1‐palmitoyl‐2‐linoleoyl‐3‐acetyl‐rac‐glycerol (PLAG) reduces hepatic injury in concanavalin A‐treated mice

Ko, Young Bok; Yoon, Sun Young; Ly, Sun Yung; Kim, Jooheon; Sohn, Ki-Young; Kim, Jae Wha

doi:10.1002/jcb.26299

Cited by 12 publications

(12 citation statements)

References 54 publications

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“…As reported elsewhere, it has been shown that PLAG is an effective therapeutic candidate in different inflammatoryassociated diseases, such as rheumatoid arthritis, atopic dermatitis, asthma and hepatitis (20,(34)(35)(36). In addition, the therapeutic efficacy of PLAG has been demonstrated in chemotherapy and radiation-induced oral mucositis in hamster and mouse models, through the effective attenuation of neutrophil infiltration into cheek pouches and tongues and a decrease in inflammatory cytokines (37).…”

Section: Discussionmentioning

confidence: 73%

Mitigating Effects of 1-Palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) on Hematopoietic Acute Radiation Syndrome after Total-Body Ionizing Irradiation in Mice

Kim¹,

Jeong

Shin

et al. 2019

Radiation Research

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Acute radiation syndrome (ARS) occurs as a result of partial-or whole-body, high-dose exposure to radiation in a very short period of time. Survival is dependent on the severity of the hematopoietic sub-syndrome of ARS. In this study, we investigated the mitigating effects of a lipid molecule, 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG), on the kinetics of hematopoietic cells, including absolute neutrophil count (ANC), red blood cells (RBCs) and platelet counts, in mice after gamma-ray total-body irradiation (TBI). Male and female BALB/c mice (11 weeks old) received a LD 70/30 dose of TBI. PLAG significantly and dosedependently attenuated radiation-induced mortality (P ¼ 0.0041 for PLAG 50 mg/kg; P , 0.0001 for PLAG 250 mg/kg) and body weight loss (P , 0.0001 for PLAG 50 and 250 mg/ kg) in mice. Single-fraction TBI sharply reduced ANC within 3 days postirradiation and maintained the neutropenic state (ANC , 500 cells/ll) by approximately 26.8 6 0.8 days. However, administration of PLAG attenuated radiationinduced severe neutropenia (ANC , 100 cells/ll) by effectively delaying the mean day of its onset and decreasing its duration. PLAG also significantly mitigated radiationinduced thrombocytopenia (P , 0.0001 for PLAG 250 mg/kg) and anemia (P ¼ 0.0023 for PLAG 250 mg/kg) by increasing mean platelet and RBC counts, as well as hemoglobin levels, in peripheral blood. Moreover, delayed administration of PLAG, even at 48 and 72 h after gamma-ray irradiation, significantly attenuated radiation-induced mortality in a time-dependent manner. When compared to olive oil and palmitic linoleic hydroxyl (PLH), only PLAG effectively attenuated radiation-induced mortality, indicating that it has a distinctive mechanism of action. Based on these preclinical observations, we concluded that PLAG has high potential as a radiation countermeasure for the improvement of survivability and the treatment of hematopoietic injury in gamma-rayinduced ARS.

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Section: Discussionmentioning

confidence: 73%

Mitigating Effects of 1-Palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) on Hematopoietic Acute Radiation Syndrome after Total-Body Ionizing Irradiation in Mice

Kim¹,

Jeong

Shin

et al. 2019

Radiation Research

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“…The precise mechanistic relevance of these observations are not clear at present and remain the subject of ongoing research in our group. However, a potential explanation is that the anti-inflammatory response may be liver centric and attempting to reduce the extent of parenchymal injury whilst the increase in inflammatory markers is allowing the potential influx of immune cells that are required for later liver injury resolution ( 60 , 61 ).…”

Section: Discussionmentioning

confidence: 99%

The Delivery of Multipotent Adult Progenitor Cells to Extended Criteria Human Donor Livers Using Normothermic Machine Perfusion

et al. 2020

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Background: Pre-clinical research with multi-potent adult progenitor cells (MAPC® cells, Multistem, Athersys Inc., Cleveland, Ohio) suggests their potential as an anti-inflammatory and immunomodulatory therapy in organ transplantation. Normothermic machine perfusion of the liver (NMP-L) has been proposed as a way of introducing therapeutic agents into the donor organ. Delivery of cellular therapy to human donor livers using this technique has not yet been described in the literature. The primary objectives of this study were to develop a technique for delivering cellular therapy to human donor livers using NMP-L and demonstrate engraftment. Methods: Six discarded human livers were perfused for 6 h at 37°C using the Liver Assist (Organ Assist, Groningen). 50 × 106 CMPTX-labeled MAPC cells were infused directly into the right lobe via the hepatic artery (HA, n = 3) or portal vein (PV, n = 3) over 20 min at different time points during the perfusion. Perfusion parameters were recorded and central and peripheral biopsies were taken at multiple time-points from both lobes and subjected to standard histological stains and confocal microscopy. Perfusate was analyzed using a 35-plex multiplex assay and proteomic analysis. Results: There was no detrimental effect on perfusion flow parameters on infusion of MAPC cells by either route. Three out of six livers met established criteria for organ viability. Confocal microscopy demonstrated engraftment of MAPC cells across vascular endothelium when perfused via the artery. 35-plex multiplex analysis of perfusate yielded 13 positive targets, 9 of which appeared to be related to the infusion of MAPC cells (including Interleukin's 1b, 4, 5, 6, 8, 10, MCP-1, GM-CSF, SDF-1a). Proteomic analysis revealed 295 unique proteins in the perfusate from time-points following the infusion of cellular therapy, many of which have strong links to MAPC cells and mesenchymal stem cells in the literature. Functional enrichment analysis demonstrated their immunomodulatory potential. Conclusion: We have demonstrated that cells can be delivered directly to the target organ, prior to host immune cell population exposure and without compromising the perfusion. Transendothelial migration occurs following arterial infusion. MAPC cells appear to secrete a host of soluble factors that would have anti-inflammatory and immunomodulatory benefits in a human model of liver transplantation.

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“…Activation of the NACHT, LRR, and PYD domains-containing protein3 inflammasome leading to interleukin-1β (IL-1β) release is a putative pathogenesis of acute gouty inflammation triggered by MSU crystals (8,9). High concentration of CXC motif chemokine ligand 8 (CXCL8/IL-8) occurs in the synovial fluid of acute gout patients (10).…”

Section: Introductionmentioning

confidence: 99%

“…PLAG reduces lipopolysaccharideinduced macrophage inflammatory protein 2 (MIP-2) and CXCL8 secretion (29). PLAG improves hepatic injury in concanavalin A-treated mice (9), and gemcitabine-induced neutropenia (30,31) and oral mucositis in hamster and mouse models (32), via modulation of neutrophil migration. In this study, the mitigating effects of PLAG in MSU-induced acute gouty inflammation through modulation of neutrophil infiltration were investigated.…”

Section: Introductionmentioning

confidence: 99%

1-Palmitoyl-2-Linoleoyl-3-Acetyl-rac-Glycerol (PLAG) Mitigates Monosodium Urate (MSU)-Induced Acute Gouty Inflammation in BALB/c Mice

et al. 2020

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Acute gouty arthritis is an auto-inflammatory disease caused by the deposition of monosodium urate (MSU) crystals in joints or tissues. Excessive neutrophil recruitment into gouty lesions is a general clinical sign and induces a pain phenotype. Attenuation of successive periods of neutrophil infiltration might be a beneficial approach to achieve therapeutic efficacy. In this study, the activity of 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) in attenuation of excess neutrophil infiltration was assessed in gout-induced lesions of BALB/c mice. Neutrophil infiltration in MSU-induced gouty lesions was analyzed using immunohistochemical staining. ELISA and RT-PCR were used to measure attenuation of expression of the major neutrophil chemoattractant, CXC motif chemokine ligand 8 (CXCL8), in a PLAG-treated animal model and in cells in vitro. The animal model revealed massive increased neutrophil infiltration in the MSU-induced gouty lesions, but the PLAG-treated mice had significantly reduced neutrophil numbers in these lesions. The results also indicated that the MSU crystals stimulated a damage-associated molecular pattern that was recognized by the P2Y6 purinergic receptor. This MSU-stimulated P2Y6 receptor was destined to intracellular trafficking. During intracellular endosomal trafficking of the receptor, endosome-dependent signaling provided expression of CXCL8 chemokines for neutrophil recruitment. PLAG accelerated initiation of the intracellular trafficking of the P2Y6 receptor and returning the receptor to the membrane. This process shortened the intracellular retention time of the receptor anchoring endosome and subsequently attenuated endosome-dependent signaling for CXCL8 expression. These study results suggested that PLAG could be used for resolution of acute inflammation induced in gout lesions.

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1‐palmitoyl‐2‐linoleoyl‐3‐acetyl‐rac‐glycerol (PLAG) reduces hepatic injury in concanavalin A‐treated mice

Cited by 12 publications

References 54 publications

Mitigating Effects of 1-Palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) on Hematopoietic Acute Radiation Syndrome after Total-Body Ionizing Irradiation in Mice

Mitigating Effects of 1-Palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) on Hematopoietic Acute Radiation Syndrome after Total-Body Ionizing Irradiation in Mice

The Delivery of Multipotent Adult Progenitor Cells to Extended Criteria Human Donor Livers Using Normothermic Machine Perfusion

1-Palmitoyl-2-Linoleoyl-3-Acetyl-rac-Glycerol (PLAG) Mitigates Monosodium Urate (MSU)-Induced Acute Gouty Inflammation in BALB/c Mice

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