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Pentalinonsterol, a Phytosterol from Pentalinon andrieuxii, is Immunomodulatory through Phospholipase A2 in Macrophages toward its Antileishmanial Action

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Abstract

Our earlier in vitro and in vivo studies have revealed that the phytosterol, pentalinonsterol (cholest-4,20,24-trien-3-one) (PEN), isolated from the roots of Pentalinon andrieuxii, possesss immunomodulatory properties in macrophages and dendritic cells. Leishmaniasis, caused by the infection of Leishmania spp. (a protozoan parasite), is emerging as the second-leading cause of mortality among the tropical diseases and there is an unmet need for a pharmacological intervention of leishmaniasis. Given the beneficial immunomodulatory actions and lipophilic properties of PEN, the objective of this study was to elucidate the mechanism(s) of action of the immunomodulatory action(s) of PEN in macrophages through the modulation of phospholipase A2 (PLA2) activity that might be crucial in the antileishmanial action of PEN. Therefore, in this study, we investigated whether PEN would modulate the activity of PLA2 in RAW 264.7 macrophages and mouse bone marrow-derived primary macrophages (BMDMs) in vitro and further determined how the upstream PLA2 activation would regulate the downstream cytokine release in the macrophages. Our current results demonstrated that (i) PEN induced PLA2 activation (arachidonic acid release) in a dose- and time-dependent manner that was regulated upstream by the mitogen-activated protein kinases (MAPKs); (ii) the PEN-induced activation of PLA2 was attenuated by the cPLA2-specific pharmacological inhibitors; and (iii) the cPLA2-specific pharmacological inhibitors attenuated the release of inflammatory cytokines from the macrophages. For the first time, our current study demonstrated that PEN exhibited its immunomodulatory actions through the activation of cPLA2 in the macrophages, which potentially could be used in the development of a pharmacological intervention against leishmaniasis.

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Abbreviations

AA :

arachidonic acid

BMDM :

bone marrow-derive macrophages

COX :

cyclooxyginases

cPLA2 :

cytosolic PLA2

EDTA :

ethylenediaminetetraacetic acid

EGTA :

ethylene glycol-bis(β-aminoethyl ether)-N,N,N′,N′-tetraacetic acid

ERK :

extracellular signal-regulated kinase

GMCSF :

granulocyte-macrophage colony-stimulating factor

LOX :

lipoxygenases

MAPKs :

mitogen-activated protein kinases

PARE :

Pentalinon andrieuxii root extract

PEN :

pentalinonsterol

PLA 2 :

phospholipase A2

PGs :

prostaglandins

PUFAp :

poly unsaturated fatty acids

TBST :

Tris-buffered saline.

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Acknowledgements

This work was supported by Department of Defence (DOD) USA grant awarded to ARS and NLP, Departments of Pathology and Internal Medicine and the Division of Pulmonary, Critical Care, and Sleep Medicine of the Ohio State University Wexner Medical Center.

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  1. These authors contributed equally: Sanjay Varikuti, Andrew B. Shelton

Authors and Affiliations

  1. Department of Pathology, The Ohio State University Medical Center, Columbus, OH, USA

    Sanjay Varikuti, Gaurav Gupta & Abhay R. Satoskar

  2. Department of Bioscience & Biotechnology, Banasthali University, Banasthali, India

    Sanjay Varikuti & Nidhi Srivastava

  3. Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Davis Heart & Lung Research Institute, The Ohio State University, Columbus, OH, USA

    Andrew B. Shelton, Sainath R. Kotha, Travis Gurney, Thomas J. Hund & Narasimham L. Parinandi

  4. Department of Biomedical Engineering, Davis Heart & Lung Research Institute, The Ohio State University, Columbus, OH, USA

    Andrew B. Shelton, Sainath R. Kotha, Travis Gurney, Thomas J. Hund & Narasimham L. Parinandi

  5. Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH, USA

    James R. Fuchs & A. Douglas Kinghorn

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Varikuti, S., Shelton, A.B., Kotha, S.R. et al. Pentalinonsterol, a Phytosterol from Pentalinon andrieuxii, is Immunomodulatory through Phospholipase A2 in Macrophages toward its Antileishmanial Action. Cell Biochem Biophys 80, 45–61 (2022). https://doi.org/10.1007/s12013-021-01030-8

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