PMID- 37239992 OWN - NLM STAT- MEDLINE DCOM- 20230529 LR - 20240302 IS - 1422-0067 (Electronic) IS - 1422-0067 (Linking) VI - 24 IP - 10 DP - 2023 May 12 TI - Development of Procathepsin L (pCTS-L)-Inhibiting Lanosterol-Carrying Liposome Nanoparticles to Treat Lethal Sepsis. LID - 10.3390/ijms24108649 [doi] LID - 8649 AB - The pathogenesis of microbial infections and sepsis is partly attributable to dysregulated innate immune responses propagated by late-acting proinflammatory mediators such as procathepsin L (pCTS-L). It was previously not known whether any natural product could inhibit pCTS-L-mediated inflammation or could be strategically developed into a potential sepsis therapy. Here, we report that systemic screening of a NatProduct Collection of 800 natural products led to the identification of a lipophilic sterol, lanosterol (LAN), as a selective inhibitor of pCTS-L-induced production of cytokines [e.g., Tumor Necrosis Factor (TNF) and Interleukin-6 (IL-6)] and chemokines [e.g., Monocyte Chemoattractant Protein-1 (MCP-1) and Epithelial Neutrophil-Activating Peptide (ENA-78)] in innate immune cells. To improve its bioavailability, we generated LAN-carrying liposome nanoparticles and found that these LAN-containing liposomes (LAN-L) similarly inhibited pCTS-L-induced production of several chemokines [e.g., MCP-1, Regulated upon Activation, Normal T Cell Expressed and Presumably Secreted (RANTES) and Macrophage Inflammatory Protein-2 (MIP-2)] in human blood mononuclear cells (PBMCs). In vivo, these LAN-carrying liposomes effectively rescued mice from lethal sepsis even when the first dose was given at 24 h post the onset of this disease. This protection was associated with a significant attenuation of sepsis-induced tissue injury and systemic accumulation of serval surrogate biomarkers [e.g., IL-6, Keratinocyte-derived Chemokine (KC), and Soluble Tumor Necrosis Factor Receptor I (sTNFRI)]. These findings support an exciting possibility to develop liposome nanoparticles carrying anti-inflammatory sterols as potential therapies for human sepsis and other inflammatory diseases. FAU - Chen, Weiqiang AU - Chen W AD - The Feinstein Institutes for Medical Research, Northwell Health, 350 Community Drive, Manhasset, New York, NY 11030, USA. AD - Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, 500 Hofstra Blvd., Hempstead, New York, NY 11549, USA. FAU - Zhu, Cassie Shu AU - Zhu CS AD - The Feinstein Institutes for Medical Research, Northwell Health, 350 Community Drive, Manhasset, New York, NY 11030, USA. AD - Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, 500 Hofstra Blvd., Hempstead, New York, NY 11549, USA. FAU - Qiang, Xiaoling AU - Qiang X AUID- ORCID: 0000-0001-9176-7407 AD - The Feinstein Institutes for Medical Research, Northwell Health, 350 Community Drive, Manhasset, New York, NY 11030, USA. AD - Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, 500 Hofstra Blvd., Hempstead, New York, NY 11549, USA. FAU - Chen, Shujin AU - Chen S AD - The Feinstein Institutes for Medical Research, Northwell Health, 350 Community Drive, Manhasset, New York, NY 11030, USA. FAU - Li, Jianhua AU - Li J AD - The Feinstein Institutes for Medical Research, Northwell Health, 350 Community Drive, Manhasset, New York, NY 11030, USA. FAU - Wang, Ping AU - Wang P AD - The Feinstein Institutes for Medical Research, Northwell Health, 350 Community Drive, Manhasset, New York, NY 11030, USA. AD - Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, 500 Hofstra Blvd., Hempstead, New York, NY 11549, USA. FAU - Tracey, Kevin J AU - Tracey KJ AD - The Feinstein Institutes for Medical Research, Northwell Health, 350 Community Drive, Manhasset, New York, NY 11030, USA. AD - Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, 500 Hofstra Blvd., Hempstead, New York, NY 11549, USA. FAU - Wang, Haichao AU - Wang H AUID- ORCID: 0000-0002-0211-9000 AD - The Feinstein Institutes for Medical Research, Northwell Health, 350 Community Drive, Manhasset, New York, NY 11030, USA. AD - Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, 500 Hofstra Blvd., Hempstead, New York, NY 11549, USA. LA - eng GR - R01GM063075/GM/NIGMS NIH HHS/United States GR - R01AT005076/AT/NCCIH NIH HHS/United States GR - R35GM145331/GM/NIGMS NIH HHS/United States GR - R01 AT005076/AT/NCCIH NIH HHS/United States GR - R35 GM145331/GM/NIGMS NIH HHS/United States GR - R01 GM063075/GM/NIGMS NIH HHS/United States PT - Journal Article DEP - 20230512 PL - Switzerland TA - Int J Mol Sci JT - International journal of molecular sciences JID - 101092791 RN - 0 (Liposomes) RN - EC 3.4.22.- (procathepsin L) RN - 1J05Z83K3M (Lanosterol) RN - 0 (Interleukin-6) RN - 0 (Cytokines) RN - 0 (Chemokines) SB - IM MH - Mice MH - Humans MH - Animals MH - *Liposomes/therapeutic use MH - Lanosterol/therapeutic use MH - Interleukin-6 MH - Cytokines MH - Chemokines MH - *Sepsis/pathology PMC - PMC10217857 OTO - NOTNLM OT - inflammation OT - innate immune cells OT - lanosterol OT - liposome OT - procathepsin-L OT - sepsis COIS- H.W., K.J.T. and J.L. are co-inventors of a provisional patent application entitled "Use of procathepsin L (pCTS-L)-inhibiting lanosterol-carrying liposome nanoparticles to treat lethal sepsis" (filed on 10 May 2023). All other co-authors do not have any conflicts of interest to declare. EDAT- 2023/05/27 09:42 MHDA- 2023/05/29 06:42 PMCR- 2023/05/12 CRDT- 2023/05/27 01:14 PHST- 2023/04/11 00:00 [received] PHST- 2023/05/03 00:00 [revised] PHST- 2023/05/10 00:00 [accepted] PHST- 2023/05/29 06:42 [medline] PHST- 2023/05/27 09:42 [pubmed] PHST- 2023/05/27 01:14 [entrez] PHST- 2023/05/12 00:00 [pmc-release] AID - ijms24108649 [pii] AID - ijms-24-08649 [pii] AID - 10.3390/ijms24108649 [doi] PST - epublish SO - Int J Mol Sci. 2023 May 12;24(10):8649. doi: 10.3390/ijms24108649.