PMID- 34387841 OWN - NLM STAT- MEDLINE DCOM- 20220301 LR - 20220301 IS - 1559-0283 (Electronic) IS - 1085-9195 (Linking) VI - 80 IP - 1 DP - 2022 Mar TI - Pentalinonsterol, a Phytosterol from Pentalinon andrieuxii, is Immunomodulatory through Phospholipase A(2) in Macrophages toward its Antileishmanial Action. PG - 45-61 LID - 10.1007/s12013-021-01030-8 [doi] AB - 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 A(2) (PLA(2)) activity that might be crucial in the antileishmanial action of PEN. Therefore, in this study, we investigated whether PEN would modulate the activity of PLA(2) in RAW 264.7 macrophages and mouse bone marrow-derived primary macrophages (BMDMs) in vitro and further determined how the upstream PLA(2) activation would regulate the downstream cytokine release in the macrophages. Our current results demonstrated that (i) PEN induced PLA(2) 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 PLA(2) was attenuated by the cPLA(2)-specific pharmacological inhibitors; and (iii) the cPLA(2)-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 cPLA(2) in the macrophages, which potentially could be used in the development of a pharmacological intervention against leishmaniasis. CI - (c) 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature. FAU - Varikuti, Sanjay AU - Varikuti S AD - Department of Pathology, The Ohio State University Medical Center, Columbus, OH, USA. AD - Department of Bioscience & Biotechnology, Banasthali University, Banasthali, India. FAU - Shelton, Andrew B AU - Shelton AB AD - Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Davis Heart & Lung Research Institute, The Ohio State University, Columbus, OH, USA. AD - Department of Biomedical Engineering, Davis Heart & Lung Research Institute, The Ohio State University, Columbus, OH, USA. FAU - Kotha, Sainath R AU - Kotha SR AD - Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Davis Heart & Lung Research Institute, The Ohio State University, Columbus, OH, USA. AD - Department of Biomedical Engineering, Davis Heart & Lung Research Institute, The Ohio State University, Columbus, OH, USA. FAU - Gurney, Travis AU - Gurney T AD - Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Davis Heart & Lung Research Institute, The Ohio State University, Columbus, OH, USA. AD - Department of Biomedical Engineering, Davis Heart & Lung Research Institute, The Ohio State University, Columbus, OH, USA. FAU - Gupta, Gaurav AU - Gupta G AD - Department of Pathology, The Ohio State University Medical Center, Columbus, OH, USA. FAU - Hund, Thomas J AU - Hund TJ AD - Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Davis Heart & Lung Research Institute, The Ohio State University, Columbus, OH, USA. AD - Department of Biomedical Engineering, Davis Heart & Lung Research Institute, The Ohio State University, Columbus, OH, USA. FAU - Fuchs, James R AU - Fuchs JR AD - Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH, USA. FAU - Kinghorn, A Douglas AU - Kinghorn AD AD - Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH, USA. FAU - Srivastava, Nidhi AU - Srivastava N AD - Department of Bioscience & Biotechnology, Banasthali University, Banasthali, India. FAU - Satoskar, Abhay R AU - Satoskar AR AD - Department of Pathology, The Ohio State University Medical Center, Columbus, OH, USA. abhay.satoskar@osumc.edu. FAU - Parinandi, Narasimham L AU - Parinandi NL AUID- ORCID: 0000-0003-3489-0286 AD - Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Davis Heart & Lung Research Institute, The Ohio State University, Columbus, OH, USA. narasinham.parinandi@osumc.edu. AD - Department of Biomedical Engineering, Davis Heart & Lung Research Institute, The Ohio State University, Columbus, OH, USA. narasinham.parinandi@osumc.edu. LA - eng PT - Journal Article DEP - 20210813 PL - United States TA - Cell Biochem Biophys JT - Cell biochemistry and biophysics JID - 9701934 RN - 0 (Pentalinonsterol) RN - 0 (Phytosterols) RN - 0 (Sterols) RN - EC 3.1.1.4 (Phospholipases A2) SB - IM MH - Animals MH - Macrophages/metabolism MH - Mice MH - Phospholipases A2/metabolism MH - *Phytosterols/metabolism MH - Sterols/metabolism/pharmacology OTO - NOTNLM OT - Antileishmanial action OT - Immunomodulation OT - Leishmania OT - Macrophage OT - Pentalinon andrieuxii OT - Pentalinonsterol OT - Phospholipase A2 EDAT- 2021/08/14 06:00 MHDA- 2022/03/03 06:00 CRDT- 2021/08/13 12:24 PHST- 2021/02/21 00:00 [received] PHST- 2021/08/04 00:00 [accepted] PHST- 2021/08/14 06:00 [pubmed] PHST- 2022/03/03 06:00 [medline] PHST- 2021/08/13 12:24 [entrez] AID - 10.1007/s12013-021-01030-8 [pii] AID - 10.1007/s12013-021-01030-8 [doi] PST - ppublish SO - Cell Biochem Biophys. 2022 Mar;80(1):45-61. doi: 10.1007/s12013-021-01030-8. Epub 2021 Aug 13.