α-Tocopherol, an antioxidant that terminates the radical chain, counteracted the anti-bacterial activity of AA, suggesting that oxidation of AA in bacteria leads to the production of cytotoxic radicals that contribute to bacterial growth arrest and death. Importantly, AA was not toxic to normal Vero epithelial cells even at 100 μg/ml, and it did not cause hemolysis of erythrocytes. In conclusion, our study shows that AA is a potentially safe drug that can be used to reduce the bacterial burden of cariogenic S. mutans.

Predictors of upstream inflammation and oxidative stress pathways during early pregnancy

BackgroundInflammation and oxidative stress are critical to pregnancy, but most human study has focused on downstream, non-causal indicators. Oxylipins are lipid mediators of inflammation and oxidative stress that act through many biological pathways. Our aim was to characterize predictors of circulating oxylipin concentrations based on maternal characteristics. MethodsOur study was conducted among 901 singleton pregnancies in the LIFECODES Fetal Growth Study, a nested case-cohort with recruitment from 2007 to 2018. We measured a targeted panel of oxylipins in early pregnancy plasma and urine samples from several biosynthetic pathways, defined by the polyunsaturated fatty acid (PUFA) precursor and enzyme group. We evaluated levels across predictors, including characteristics of participants’ pregnancy, socioeconomic determinants, and obstetric and medical history. ResultsCurrent pregnancy and sociodemographic characteristics were the most important predictors of circulating oxylipins concentrations. Plasma oxylipins were lower and urinary oxylipins higher for participants with a later gestational age at sampling (13–23 weeks), higher prepregnancy BMI (obesity class I, II, or III), Black or Hispanic race and ethnicity, and lower socioeconomic status (younger age, lower education, and uninsured). For example, compared to those with normal or underweight prepregnancy BMI, participants with class III prepregnancy obesity had 45–46% lower plasma epoxy-eicosatrienoic acids, the anti-inflammatory oxylipins produced from arachidonic acid (AA) by cytochrome P450, and had 81% higher urinary 15-series F2-isoprostanes, an indicator of oxidative stress produced from non-enzymatic AA oxidation. Similarly, in urine, Black participants had 92% higher prostaglandin E2 metabolite, a pro-inflammatory oxylipin, and 41% higher 5-series F2-isoprostane, an oxidative stress indicator. ConclusionsIn this large pregnancy study, we found that circulating levels of oxylipins were different for participants of lower socioeconomic status or of a systematically marginalized racial and ethnic groups. Given associations differed along biosynthetic pathways, results provide insight into etiologic links between maternal predictors and inflammation and oxidative stress.

Identification of novel F2-isoprostane metabolites by specific UDP-glucuronosyltransferases

UDP-glucuronosyltransferases (UGTs) catalyze the conjugation of glucuronic acid with endogenous and exogenous lipophilic small molecules to facilitate their inactivation and excretion from the body. This represents approximately 35 % of all phase II metabolic transformations. Fatty acids and their oxidized eicosanoid derivatives can be metabolized by UGTs. F2-isoprostanes (F2-IsoPs) are eicosanoids formed from the free radical oxidation of arachidonic acid. These molecules are potent vasoconstrictors and are widely used as biomarkers of endogenous oxidative damage. An increasing body of evidence demonstrates the efficacy of measuring the β-oxidation metabolites of F2-IsoPs rather than the unmetabolized F2-IsoPs to quantify oxidative damage in certain settings. Yet, the metabolism of F2-IsoPs is incompletely understood. This study sought to identify and characterize novel phase II metabolites of 15-F2t-IsoP and 5-epi-5-F2t-IsoP, two abundantly produced F2-IsoPs, in human liver microsomes (HLM). Utilizing liquid chromatography-mass spectrometry, we demonstrated that glucuronide conjugates are the major metabolites of these F2-IsoPs in HLM. Further, we showed that these molecules are metabolized by specific UGT isoforms. 15-F2t-IsoP is metabolized by UGT1A3, 1A9, and 2B7, while 5-epi-5-F2t-IsoP is metabolized by UGT1A7, 1A9, and 2B7. We identified, for the first time, the formation of intact glucuronide F2-IsoPs in human urine and showed that F2-IsoP glucuronidation is reduced in people supplemented with eicosapentaenoic and docosahexaenoic acids for 12 weeks. These studies demonstrate that endogenous F2-IsoP levels can be modified by factors other than redox mechanisms.

Proteomic and metabolomic analysis of ageing beef exudate to determine that iron metabolism enhances muscle protein and lipid oxidation

The study aimed to assess differences in proteomic and metabolite profiles in ageing (1, 2, 4, and 6 days at 4 °C) beef exudates and determine their relationship with beef muscle iron metabolism and oxidation. Proteomic and metabolomic analyses identified 877 metabolites and 1957 proteins. The joint analysis identified 24 differential metabolites (DMs) and 56 differentially expressed proteins (DEPs) involved in 15 shared pathways. Ferroptosis was identified as the only iron metabolic pathway, and 4 DMs (l-glutamic acid, arachidonic acid, glutathione and gamma-glutamylcysteine) and 5 DEPs (ferritin, phospholipid hydroperoxide glutathione peroxidase, heme oxygenase 1, major prion protein, and acyl-CoA synthetase long chain family member 4) were involved in iron metabolism by regulating heme and ferritin degradation, Fe2+ and Fe3+ conversion, arachidonic acid oxidation and inactivation of glutathione peroxidase (GPX) 4, leading to increased levels of free iron, ROS, protein and lipid oxidation (P < 0.05). Overall, abnormal iron metabolism during ageing induced oxidative stress in muscle tissue.

Multiple selected ion monitoring mode for sensitive imaging of eicosanoids in tissues using nanospray desorption electrospray ionization (nano-DESI) mass spectrometry

Nanospray desorption electrospray ionization mass spectrometry imaging (nano-DESI MSI) enables sensitive label-free mapping of multiple classes of molecules in biological samples. Previously, we demonstrated that combining nano-DESI MSI with selected ion monitoring (SIM) increases the sensitivity of the technique in a narrow m/z range. In this study, we use a series of adjacent multiple SIM (mSIM) windows to acquire nano-DESI MSI data with high sensitivity over a broader m/z range. We demonstrate that this approach substantially improves the quality of imaging data obtained for low-abundance eicosanoids, important lipid mediators derived from eicosapolyenoic acid products of arachidonic acid oxidation. Despite their importance as mediators of inflammation, asthma, fever, pain, hypertension, and stroke, eicosanoids have not been extensively investigated using MSI. This is mainly attributed to their low ionization efficiency and low, subnanomolar, concentrations in tissue, which make it difficult to detect these species in MSI experiments alongside abundant phospholipids. We demonstrate substantial enhancements in the signal-to-noise ratios (S/N) of eicosanoids using imaging in mSIM mode. We have also developed data processing and visualization tools to support this type of MSI data acquisition. S/N enhancements observed in mSIM mode are independent of the properties of analytes making this approach applicable to other low-abundance species in biological and environmental samples.

Formation of Lipid-Derived Flavors in Dry-Cured Mackerel (Scomberomorus niphonius) via Simulation of Autoxidation and Lipoxygenase-Induced Fatty Acid Oxidation.

In this study, lipoxygenase (LOX) extracted from dry-cured mackerel was purified, resulting in a 4.1-fold purification factor with a specific activity of 493.60 U/min·g. LOX enzymatic properties were assessed, referring to its optimal storage time (1-2 days), temperature (30 °C), and pH value (7.0). The autoxidation and LOX-induced oxidation of palmitic acid (C16:0), stearic acid (C18:0), oleic acid (C18:2n9c), linoleic acid (C18:2n6c), arachidonic acid (C20:4), EPA (C20:5), and DHA (C22:6n3) were simulated to explore the main metabolic pathways of key flavors in dry-cured mackerel. The results showed that the highest LOX activity was observed when arachidonic acid was used as a substrate. Aldehydes obtained from LOX-treated C18:1n9c and C18:2n6c oxidation, which are important precursors of flavors, were the most abundant. The key flavors in dry-cured mackerel were found in the oxidative products of C16:0, C18:0, C18:1n9c, C18:2n6c, and C20:4. Heptanaldehyde could be produced from autoxidation or LOX-induced oxidation of C18:0 and C18:1n9c, while nonal could be produced from C18:1n9c and C18:2n6c oxidation. Metabolic pathway analysis revealed that C18:1n9c, C18:2n6c, EPA, and DHA made great contributions to the overall flavor of dry-cured mackerel. This study may provide a relevant theoretical basis for the scientific control of the overall taste and flavor of dry-cured mackerel and further standardize its production.

Omega-3 to omega-6 fatty acid oxidation ratio as a novel inflammation resolution marker for metabolic complications in obesity

Background and aimsThe oxidative metabolism of polyunsaturated fatty acids (PUFAs) leads to bioactive isoprostanoids. The aim was to establish the associations of a complete urinary isoprostanoid profiling in a cohort study of carefully phenotyped obese subjects to determine possible potential differential implications for omega-6 PUFA- and omega-3 PUFA-derived isoprostanoids for obesity, metabolic indicators, and inflammation. Methods and resultsPUFA peroxidation compounds were determined in urine samples from obese human subjects (n = 46) by liquid chromatography coupled to tandem mass spectrometry. Increased omega-6 arachidonic acid (AA) oxidation, mainly represented by 5-F2c isoprostane (5-F2c-IsoP) and metabolites of 15-F2t-IsoP, was associated with body mass index, glycated hemoglobin (HbA1c) and mean arterial blood pressure. In addition, we identified the omega-3 PUFA-derived urinary metabolites 14-F4t-NeuroP from docosahexaenoic acid (DHA) and 5-F3t-IsoP from eicosapentaenoic acid (EPA), which declined with age. The omega-3 to omega-6 oxidation ratio was a significant predictor of inflammation in obesity. ConclusionThe findings point to full urinary isoprostanoid profiling as a more sensitive measure of PUFA oxidative stress in obesity-induced metabolic complications compared with individual isoprostanoid measures. Furthermore, the results suggest the balance between the omega-3 and omega-6 PUFA oxidation as determinative for the consequences of oxidative stress on inflammation in obesity.

Daidzein phosphorylates and activates 5-lipoxygenase via the MEK/ERK pathway: a mechanism for inducing the production of 5-lipoxygenase metabolite that inhibit influenza virus intracellular replication

We previously reported that the soy isoflavone daidzein (Dz) suppresses the intracellular replication of influenza virus and that arachidonic acid-derived oxidation product via lipid oxidase 5-lipoxygenase (5-LOX) is involved in its antiviral effect. The activation of 5-LOX by Dz triggers anti-influenza activity; however, the mechanism of activation of 5-LOX remains unclear. Therefore, in this study, we aimed to clarify the activation mechanism using human monocyte-derived THP-1 cells differentiated using phorbol 12-myristate 13-acetate. THP-1 cells expressed 5-LOX endogenously and Dz did not induce 5-LOX expression. However, 8 h after treatment with Dz, the amount of 5-hydroxyeicosatetraenoic acid (5-HETE), an arachidonic acid oxidation product via 5-LOX, increased significantly suggesting that the enzyme is activated regardless of changes in 5-LOX protein levels. Intracellular Ca2+ content, ATP concentration, 5-LOX protein phosphorylation, and 5-LOX intracellular localization are known 5-LOX activation factors. The intracellular Ca2+ and ATP concentrations were not affected by Dz treatment. The enzymatic activity of 5-LOX is regulated by the phosphorylation of three serine residues and four tyrosine residues. Pretreatment with inhibitors of each kinase revealed that Dz-induced 5-HETE production was suppressed by the MEK/ERK inhibitor. 5-LOX in which the Ser663 residue was phosphorylated was found to be increased in the nuclear fraction of Dz-treated THP-1 cells. Furthermore, immunocytochemistry showed that 5-LOX translocates to the nuclear envelope following Dz treatment. These results indicate that Dz activates 5-LOX by phosphorylating Ser663 via the MEK/ERK pathway. Thus, these results demonstrate that Dz exerts anti-influenza virus activity via the MEK/ERK signal transduction pathway.

Placental F4-Neuroprostanes and F2-Isoprostanes are altered in gestational diabetes mellitus and maternal obesity

We investigated whether gestational diabetes mellitus (GDM) associated with maternal obesity modifies the placental profile of F4-Neuroprostanes and F2-Isoprostanes, metabolites of non-enzymatic oxidation of docosahexaenoic acid (DHA) and arachidonic acid (AA), respectively. Twenty-five placental samples were divided into lean (n=11), obesity (n=7) and overweight/obesity+GDM (n=7) groups. F4-Neuroprostanes and F2-Isoprostanes were higher in obesity compared to lean controls, but reduced to levels similar to lean women when obesity is further complicated with GDM. Lower content of F2-Isoprostanes suggests adaptive placental responses in GDM attenuating oxidative stress. However, low levels of placental F4-Neuroprostanes may indicate impaired DHA metabolism in GDM, affecting fetal development and offspring health. These results were not related to differences in placental content of DHA, AA and polyunsaturated fatty acids status nor to maternal diet or gestational weight gain. Placental DHA and AA metabolism differs in obesity and GDM, highlighting the importance of investigating the signalling roles of F4-Neuroprostanes and F2-Isoprostanes in the human term placenta.

A potent and selective inhibitor for the modulation of MAGL activity in the neurovasculature.

Chronic inflammation and blood–brain barrier dysfunction are key pathological hallmarks of neurological disorders such as multiple sclerosis, Alzheimer’s disease and Parkinson’s disease. Major drivers of these pathologies include pro-inflammatory stimuli such as prostaglandins, which are produced in the central nervous system by the oxidation of arachidonic acid in a reaction catalyzed by the cyclooxygenases COX1 and COX2. Monoacylglycerol lipase hydrolyzes the endocannabinoid signaling lipid 2-arachidonyl glycerol, enhancing local pools of arachidonic acid in the brain and leading to cyclooxygenase-mediated prostaglandin production and neuroinflammation. Monoacylglycerol lipase inhibitors were recently shown to act as effective anti-inflammatory modulators, increasing 2-arachidonyl glycerol levels while reducing levels of arachidonic acid and prostaglandins, including PGE2 and PGD2. In this study, we characterized a novel, highly selective, potent and reversible monoacylglycerol lipase inhibitor (MAGLi 432) in a mouse model of lipopolysaccharide-induced blood–brain barrier permeability and in both human and mouse cells of the neurovascular unit: brain microvascular endothelial cells, pericytes and astrocytes. We confirmed the expression of monoacylglycerol lipase in specific neurovascular unit cells in vitro, with pericytes showing the highest expression level and activity. However, MAGLi 432 did not ameliorate lipopolysaccharide-induced blood–brain barrier permeability in vivo or reduce the production of pro-inflammatory cytokines in the brain. Our data confirm monoacylglycerol lipase expression in mouse and human cells of the neurovascular unit and provide the basis for further cell-specific analysis of MAGLi 432 in the context of blood–brain barrier dysfunction caused by inflammatory insults.

The Quantitative Profiling of Oxylipins from Arachidonic Acid by LC-MS/MS in Feces at Birth 3 Days and 21 Days of Piglets.

Oxylipins (also called eicosanoids) are enzymatically or nonenzymatically generated by oxidation of arachidonic acid (ARA) and are major mediators of ARA effects in the body. Previous studies demonstrated the importance of ARA in infant growth, brain development, immune response, and health. With the developments in lipidomic methodologies, it is important for exploring more ARA-deprived oxylipins to better understand the physiological functions of ARA. The concentrations of oxylipins in feces were determined from days 3 to 21 postnatally of suckling piglets in vivo. Feces were collected at two critical time points of the suckling piglets (3d and 21d after birth) and about 48 oxylipins were analyzed by using a target metabolomics approach based on Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS). Here, 21 oxylipins were derived from ARA, and 11 differential oxylipins (Log2|fold change| ≥ 1.0) at birth 3d and 21d were identified. Particularly, 12-HETE was more abundant in feces at birth 3 days rather than 21 days. Considering that 12-HETE was a racemic mixture of stereoisomers containing the S and R enantiomers, we further detected the concentrations of 12(S)-HETE and 12(R)-HETE between the two time points by chiral LC-MS/MS analysis. There was no significant difference in the concentrations of 12(S)-HETE and 12(R)-HETE. It was showed that ARA - derived oxylipins might be related to the physiological changes of piglets during growing. Our results provided new information for describing the physiological changes of the piglets over the suckling period.

A Study to Validate the Relevance of Semen F2-Isoprostanes on Human Male Infertility.

F2-isoprostanes (F2-IsoPs), byproducts of arachidonic acid oxidation, are one of the most reliable indices for assessing lipid peroxidation in vivo. This study aimed at evaluating the seminal F2-IsoP level in 147 patients with different reproductive conditions (varicocele, urogenital infection, idiopathic infertility) and 45 fertile controls to establish a cut-off value discriminating physiological and pathological ranges. Semen analyses were performed following WHO guidelines; F2-IsoP levels were measured by gas chromatography/negative-ion chemical ionization tandem mass spectrometry. Considering the whole group of patients, F2-IsoPs correlated negatively with normal morphology (r = −0.283, p < 0.01), viability (r = −0.245, p < 0.01), total progressive motility (r = −0.309, p < 0.01) and rapid motility (r = −0.535, p < 0.01). The area under the ROC curve for F2-IsoP levels was 0.839, indicating a good performance of the test; the Youden index showed a cut-off value of 29.96 ng/mL. Fertile men (except one) were distributed in the group of patients with F2-IsoP level < 29.96 ng/mL. Varicocele and urogenital infection groups showed the highest levels of F2-IsoPs in semen. For the first time, a cut-off for F2-IsoPs is identified in human semen. It allows discriminating different male infertility conditions by the semen F2-IsoP amounts, as an additional parameter for clinical evaluation.

Mice lacking 5-lipoxygenase display motor deficits associated with cortical and hippocampal synapse abnormalities

Neural-immune interactions are related to the synapse plasticity and other dynamic processes in the nervous system. The absence or dysfunction of cellular/molecular elements from the immune system lead to impairments in the central and peripheral nervous system with behavior consequences such as cognitive, sensory, and locomotor deficits as well as social disabilities and anxiety disturbances. Cellular interactions between immune cells such as macrophages, microglia, and neutrophils with glial or neuronal cells have been of increasing interest over the last years. However, little is known about the role of immune-derived soluble factors in the context of homeostasis of the nervous system. Leukotrienes (LTs) are lipid mediators derived from the oxidation of arachidonic acid by 5-lipoxygenase (5-LO), and are classically involved in inflammation, allergies, and asthma. Here, we demonstrated that adult mice lacking 5-LO (5-LO−/−) showed motor deficits in rotarod test and increased repetitive behavior (marble burying test). These behavioral changes are accompanied by increased levels of synapse proteins (PSD95 and synaptophysin) at the motor cortex and hippocampus, but not with BDNF alterations. No changes in microglial cell density or morphology were seen in the brains of 5-LO−/− mice. Furthermore, expression of fractalkine receptor CX3CR1 was increased and of its ligand CX3CL1 was decreased in the cortex of 5-LO−/− mice. Here we provide evidence for the involvement of 5-LO products structuring synapses network with motor behavior consequences. We suggest that the absence of 5-LO products lead to modified microglial/neuron interaction, reducing microglial pruning.

Limitations of drug concentrations used in cell culture studies for understanding clinical responses of NSAIDs.

In this review, the in vitro cellular effects of six nonsteroidal anti-inflammatory drugs (NSAIDs), salicylate, ibuprofen, naproxen, indomethacin, celecoxib and diclofenac, are examined. Inhibition of prostanoid synthesis in vitro generally occurs within the therapeutic range of plasma concentrations that are observed in vivo, consistent with the major action of NSAIDs being inhibition of prostanoid production. An additional probable cellular action of NSAIDs has been discovered recently, viz. decreased oxidation of the endocannabinoids, 2-arachidonoyl glycerol and arachidonyl ethanolamide. Many effects of NSAIDs, other than decreased oxidation of arachidonic acid and endocannabinoids, have been put forward but almost all of these additional processes are observed at supratherapeutic concentrations when the concentration of albumin, the major protein that binds NSAIDs, is taken into account. However, one exception is salicylate, a very potent inhibitor of the neutrophilic enzyme, myeloperoxidase, the inhibition of which leads to reduced production of the inflammatory mediator, hypochlorous acid, and inhibition of the inflammation associated with rheumatoid arthritis.

Do Seminal Isoprostanes Have a Role in Assisted Reproduction Outcome?

F2-isoprostanes (F2-IsoPs), stereoisomers of prostaglandin F2α generated by the free radical-induced oxidation of arachidonic acid, have been associated with different male infertility conditions. This study aimed to evaluate the role of seminal isoprostane levels and sperm characteristics in the reproductive outcome and embryo quality of 49 infertile couples. Semen analysis was performed following WHO guidelines. Sperm chromatin maturity was detected using an aniline blue (AB) assay, and DNA integrity was assessed using the acridine orange (AO) test. Seminal F2-IsoP levels were quantified by gas chromatography/negative ion chemical ionization tandem mass spectrometry (GC/NICI–MS/MS) analysis. Correlations among variables and their impact on in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) outcome were investigated. F2-IsoP levels are positively correlated with double-stranded DNA sperm (p < 0.001) and negatively correlated with mature sperm chromatin (p < 0.001). Patients with positive outcomes had an increased percentage of sperm with double-stranded DNA, as did patients producing high-quality embryo, who showed higher F2-IsoP levels compared to those detected in the low-quality embryo group. An intriguing relationship between a mild increase in F2-IsoP levels, DNA integrity, and embryo quality seems to indicate that the non-enzymatic oxidation of arachidonic acid can be also a marker of metabolic activity in human semen.

Changes in Serum, Red Blood Cell, and Colonic Fatty Acids in a Personalized Omega-3 Fatty Acid Supplementation Trial

This study evaluated changes in fatty acids from sera, red blood cells, and colonic biopsies from a phase Ib clinical trial of personalized ω-3 fatty acid dosing in 47 healthy volunteers. The trial aimed to reduce colonic prostaglandin E2 (PGE2), a pro-inflammatory product of arachidonic acid (AA) oxidation. The personalized doses ranged 2–10 grams/day (54% eicosapentaenoic acid, EPA, 24% other ω-3 fatty acids). In colon, increases in ω-3 highly unsaturated fatty acids (HUFA) and EPA:AA ratios each were correlated with decreases in PGE2. Changes in either colonic EPA:AA ratios or ω-3 HUFA were significantly correlated with changes in the same fatty acid measures in red blood cells or serum. The only blood-based measure significantly correlated with changes in colonic PGE2 was change in red blood cell ω-3 HUFA (ρ = −0.39), and the increase in red blood cell ω-3 HUFA was significantly greater in participants who had at least a median reduction in colonic PGE2 vs. those who did not. In summary, fatty acid changes in blood did reflect fatty acid changes in the colon, but additional factors will be needed for optimizing dosing models that seek to predict the anti-inflammatory effects of ω-3 fatty acids on the colon.

Epigallocatechin Gallate During Dietary Restriction - Potential Mechanisms of Enhanced Liver Injury.

Green tea extract (GTE) is popular in weight loss, and epigallocatechin gallate (EGCG) is considered as the main active component. However, GTE is the primary cause of herbal and dietary supplement-induced liver injury in the United States. Whether there is a greater risk of liver injury when EGCG is consumed during dieting for weight loss has not been previously reported. This study found for the first time that EGCG could induce enhanced lipid metabolism pathways, suggesting that EGCG had the so-called “fat burning” effect, although EGCG did not cause liver injury at doses of 400 or 800 mg/kg in normal mice. Intriguingly, we found that EGCG caused dose-dependent hepatotoxicity on mice under dietary restriction, suggesting the potential combination effects of dietary restriction and EGCG. The combination effect between EGCG and dietary restriction led to overactivation of linoleic acid and arachidonic acid oxidation pathways, significantly increasing the accumulation of pro-inflammatory lipid metabolites and thus mediating liver injury. We also found that the disruption of Lands’ cycle and sphingomyelin-ceramides cycle and the high expression of taurine-conjugated bile acids were important metabolomic characteristics in EGCG-induced liver injury under dietary restriction. This original discovery suggests that people should not go on a diet while consuming EGCG for weight loss; otherwise the risk of liver injury will be significantly increased. This discovery provides new evidence for understanding the “drug-host” interaction hypothesis of drug hepatotoxicity and provides experimental reference for clinical safe use of green tea-related dietary supplements.

Физиологические механизмы действия салицилатов на сердечно-сосудистую систему

In modern literature, there is an increased interest in studying the biological and therapeutic effects of salicylates. Extensive clinical trials have demonstrated the effectiveness of acetylsalicylic acid (ASA) and its complex compounds in the treatment and prevention of ischemic heart disease, chronic heart failure, hypertension, and others, which makes it possible to assess the breadth of beneficial effects of ASA on the functioning of the cardiovascular system (CVS) and to state lack of other equivalent medicines in the coming years. The essential direction remains the expansion and enhancement of the known therapeutic activity (antipyretic, analgesic, anti-inflammatory, antioxidant, antidepressant, anti-migraine, anxiolytic, etc.) against the background of reducing and/or eliminating side effects since ASA occupies a leading position among all non-steroidal anti-inflammatory drugs in terms of volumes and one of the first places for the number of side effects. A promising solution to this problem is the creation of complex compounds of salicylates, since the formation of new coordination compounds based on them may lead to the emergence of new useful biological properties, as well as the strengthening of physiological effects characteristic of ASA, which will help to solve the problem of reducing side effects, resistance to aspirin therapy and increasing the therapeutic potential of the initial compound to obtain effective new-generation drugs. The article summarizes extensive information about the physiological and molecular mechanisms of action of ASA and its derivatives on CVS in health and disease, including on various physiological and biochemical links of the body's homeostasis: vasoregulatory function of the vascular endothelium, vascular-platelet hemostasis; fibrinolysis; processes of free radical oxidation and antioxidant protection; cyclooxygenase and lipoxygenase pathways of arachidonic acid oxidation; molecular markers of inflammation processes (prostaglandins; pro- and anti-inflammatory cytokines; anti-inflammatory lipid mediators). We analyzed and described the literature data and our own experimental studies of salicylates' effects on central hemodynamics and tissue microcirculation. We concluded that it is promising to study quantitative and qualitative changes in microcirculatory processes under the influence of ASA and its derivatives, which will clarify the mechanisms of these compounds' biological action on the CVS.

Lipoxin (LTX A4 5S, 6R, 15R) levels drastically decrease after 5 years of hemodialysis treatment.

The increased risk of atherosclerosis in patients with chronic kidney disease (CKD) is associated with the increased concentration of fatty acids from the omega-6 family. Products of arachidonic acid oxidation, including prostaglandins, thromboxanes, hydroxyleicosa-tetraenoic acids (HETES) and hydroxyoctadecadienoic acids (HODES) are involved in the pathogenesis of cancer and cardiovascular diseases due to increased oxidative stress. The aim of our study was to determine the relations resulting from the duration of CKD treatment. One of our main concerns is, whether and when the cascade of synthesis of inflammatory mediators may be insufficient in patients with CKD during many years of treatment. The study involved 121 patients with CKD and 87 healthy volunteers. Eicosanoid profiles 9(S)-HODE, 13(S)-HODE, 5(S)-HETE, 12(S)-HETE, 15(S)-HETE, 5(S)-oxoETE, 16(RS)-HETE, and 5(S),6(R)-lipoxinA4, 5(S),6(R),15(R)-lipoxinA4 were extracted in plasma. The HPLC separations were performed by means of 1260 liquid chromatography. Patients with CKD have a significantly higher concentration of the following inflammatory mediators: 13(S)-HODE, 5(S)-HETE, 12(S)-HETE, 15(S)-HETE, 5(S)-oxoETE, 16(RS)-HETE, and 5(S),6(R), 15(R)-lipoxinA4 relative to the control group. However, the concentrations of 9(S)-HODE were lower in the CKD group. The comparison of sexes did not show significant differences in terms of CKD. A tendency for lower concentrations of HETE and HODE were observed in the group of men. 15LOX, 12LOX and 5LOX pathways in chronic kidney disease are increased, while COX are suppressed (9-HODE). The analysis of the treatment time of patients with CKD shows that incorrect levels of 5(S), 6(R) and 15(R)-lipoxinA4 are developed. We present a new evidence of possible concepts and future clinical interventions in patients suffering from chronic kidney disease for many years. These data for the first time demonstrate that lipoxin levels drastically decrease in the course of CKD. Therefore, synthetic LXA4 analogues may be used as an antioxidant therapy in CKD, which requires further research.