scholarly journals Arachidonic Acid Metabolism and Kidney Inflammation

2019 ◽  
Vol 20 (15) ◽  
pp. 3683 ◽  
Author(s):  
Tianqi Wang ◽  
Xianjun Fu ◽  
Qingfa Chen ◽  
Jayanta Kumar Patra ◽  
Dongdong Wang ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Cytochrome P450 ◽  
Cell Membrane ◽  
Inflammatory Responses ◽  
Membrane Lipids ◽  
Cell Damage ◽  
Ischemia Reperfusion ◽  
Leukotriene B4 ◽  
P450 Monooxygenase ◽  
Wide Range

As a major component of cell membrane lipids, Arachidonic acid (AA), being a major component of the cell membrane lipid content, is mainly metabolized by three kinds of enzymes: cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP450) enzymes. Based on these three metabolic pathways, AA could be converted into various metabolites that trigger different inflammatory responses. In the kidney, prostaglandins (PG), thromboxane (Tx), leukotrienes (LTs) and hydroxyeicosatetraenoic acids (HETEs) are the major metabolites generated from AA. An increased level of prostaglandins (PGs), TxA2 and leukotriene B4 (LTB4) results in inflammatory damage to the kidney. Moreover, the LTB4-leukotriene B4 receptor 1 (BLT1) axis participates in the acute kidney injury via mediating the recruitment of renal neutrophils. In addition, AA can regulate renal ion transport through 19-hydroxystilbenetetraenoic acid (19-HETE) and 20-HETE, both of which are produced by cytochrome P450 monooxygenase. Epoxyeicosatrienoic acids (EETs) generated by the CYP450 enzyme also plays a paramount role in the kidney damage during the inflammation process. For example, 14 and 15-EET mitigated ischemia/reperfusion-caused renal tubular epithelial cell damage. Many drug candidates that target the AA metabolism pathways are being developed to treat kidney inflammation. These observations support an extraordinary interest in a wide range of studies on drug interventions aiming to control AA metabolism and kidney inflammation.

scholarly journals Lipidomics Provides New Insight into Pathogenesis and Therapeutic Targets of the Ischemia—Reperfusion Injury

2021 ◽  
Vol 22 (6) ◽  
pp. 2798
Author(s):  
Zoran Todorović ◽  
Siniša Đurašević ◽  
Maja Stojković ◽  
Ilijana Grigorov ◽  
Slađan Pavlović ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Time Course ◽  
Membrane Lipids ◽  
Lipid Analysis ◽  
Cell Damage ◽  
Ischemia Reperfusion ◽  
Enzyme Inactivation ◽  
Critical Event ◽  
Tissue Ischemia ◽  
Insight Into

Lipids play an essential role in both tissue protection and damage. Tissue ischemia creates anaerobic conditions in which enzyme inactivation occurs, and reperfusion can initiate oxidative stress that leads to harmful changes in membrane lipids, the formation of aldehydes, and chain damage until cell death. The critical event in such a series of harmful events in the cell is the unwanted accumulation of fatty acids that leads to lipotoxicity. Lipid analysis provides additional insight into the pathogenesis of ischemia/reperfusion (I/R) disorders and reveals new targets for drug action. The profile of changes in the composition of fatty acids in the cell, as well as the time course of these changes, indicate both the mechanism of damage and new therapeutic possibilities. A therapeutic approach to reperfusion lipotoxicity involves attenuation of fatty acids overload, i.e., their transport to adipose tissue and/or inhibition of the adverse effects of fatty acids on cell damage and death. The latter option involves using PPAR agonists and drugs that modulate the transport of fatty acids via carnitine into the interior of the mitochondria or the redirection of long-chain fatty acids to peroxisomes.

scholarly journals Insights into the Mode of Action of Chitosan as an Antibacterial Compound

2008 ◽  
Vol 74 (12) ◽  
pp. 3764-3773 ◽  
Author(s):  
Dina Raafat ◽  
Kristine von Bargen ◽  
Albert Haas ◽  
Hans-Georg Sahl
Keyword(s):  
Antimicrobial Activity ◽  
Cell Wall ◽  
Cell Membrane ◽  
Mode Of Action ◽  
Membrane Lipids ◽  
Expression Profiles ◽  
Transcriptional Response ◽  
Response Analysis ◽  
Sequence Of Events ◽  
Wide Range

ABSTRACT Chitosan is a polysaccharide biopolymer that combines a unique set of versatile physicochemical and biological characteristics which allow for a wide range of applications. Although its antimicrobial activity is well documented, its mode of action has hitherto remained only vaguely defined. In this work we investigated the antimicrobial mode of action of chitosan using a combination of approaches, including in vitro assays, killing kinetics, cellular leakage measurements, membrane potential estimations, and electron microscopy, in addition to transcriptional response analysis. Chitosan, whose antimicrobial activity was influenced by several factors, exhibited a dose-dependent growth-inhibitory effect. A simultaneous permeabilization of the cell membrane to small cellular components, coupled to a significant membrane depolarization, was detected. A concomitant interference with cell wall biosynthesis was not observed. Chitosan treatment of Staphylococcus simulans 22 cells did not give rise to cell wall lysis; the cell membrane also remained intact. Analysis of transcriptional response data revealed that chitosan treatment leads to multiple changes in the expression profiles of Staphylococcus aureus SG511 genes involved in the regulation of stress and autolysis, as well as genes associated with energy metabolism. Finally, a possible mechanism for chitosan's activity is postulated. Although we contend that there might not be a single classical target that would explain chitosan's antimicrobial action, we speculate that binding of chitosan to teichoic acids, coupled with a potential extraction of membrane lipids (predominantly lipoteichoic acid) results in a sequence of events, ultimately leading to bacterial death.

Potential role of a series of lysine-/leucine-rich antimicrobial peptide in inhibiting lipopolysaccharide-induced inflammation

2018 ◽  
Vol 475 (22) ◽  
pp. 3687-3706 ◽  
Author(s):  
Weibing Dong ◽  
Xin Zhu ◽  
Xuan Zhou ◽  
Ying Yang ◽  
Xin Yan ◽  
...  
Keyword(s):  
Cell Membrane ◽  
Signaling Pathway ◽  
Inflammatory Responses ◽  
Antimicrobial Activities ◽  
Host Cells ◽  
Inflammatory Factors ◽  
Human Macrophage ◽  
U937 Cells ◽  
Wide Range ◽  
Anti Inflammatory

Antimicrobial peptides have broad-spectrum killing activities against bacteria, enveloped viruses, fungi and several parasites via cell membrane permeation and exhibit primarily immunomodulatory and anti-infective functions in their interactions with host cells. However, the mechanism underlying their anti-inflammatory activity remains to be elucidated. L-K6, an analog of temporin-1CEb isolated from the skin secretion of Rana chensinensis, has demonstrated a wide range of antimicrobial activities against gram-negative and gram-positive bacteria. In this study, the potent anti-inflammatory mechanism of L-K6 and its analogs in lipopolysaccharide (LPS)-stimulated human macrophage U937 cells were evaluated. We found that L-K6 suppressed the expression of inflammatory factors by two downstream signaling components in the MyD88-dependent pathway, including the mitogen-activated protein kinases (MAPKs) and the NF (nuclear factor)-κB signaling pathway, but its analog L-K5, which had the same amino acid sequence as L-K6 but no Lys residue at the –COOH terminal, only inhibited the phosphorylation of I-κB and NF-κB. Importantly, L-K6 and L-K5 were actively taken up by U937 cells through an independent cell membrane disruption mechanism and were eventually localized to the perinuclear region. The L-K6 uptake process was mediated by endocytosis, but L-K5 was specifically taken up by U937 cells via TLR4 endocytosis. Our results demonstrated that L-K6 can neutralize LPS and diassociate LPS micelles to inhibit LPS from triggering the proinflammatory signaling pathway, and by partially inhibiting inflammatory responses by the intracellular target. However, L-K5 may mainly inhibit proinflammatory responses by intracellular reporters to modulate the NF-κB signaling pathway.

Abstract 135: Alubuminuria Causes Disorder of Cytochrome P450 Metabolism of Arachidonic Acid in the Kidney of Nephrotic Rats

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Yoshikazu Muroya ◽  
Osamu Ito ◽  
Rong Rong ◽  
Yoshiko Sakata ◽  
Kenta Takashima ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Cytochrome P450 ◽  
Western Blot ◽  
Protein Level ◽  
Cell Damage ◽  
Sprague Dawley ◽  
Renal Circulation ◽  
Puromycin Aminonucleoside ◽  
Tubulointerstitial Damage ◽  
Cyp Metabolism

Alubuminuria is an aggravating factor for chronic kidney disease. Fatty acids bound to albumin are overloaded to the proximal tubules in alubuminuria and contribute to tubulointerstitial damage. It is known not only the β-oxidation ability but the ability of cytochrome P450 (CYP) metabolism of arachidonic acid (AA) is high in the kidney. Epoxyeicosatrienoic acids synthesized primarily by CYP2C and 20-hydroxyeicosatetraenoic acid synthesized by CYP4A affect tubular function and renal circulation. However, it isn’t clear CYP metabolism of AA would change in alubuminuria. The study tested changes of CYP metabolism of AA in the kidney of nephrotic rats. Sprague-Dawley rat (SD) and Nagase Analbuminemic rat (NAR) with inherited hypoalbuminemia were used and nephrotic syndrome was induced by Puromycin Aminonucleoside (PAN; 100 mg/kg, iv). Rats were randomly divided into four groups; (1) SD group; (2) SD treated with PAN group (PAN group); (3) NAR group; (4)NAR treated with PAN group (NAR+PAN group). Rats were killed on the 14th day and urinary 8OHdG, a marker of oxidative stress in the kidney, and urinary NAG, a marker of proximal tubular cell damage, were measured. The protein level of enzymes in the kidney was analyzed by Western blot and immunohistochemistry. Compared with the SD group, albuminuria, 8OHdG and NAG increased respectively to 847%, 154% and 903% in the PAN group, and Western blot showed the protein levels of CYP2C23 and CYP4A decreased to 45% and 49% without change of the protein level of PPARα, a nuclear receptor regulating fatty acid metabolism, in the PAN group. Immunohistochemistry showed the localization of CYP2C23 and CYP4A in the proximal tubule and confirmed the results by Western blot. Otherwise, we could find no difference in albuminuria, tubulointerstitial damage and the protein level of CYP2C23 between the NAR group and the NAR+PAN group. Compared with the NAR group, the protein level of CYP4A decreased to 68% in the NAR+PAN group. Alubuminuria caused tubulointerstitial damage and decreased the expressions of CYP2C23 and CYP4A in the nephrotic kidney. This study suggested the disorder of CYP metabolism of AA would affect renal circulation in alubuminuria and CYP4A would be affected by anything except alubuminuria in PAN rats.

scholarly journals Mechanisms of Non-Vesicular Exchange of Lipids at Membrane Contact Sites: Of Shuttles, Tunnels and, Funnels

2021 ◽  
Vol 9 ◽  
Author(s):  
Pascal F. Egea
Keyword(s):  
Cell Membrane ◽  
Cell Biology ◽  
Membrane Lipids ◽  
Atp Synthesis ◽  
Vesicular Trafficking ◽  
Lipid Transfer ◽  
Organelle Biogenesis ◽  
Membrane Contact Sites ◽  
Wide Range ◽  
Membrane Bound

Eukaryotic cells are characterized by their exquisite compartmentalization resulting from a cornucopia of membrane-bound organelles. Each of these compartments hosts a flurry of biochemical reactions and supports biological functions such as genome storage, membrane protein and lipid biosynthesis/degradation and ATP synthesis, all essential to cellular life. Acting as hubs for the transfer of matter and signals between organelles and throughout the cell, membrane contacts sites (MCSs), sites of close apposition between membranes from different organelles, are essential to cellular homeostasis. One of the now well-acknowledged function of MCSs involves the non-vesicular trafficking of lipids; its characterization answered one long-standing question of eukaryotic cell biology revealing how some organelles receive and distribute their membrane lipids in absence of vesicular trafficking. The endoplasmic reticulum (ER) in synergy with the mitochondria, stands as the nexus for the biosynthesis and distribution of phospholipids (PLs) throughout the cell by contacting nearly all other organelle types. MCSs create and maintain lipid fluxes and gradients essential to the functional asymmetry and polarity of biological membranes throughout the cell. Membrane apposition is mediated by proteinaceous tethers some of which function as lipid transfer proteins (LTPs). We summarize here the current state of mechanistic knowledge of some of the major classes of LTPs and tethers based on the available atomic to near-atomic resolution structures of several “model” MCSs from yeast but also in Metazoans; we describe different models of lipid transfer at MCSs and analyze the determinants of their specificity and directionality. Each of these systems illustrate fundamental principles and mechanisms for the non-vesicular exchange of lipids between eukaryotic membrane-bound organelles essential to a wide range of cellular processes such as at PL biosynthesis and distribution, lipid storage, autophagy and organelle biogenesis.

scholarly journals Inflammation in Dry Eye Syndrome: Identification and Targeting of Oxylipin-Mediated Mechanisms

Biomedicines ◽  
2020 ◽  
Vol 8 (9) ◽  
pp. 344
Author(s):  
Dmitry V. Chistyakov ◽  
Olga S. Gancharova ◽  
Viktoriia E. Baksheeva ◽  
Veronika V. Tiulina ◽  
Sergei V. Goriainov ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Dimethyl Sulfoxide ◽  
Dry Eye ◽  
Inflammatory Responses ◽  
Specific Effect ◽  
Leukotriene B4 ◽  
Dry Eye Syndrome ◽  
Acid Activation ◽  
Alpha Linolenic Acid ◽  
Tear Production

Dry eye syndrome (DES) is characterized by decreased tear production and stability, leading to desiccating stress, inflammation and corneal damage. DES treatment may involve targeting the contributing inflammatory pathways mediated by polyunsaturated fatty acids and their derivatives, oxylipins. Here, using an animal model of general anesthesia-induced DES, we addressed these pathways by characterizing inflammatory changes in tear lipidome, in correlation with pathophysiological and biochemical signs of the disease. The decline in tear production was associated with the infiltration of inflammatory cells in the corneal stroma, which manifested one to three days after anesthesia, accompanied by changes in tear antioxidants and cytokines, resulting in persistent damage to the corneal epithelium. The inflammatory response manifested in the tear fluid as a short-term increase in linoleic and alpha-linolenic acid-derived oxylipins, followed by elevation in arachidonic acid and its derivatives, leukotriene B4 (5-lipoxigenase product), 12-hydroxyeicosatetraenoic acid (12-lipoxigeanse product) and prostaglandins, D2, E2 and F2α (cyclooxygenase products) that was observed for up to 7 days. Given these data, DES was treated by a novel ophthalmic formulation containing a dimethyl sulfoxide-based solution of zileuton, an inhibitor of 5-lipoxigenase and arachidonic acid release. The therapy markedly improved the corneal state in DES by attenuating cytokine- and oxylipin-mediated inflammatory responses, without affecting tear production rates. Interestingly, the high efficacy of the proposed therapy resulted from the synergetic action of its components, namely, the general healing activity of dimethyl sulfoxide, suppressing prostaglandins and the more specific effect of zileuton, downregulating leukotriene B4 (inhibition of T-cell recruitment), as well as upregulating docosahexaenoic acid (activation of resolution pathways).

scholarly journals HMGB1 release induced by liver ischemia involves Toll-like receptor 4–dependent reactive oxygen species production and calcium-mediated signaling

2007 ◽  
Vol 204 (12) ◽  
pp. 2913-2923 ◽  
Author(s):  
Allan Tsung ◽  
John R. Klune ◽  
Xianghong Zhang ◽  
Geetha Jeyabalan ◽  
Zongxian Cao ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Cell Damage ◽  
Ischemia Reperfusion ◽  
High Mobility ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Liver Ischemia ◽  
Toll Like Receptor ◽  
Downstream Signaling ◽  
Wide Range

Ischemic tissues require mechanisms to alert the immune system of impending cell damage. The nuclear protein high-mobility group box 1 (HMGB1) can activate inflammatory pathways when released from ischemic cells. We elucidate the mechanism by which HMGB1, one of the key alarm molecules released during liver ischemia/reperfusion (I/R), is mobilized in response to hypoxia. HMGB1 release from cultured hepatocytes was found to be an active process regulated by reactive oxygen species (ROS). Optimal production of ROS and subsequent HMGB1 release by hypoxic hepatocytes required intact Toll-like receptor (TLR) 4 signaling. To elucidate the downstream signaling pathways involved in hypoxia-induced HMGB1 release from hepatocytes, we examined the role of calcium signaling in this process. HMGB1 release induced by oxidative stress was markedly reduced by inhibition of calcium/calmodulin-dependent kinases (CaMKs), a family of proteins involved in a wide range of calcium-linked signaling events. In addition, CaMK inhibition substantially decreased liver damage after I/R and resulted in accumulation of HMGB1 in the cytoplasm of hepatocytes. Collectively, these results demonstrate that hypoxia-induced HMGB1 release by hepatocytes is an active, regulated process that occurs through a mechanism promoted by TLR4-dependent ROS production and downstream CaMK-mediated signaling.

scholarly journals Arachidonic acid in postshock mesenteric lymph induces pulmonary synthesis of leukotriene B4

2008 ◽  
Vol 104 (4) ◽  
pp. 1161-1166 ◽  
Author(s):  
Janeen R. Jordan ◽  
Ernest E. Moore ◽  
Eric L. Sarin ◽  
Sagar S. Damle ◽  
Sara B. Kashuk ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Lung Injury ◽  
Ischemia Reperfusion ◽  
Leukotriene B4 ◽  
Polymorphonuclear Neutrophil ◽  
Sprague Dawley ◽  
Bioactive Lipids ◽  
Mesenteric Lymph ◽  
Sprague Dawley Rats

Mesenteric lymph is the mechanistic link between splanchnic hypoperfusion and acute lung injury (ALI), but the culprit mediator(s) remains elusive. Previous work has shown that administration of a phospholipase A2(PLA2) inhibitor attenuated postshock ALI and also identified a non-ionic lipid within the postshock mesenteric lymph (PSML) responsible for polymorphonuclear neutrophil (PMN) priming. Consequently, we hypothesized that gut-derived leukotriene B4(LTB4) is a key mediator in the pathogenesis of ALI. Trauma/hemorrhagic shock (T/HS) was induced in male Sprague-Dawley rats and the mesenteric duct cannulated for lymph collection/diversion. PSML, arachidonic acid (AA), and a LTB4receptor antagonist were added to PMNs in vitro. LC/MS/MS was employed to identify bioactive lipids in PSML and the lungs. T/HS increased AA in PSML and increased LTB4and PMNs in the lung. Lymph diversion decreased lung LTB4by 75% and PMNs by 40%. PSML stimulated PMN priming (11.56 ± 1.25 vs. 3.95 ± 0.29 nmol O2−/min; 3.75 × 105cells/ml; P < 0.01) that was attenuated by LTB4receptor blockade (2.64 ± 0.58; P < 0.01). AA stimulated PMNs to produce LTB4, and AA-induced PMN priming was attenuated by LTB4receptor antagonism. Collectively, these data indicate that splanchnic ischemia/reperfusion activates gut PLA2-mediated release of AA into the lymph where it is delivered to the lungs, provoking LTB4production and subsequent PMN-mediated lung injury.

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