Effect of acyl and alkyl analogs of platelet-activating factor on inflammatory signaling

Marathe, Gopal K.; Chaithra, Vyala Hanumanthareddy; Ke, Liang‐Yin; Chen, Chu‐Huang

doi:10.1016/j.prostaglandins.2020.106478

Cited by 10 publications

(21 citation statements)

References 102 publications

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“… 34 Whether PLA2G7 might prevent or worsen cachexia‐associated thrombosis through PAF hydrolysis or generation of pro‐inflammatory lipid species, respectively, is unknown. However, the absence of an effect of darapladib on PAF levels in this study and previous reports 21 , 22 as well as the growing debate concerning the pro‐inflammatory function of PLA2G7 through LPC production 20 , 27 , 28 challenge the hypothesis that PLA2G7 is involved in cachexia‐associated thrombosis.…”

Section: Discussioncontrasting

confidence: 66%

“…An important issue regarding PLA2G7 is whether its increase is a cause or a consequence of inflammation in several pathologies. 20 , 27 , 28 Here, we show that, despite a significant contribution, tumour is probably not the only source of circulating PLA2G7 in cachectic tumour‐bearing mice. We believe that immune cells and other tissue‐resident cell types from the host also play an important part to the circulating levels of PLA2G7 in CCx as they do in other inflammatory diseases.…”

Section: Discussionmentioning

confidence: 65%

“…Surprisingly, despite an important reduction of PAF‐AH activity in tumours ( Figure 2C ), C26‐sh Pla2g7 mice only showed an around 20% decrease in plasma PAF‐AH activity levels ( Figure 2J ), suggesting that tumour may not be the only contributor to the circulating amounts of PLA2G7 in cachectic mice. As PLA2G7 is known to be secreted by monocytes/macrophages, mast cells, T cells, and other tissue‐resident cell types in different inflammatory diseases, 11 , 12 , 20 the overall pro‐inflammatory status might have an important contribution to elevated PLA2G7 levels in CCx. This was supported by comparable enlargements of spleen and lymph nodes and by similar increases in circulating levels of the pro‐inflammatory factors IL‐6 and PAF in C26‐sh Pla2g7 and C26‐shCTR mice ( Figures 2K and 2L ).…”

Section: Resultsmentioning

confidence: 99%

“…This is in agreement with recent reviews that questioned the pro‐inflammatory effects of PLA2G7 through LPC production. 20 , 27 , 28 Considering the latter, it may explain in part why darapladib treatment has been inefficient in preventing cardiovascular death, myocardial infarction, stroke, or major coronary events in patients with coronary heart diseases. 13 , 15 It is still possible that PLA2G7 enzymatic activity might require additional pro‐cachectic pathways to functionally impact cachectic phenotypes.…”

Section: Discussionmentioning

confidence: 99%

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Association of circulating PLA2G7 levels with cancer cachexia and assessment of darapladib as a therapy

Morigny

Kaltenecker

Zuber

et al. 2021

J cachexia sarcopenia muscle

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Background Cancer cachexia (CCx) is a multifactorial wasting disorder characterized by involuntary loss of body weight that affects many cancer patients and implies a poor prognosis, reducing both tolerance to and efficiency of anticancer therapies. Actual challenges in management of CCx remain in the identification of tumour-derived and host-derived mediators involved in systemic inflammation and tissue wasting and in the discovery of biomarkers that would allow for an earlier and personalized care of cancer patients. The aim of this study was to identify new markers of CCx across different species and tumour entities. Methods Quantitative secretome analysis was performed to identify specific factors characteristic of cachexia-inducing cancer cell lines. To establish the subsequently identified phospholipase PLA2G7 as a marker of CCx, plasma PLA2G7 activity and/or protein levels were measured in well-established mouse models of CCx and in different cohorts of weight-stable and weight-losing cancer patients with different tumour entities. Genetic PLA2G7 knock-down in tumours and pharmacological treatment using the well-studied PLA2G7 inhibitor darapladib were performed to assess its implication in the pathogenesis of CCx in C26 tumour-bearing mice. Results High expression and secretion of PLA2G7 were hallmarks of cachexia-inducing cancer cell lines. Circulating PLA2G7 activity was increased in different mouse models of CCx with various tumour entities and was associated with the severity of body wasting. Circulating PLA2G7 levels gradually rose during cachexia development. Genetic PLA2G7 knock-down in C26 tumours only partially reduced plasma PLA2G7 levels, suggesting that the host is also an important contributor. Chronic treatment with darapladib was not sufficient to counteract inflammation and tissue wasting despite a strong inhibition of the circulating PLA2G7 activity. Importantly, PLA2G7 levels were also increased in colorectal and pancreatic cancer patients with CCx. Conclusions Overall, our data show that despite no immediate pathogenic role, at least when targeted as a single entity, PLA2G7 is a consistent marker of CCx in both mice and humans. The early increase in circulating PLA2G7 levels in pre-cachectic mice supports future prospective studies to assess its potential as biomarker for cancer patients.

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Section: Discussioncontrasting

confidence: 66%

Section: Discussionmentioning

confidence: 65%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Association of circulating PLA2G7 levels with cancer cachexia and assessment of darapladib as a therapy

Morigny

Kaltenecker

Zuber

et al. 2021

J cachexia sarcopenia muscle

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“…First, there is a tremendous heterogeneity of GPC species produced enzymatically and even more via non-enzymatic processes which can exert PAFR agonistic effects (5,15). Moreover, some members of the PAF family of mediators include the 1-acyl species which are in much greater abundance than 1-alkyl GPC, yet have much lower binding affinities and have been suggested to act as antagonists (120,134,135). PAF is rapidly metabolized, with a half-life in biological fluids measured in minutes.…”

Section: Discussionmentioning

confidence: 99%

New Insights Into the Pathologic Roles of the Platelet-Activating Factor System

2021

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Described almost 50 years ago, the glycerophosphocholine lipid mediator Platelet-activating factor (PAF) has been implicated in many pathologic processes. Indeed, elevated levels of PAF can be measured in response to almost every type of pathology involving inflammation and cell damage/death. In this review, we provide evidence for PAF involvement in pathologic processes, with focus on cancer, the nervous system, and in photobiology. Importantly, recent insights into how PAF can generate and travel via bioactive extracellular vesicles such as microvesicle particles (MVP) are presented. What appears to be emerging from diverse pathologies in different organ systems is a common theme where pro-oxidative stressors generate oxidized glycerophosphocholines with PAF agonistic effects, which then trigger more enzymatic PAF synthesis via the PAF receptor. A downstream consequence of PAF receptor activation is the generation and release of MVP which provide a mechanism to transmit PAF as well as other bioactive agents. The knowledge gaps which when addressed could result in novel therapeutic strategies are also discussed. Taken together, an enhanced understanding of the PAF family of lipid mediators is essential in our improved comprehension of the relationship amongst the diverse cutaneous, cancerous, neurologic and systemic pathologic processes.

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Platelet activating factor: Have we been missing the forest for the trees?

Antonopoulou

Demopoulos

2022

BioFactors

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Effect of acyl and alkyl analogs of platelet-activating factor on inflammatory signaling

Cited by 10 publications

References 102 publications

Association of circulating PLA2G7 levels with cancer cachexia and assessment of darapladib as a therapy

Association of circulating PLA2G7 levels with cancer cachexia and assessment of darapladib as a therapy

New Insights Into the Pathologic Roles of the Platelet-Activating Factor System

Platelet activating factor: Have we been missing the forest for the trees?

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