Lipoxin A4 inhibited the activation of hepatic stellate cells -T6 cells by modulating profibrotic cytokines and NF-κB signaling pathway Publication date: February 2020 Source: Prostaglandins & Other Lipid Mediators, Volume 146 Author(s): Ting Zhang, Hua Hao, Zi-Qin Zhou, Tao Zeng, Jia-Min Zhang, Xiao-Yan Zhou Abstract Background The deposition of extracellular matrix (ECM) during hepatic fibrosis is an intermediate process in the progression of multiple chronic liver diseases to cirrhosis. Because activated hepatic stellate cells (HSCs) are the main source of ECM, HSCs activation is the central link in the formation of liver fibrosis. It was reported that the analogs of lipoxin A4 (LXA4) had anti-fibrotic effects, but the mechanisms are still not clear. This study was conducted to explore the possible mechanisms involved in the process of LXA4-mediated inhibition of HSCs activation. Methods Rat HSC-T6 cells were activated by LPS and treated with LXA4 and/or BOC-2. The levels of ECM were assessed by hydroxyproline (Hyp) kit. The protein levels of α-SMA, Collagen I and III, MMP-2, MMP-9, TGF-β1, PDGF A and B, NF-κB P65, phosphorylated NF-κB P65 (P-P65) and NF-κB inhibitor α (I-κBα) were measured via western blot. The mRNA levels of MMP-2 and MMP-9 were observed by real-time PCR. The contents of TGF-β1 and PDGF were assessed by ELISA kits. Nuclear transfer assay kit was used to assess the activation and translation of NF-κB P65. Results (1) LPS activated HSC-T6 cells and up-regulated α-SMA, but LXA4 decreased LPS-induced α-SMA in HSC-T6 cells. (2) LXA4 inhibited LPS-induced Hyp production, meanwhile down-regulated LPS-induced Collagen I, Collagen III, MMP-2, and MMP-9 in HSC-T6 cells. (3) LXA4 decreased LPS-induced TGF-β1 and PDGF in HSC-T6 cells. (4) LXA4 repressed LPS-activated NF-κB signaling pathway, causing a reduction of I-κBα degradation, NF-κB phosphorylation, and NF-κB p65 transposition in HSC-T6 cells. (4) BOC-2, the blocker of LXA4 receptor, inhibited all the effects of LXA4. Conclusion LXA4 inhibited HSCs activation through down-regulation TGF-β1/PDGF, and repression NF-κB signal pathway.

The role of sphingosine 1-phosphate receptors on retinal pigment epithelial cells barrier function and angiogenic effects Publication date: December 2019 Source: Prostaglandins & Other Lipid Mediators, Volume 145 Author(s): Ryo Terao, Megumi Honjo, Kiyohito Totsuka, Yukihiro Miwa, Toshihide Kurihara, Makoto Aihara Abstract Sphingosine-1-phosphate (S1P) is a lysophospholipid mediator, promoting angiogenesis and inflammation via interactions with its receptors (S1P1–5), but the receptors and signaling pathways responsible for the progression of choroidal neovascularization (CNV) remain unknown. We investigated the roles of S1P/S1P receptors in RPE cells. ARPE-19 cells were treated with S1P dissolved in carrier proteins of albumin or apolipoprotein M (ApoM). The mRNA expression levels of interleukin-8 (IL-8), C-C motif chemokine ligand 2 (CCL2), and vascular endothelial growth factor (VEGF) were evaluated using quantitative real-time polymerase chain reaction. The protein level of hypoxia-inducible factor (HIF)-1α was assessed via enzyme-linked immunosorbent assay. HIF transcriptional activity was evaluated with a dual-reporter luciferase assay. Cellular barrier integrity was evaluated using transepithelial electrical resistance and the FITC-dextran permeability assay. The suppressive effect of an S1P antagonist on CNV progression was investigated with a laser-induced CNV model in mice. The increase in expression of IL-8, CCL2, and VEGF due to albumin-bound S1P was significantly mitigated by an S1P2 antagonist. The expression of HIF-1α significantly decreased with inhibition of S1P2 and S1P3. In addition, albumin-bound S1P disrupted the barrier integrity of retinal pigment epithelial cells via S1P2, whereas integrity was strengthened by ApoM-bound S1P. CNV lesions were significantly reduced in the mouse model with intravitreal injection of S1P2 antagonist. This study demonstrated that S1P significantly promotes angiogenesis, inflammation, and barrier integrity, which was attenuated by inhibition of S1P2 or S1P3, suggesting that regulation of S1P2 and S1P3 is a novel therapeutic target for CNV. Graphical abstract

Evaluation of analgesic and antiplatelet activity of 2-((3-(chloromethyl)benzoyl)oxy)benzoic acid Publication date: December 2019 Source: Prostaglandins & Other Lipid Mediators, Volume 145 Author(s): Caroline, Kuncoro Foe, Senny Yesery Esar, Ami Soewandi, Hevi Wihadmadyatami, Ratna Megawati Widharna, Wahyu Dewi Tamayanti, Elisabeth Kasih, Yudy Tjahjono Abstract Acetylsalicylic acid is used as a non-steroidal anti-inflammatory drugs (NSAID) and antiplatelet agents by inhibiting cyclooxygenases. However, therapy using acetylsalicylic acid could induce gastric bleeding and cause other gastrointestinal toxicity. The aim of this study was to demonstrate the synthesis of a new compound bearing salicylic acid residue namely 2-((3-(chloromethyl)benzoyl)oxy)benzoic acid, to analyze its potential as a ligand for human cyclooxygenase-2 (COX-2) receptor, to evaluate its toxicity level and its effectiveness for analgesic and antiplatelet agent compared with acetylsalicylic acid. Synthesis of 2-((3-(chloromethyl)benzoyl)oxy)benzoic acid was conducted by microwave irradiation. The purity of this compound was evaluated with TLC, IR, NMR, and EDS spectroscopy. The chemical characterization and docking studies against human COX-2 (PDB:5F1A) was performed in-silico. The acute oral toxicity assay was performed under OECD guidelines. The analgesic activity study was performed by plantar and writhing test on animal model. For anti-platelet activity study, we performed tail-bleeding assay and flow cytometry based platelet aggregation assay. We could successfully synthesize a pure white crystalline 2-((3-(chloromethyl)benzoyl)oxy)benzoic acid. In-Silico G-Score result of those compounds gives us preliminary hint of the potential affinity of this compound as a ligand for COX-2 receptor (PDB: 5F1A). Acute toxicity and microscopic gastrointestinal assessments indicated non-observable harmful toxicity parameters. The plantar response time of 2-((3-(chloromethyl)benzoyl)oxy)benzoic acid treated groups showed a significant increment (P < 0.01), and the nociceptive response in writhing test demonstrated a significant dose-dependent decrement. This indicated that its analgesic activity was better than acetylsalicylic acid. The platelet aggregation of 2-((3-(chloromethyl)benzoyl)oxy)benzoic acid was lower than its controls, indicating an aggregation inhibition pattern. The animals treated with 2-((3-(chloromethyl)benzoyl)oxy)benzoic acid gave a longer bleeding time. Overall, this study demonstrated a successful synthesis of pure 2-((3-(chloromethyl)benzoyl)oxy) benzoic acid. We postulated that this compound was better than acetylsalicylic acid, exhibiting excellent analgesic and antiplatelet activity with no toxicity impact. Graphical abstract

Eicosanoids derived from cytochrome P450 pathway of arachidonic acid and inflammatory shock Publication date: December 2019 Source: Prostaglandins & Other Lipid Mediators, Volume 145 Author(s): Bahar Tunctan, Sefika Pinar Senol, Meryem Temiz-Resitoglu, Demet Sinem Guden, Seyhan Sahan-Firat, John R. Falck, Kafait U. Malik Abstract Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. Septic shock, the most common form of vasodilatory shock, is a subset of sepsis in which circulatory and cellular/metabolic abnormalities are severe enough to increase mortality. Inflammatory shock constitutes the hallmark of sepsis, but also a final common pathway of any form of severe long-term tissue hypoperfusion. The pathogenesis of inflammatory shock seems to be due to circulating substances released by pathogens (e.g., bacterial endotoxins) and host immuno-inflammatory responses (e.g., changes in the production of histamine, bradykinin, serotonin, nitric oxide [NO], reactive nitrogen and oxygen species, and arachidonic acid [AA]-derived eicosanoids mainly through NO synthase, cyclooxygenase, and cytochrome P450 [CYP] pathways, and proinflammatory cytokine formation). Therefore, refractory hypotension to vasoconstrictors with end-organ hypoperfusion is a life threatening feature of inflammatory shock. This review summarizes the current knowledge regarding the role of eicosanoids derived from CYP pathway of AA in animal models of inflammatory shock syndromes with an emphasis on septic shock in addition to potential therapeutic strategies targeting specific CYP isoforms responsible for proinflammatory/anti-inflammatory mediator production.

Urinary prostaglandin D2 and E2 metabolites associate with abdominal obesity, glucose metabolism, and triglycerides in obese subjects Publication date: December 2019 Source: Prostaglandins & Other Lipid Mediators, Volume 145 Author(s): Sven-Christian Pawelzik, Antoine Avignon, Helena Idborg, Catherine Boegner, Françoise Stanke-Labesque, Per-Johan Jakobsson, Ariane Sultan, Magnus Bäck Abstract Obesity is associated with low-grade chronic inflammation, which contributes to the development of the metabolic syndrome and its associated complications, such as insulin resistance and type-2 diabetes. Limited data from animal and human studies support local generation of pro-inflammatory prostanoid lipid mediators in white adipose tissue. However, the link between systemic prostanoid levels and parameters characterizing the metabolic syndrome is missing in human obesity. Therefore, we performed a targeted lipidomic analysis using urine samples from obese human subjects (n = 45) and show for the first time in humans that urinary prostanoid levels correlate with metabolic parameters that indicate a dysregulated glucose and triglyceride metabolism. We identified tetranor-PGDM and tetranor-PGEM as the two major urinary prostanoid metabolites in obese subjects with levels of 247 ± 31 and 23.3 ± 4.0 pmol/mg creatinine, respectively. Tetranor-PGDM was significantly associated with serum triglycerides, while tetranor-PGEM was associated with abdominal obesity as defined by an increased waist-to-hip ratio (WHR), with glycated hemoglobin (HbA1c), and with impaired oral glucose tolerance. These results confirm the previously established notion of low-grade chronic inflammation in obesity and further identify an association of the prostanoid pathway with obesity-associated dyslipidemia, abdominal obesity, and insulin resistance.

Editorial Board Publication date: December 2019 Source: Prostaglandins & Other Lipid Mediators, Volume 145 Author(s):

Oxidative pathways of arachidonic acid as targets for regulation of platelet activation Publication date: December 2019 Source: Prostaglandins & Other Lipid Mediators, Volume 145 Author(s): Andres Trostchansky, Rodrigo Moore-Carrasco, Eduardo Fuentes Abstract Platelet activation plays an important role in acute and chronic cardiovascular disease states. Multiple pathways contribute to platelet activation including those dependent upon arachidonic acid. Arachidonic acid is released from the platelet membrane by phospholipase A2 action and is then metabolized in the cytosol by specific arachidonic acid oxidation enzymes including prostaglandin H synthase, 12-lipoxygenase, and cytochrome P450 to produce pro- and anti-inflammatory eicosanoids. This review aims to analyze the role of arachidonic acid oxidation on platelet activation, the enzymes that use it as a substrate associated as novel therapeutics target for antiplatelet drugs.

Lipid Mediators of Inflammation and Resolution in Individuals with Tuberculosis and Tuberculosis-Diabetes Publication date: Available online 11 November 2019 Source: Prostaglandins & Other Lipid Mediators Author(s): Rupak Shivakoti, Jesmond Dalli, Dileep Kadam, Sanjay Gaikwad, Madhusudan Barthwal, Romain A. Colas, Francesca Mazzacuva, Rahul Lokhande, Sujata Dharmshale, Renu Bharadwaj, Anju Kagal, Neeta Pradhan, Sona Deshmukh, Sachin Atre, Tushar Sahasrabudhe, Arjun Kakrani, Vandana Kulkarni, Swapnil Raskar, Nishi Suryavanshi, Sandy Chon ABSTRACT Individuals with concurrent tuberculosis (TB) and Type 2 diabetes (DM) have a higher risk of adverse outcomes. To better understand potential immunological differences, we utilized a comprehensive panel to characterize pro-inflammatory and pro-resolving (i.e., mediators involved in the resolution of inflammation) lipid mediators in individuals with TB and TB-DM. A nested cross-sectional study of 40 individuals (20 newly diagnosed DM and 20 without DM) was conducted within a cohort of individuals with active drug-susceptible treatment-naïve pulmonary TB. Lipid mediators were quantified in serum samples through lipid mediator profiling. We conducted correlation-based analysis of these mediators. Overall, the arachidonic acid-derived leukotriene and prostaglandin families were the most abundant pro-inflammatory lipid mediators, while lipoxins and maresins families were the most abundant pro-resolving lipid mediators in individuals with TB and TB-DM. Individuals with TB-DM had increased correlations and connectivity with both pro-inflammatory and pro-resolving lipid mediators compared to those with TB alone. We identified the most abundant lipid mediator metabolomes in circulation among individuals with TB and TB-DM; in addition, our data shows a substantial number of significant correlations between both pro-inflammatory and pro-resolving lipid mediators in individuals with TB-DM, delineating a molecular balance that potentially defines this comorbidity.

A JOURNEY OF CELECOXIB FROM PAIN TO CANCER Publication date: Available online 11 November 2019 Source: Prostaglandins & Other Lipid Mediators Author(s): Pratiksha Saxena, Pramod K. Sharma, Priyank Purohit Abstract The most enthralling and versatile class of drugs called the Non-steroidal anti-inflammatory (NSAIDs) showed its therapeutic utility in inflammation, beginning from the era of classic drug ‘Aspirin’. NSAIDs and their well-established action based on inhibiting the COX-1 and COX-2 enzyme leads to blockage of prostaglandin pathway. They further categorized into first generation (non-selective inhibitor) and second generation (selective COX-2 inhibitors). Selective COX-2 inhibitors has advantage over non-selective in terms of their improved safety profile of gastro-intestinal tract. Rejuvenating and recent avenues for COXIBS (selective COX-2 inhibitors) explains its integrated role in identification of biochemical pain signaling as well as its pivotal key role in cancer chemotherapy. A key role player in this class is the Celecoxib (only FDA approved COXIB) a member of Biopharmaceutical classification system (BCS) II. Low solubility and bioavailability issues related with celecoxib lead to the development and advancement in the discovery and research of some possible formulation administered either orally, topically or via transdermal route. This review article intent to draw the bead on Celecoxib and it clearly explain extensive knowledge of its disposition profile, its dynamic role in cancer at cellular level and cardiovascular risk assessment. Some of the possible formulations approaches with celecoxib and its improvement aspects are also briefly discussed. Graphical abstract

Parasitic load determination by differential expression of 5-Lipoxygenase and PGE2 Synthases in Visceral Leishmaniasis Publication date: Available online 11 November 2019 Source: Prostaglandins & Other Lipid Mediators Author(s): Sheetal Saini, Bharat Singh, Satya Prakash, Smita Kumari, Amit Kumar Kureel, Anuradha Dube, Amogh Anant Sahasrabuddhe, Ambak Kumar Rai Abstract Infection with L. donovani affects mainly visceral organs. Importantly, the parasitic load differs in different visceral organs; therefore there is a need to understand the organ specific immune regulation, particularly in the spleen and liver. Comparative studies between these organs in Leishmania infected hamster (Mesocricetus auratus) are lacking. Our study highlights the importance of eicosanoids in the organ specific pathology of visceral leishmaniasis. Among other immune cells, macrophages (mφ) which harbor Leishmania parasite are major producers of eicosanoids. In this study, we intend to explore linkage between organ specific immune response and eicosanoids. We suggest that eicosanoids (early immune modulators) and their organ specific expressions, possibly tune the outcome of mφ differently at different sites. We have observed that liver showed better containment of parasitic load than spleen, where we have found higher expression of 5-lipoxygenase (5-LO) enzyme along with IL-12 and iNOS. However, in spleen, enzymes of the PGE2 pathway (PGE2 cytosolic and PGE2 microsomal) along with IL-10 were predominantly higher. To further corroborate our findings, in vitro assays were carried out using purified eicosanoids (LTB4 and PGE2) and the inhibitors of these pathways. Findings establish that the 5-lipoxygenase pathway (i.e. LTB4) is anti-parasitic and its inhibition increases the parasitic load (qPCR based kDNA detection). On the contrary, PGE2 pathway supports establishment of infection in mφ. Taken together, 5-LO pathway plays a protective role in liver during L. donovani infection. However, the PGES pathway favors the parasite growth, particularly in the spleen at a later stage. Graphical abstract