title: Curcumins promote monocytic gene expression related to β-amyloid and superoxide dismutase clearance.
abstract: Neurodegenerative diseases are associated with accumulation of modified proteins or peptides including amyloid-β (Aβ) in Alzheimer's disease (AD), and misfolded superoxide dismutase-1 (SOD-1) in amyotrophic lateral sclerosis (ALS). Clearance of Aβ or SOD-1 by the innate immune system may be important for controlling or preventing disease onset. Curcumins restore Aβ phagocytosis by peripheral blood mononuclear cells (PBMCs) from AD patients and Aβ clearance with upregulation of key genes including MGAT3, vitamin D receptor (VDR) and Toll-like receptors (TLRs). Certain curcumins inhibit inflammatory processes of PBMCs from ALS patients. We developed an in vitro system using human monocytes from patients and monocytic cell lines (i.e. U-937, THP-1) for evaluating curcuminoid potency of innate immune cell stimulation. Bisdemethoxycurcumin and certain analogs potentiated MGAT3,VDR and TLR gene expression 3- to 300-fold in U-937 cells. The effect of curcumins on inflammation in monocytes from patients with ALS was examined. Recursive medicinal chemistry was applied to identify compounds that stimulate the innate immune system for use in the clearance of Aβ in AD and the reversal of neuroinflammation and defective SOD-1 accumulation in ALS.
authors.affiliation: Human BioMolecular Research Institute, San Diego, Calif 92121, USA. Jcashman@HBRI.org
authors.forename: J R
authors.initials: JR
authors.lastname: Cashman
authors.forename: S
authors.initials: S
authors.lastname: Gagliardi
authors.forename: M
authors.initials: M
authors.lastname: Lanier
authors.forename: S
authors.initials: S
authors.lastname: Ghirmai
authors.forename: K J
authors.initials: KJ
authors.lastname: Abel
authors.forename: M
authors.initials: M
authors.lastname: Fiala
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism / Q000473:pathology*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D003474:Curcumin / Q000031:analogs & derivatives / Q000494:pharmacology*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D036381:Diarylheptanoids; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D009000:Monocytes / Q000187:drug effects*; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism*; D051193:Toll-Like Receptors / Q000235:genetics / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D036381:Diarylheptanoids; D012333:RNA, Messenger; D018167:Receptors, Calcitriol; D051193:Toll-Like Receptors; C034786:bisdemethoxycurcumin; D013482:Superoxide Dismutase; D017351:N-Acetylglucosaminyltransferases; C054599:beta-1,4-mannosyl-glycoprotein beta-1,4-N-acetylglucosaminyltransferase; D003474:Curcumin