Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0276640 (TEM)
 20,729 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human familial lecithin:cholesterol acyltransferase (LCAT) deficiency (FLD) is characterized by low HDL, accumulation of an abnormal cholesterol-rich multilamellar particle called lipoprotein-X (LpX) in plasma, and renal disease. The aim of our study was to determine if LpX is nephrotoxic and to gain insight into the pathogenesis of FLD renal disease. We administered a synthetic LpX, nearly identical to endogenous LpX in its physical, chemical and biologic characteristics, to wild-type and Lcat-/- mice. Our in vitro and in vivo studies demonstrated an apoA-I and LCAT-dependent pathway for LpX conversion to HDL-like particles, which likely mediates normal plasma clearance of LpX. Plasma clearance of exogenous LpX was markedly delayed in Lcat-/- mice, which have low HDL, but only minimal amounts of endogenous LpX and do not spontaneously develop renal disease. Chronically administered exogenous LpX deposited in all renal glomerular cellular and matrical compartments of Lcat-/- mice, and induced proteinuria and nephrotoxic gene changes, as well as all of the hallmarks of FLD renal disease as assessed by histological, TEM, and SEM analyses. Extensive in vivo EM studies revealed LpX uptake by macropinocytosis into mouse glomerular endothelial cells, podocytes, and mesangial cells and delivery to lysosomes where it was degraded. Endocytosed LpX appeared to be degraded by both human podocyte and mesangial cell lysosomal PLA2 and induced podocyte secretion of pro-inflammatory IL-6 in vitro and renal Cxl10 expression in Lcat-/- mice. In conclusion, LpX is a nephrotoxic particle that in the absence of Lcat induces all of the histological and functional hallmarks of FLD and hence may serve as a biomarker for monitoring recombinant LCAT therapy. In addition, our studies suggest that LpX-induced loss of endothelial barrier function and release of cytokines by renal glomerular cells likely plays a role in the initiation and progression of FLD nephrosis.
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PMID:Lipoprotein X Causes Renal Disease in LCAT Deficiency. 2691 98

Natural products are important leads in drug discovery. The search for effective plant-derived agents or their synthetic analogues has continued to be of interest to biologists and chemists for a long time. Herein, we have synthesized a novel compound, P1C, and P1C-Tit*CAgNPs from chitosan; P1C is a precursor and an anti-inflammatory candidate, which has been validated by molecular docking studies. The synthesized P1C-Tit*CAgNPs showed monodisperse, spherical, and cationic nature and antioxidant properties, protecting destabilization of the erythrocyte membrane by the azo compound 2,2'-azobis(2-amidinopropane)dihydrochloride (AAPH); the involvement of NPs as a protective agent for biomolecules, such as DNA and protein, followed by the treatment of NPs with AAPH was confirmed. The inhibition of cellular damage and leakage of cellular inflammatory agents was confirmed by AFM, SEM, TEM, SDS-PAGE, LDH, and PLA2 enzyme inhibition via in vitro studies. The anti-inflammatory property of P1C was further validated by in silico molecular docking studies and showed that, the P1C best pose aligned to PLA2 compared to standard drug. The significant anticancer property of P1C-Tit*CAgNPs was confirmed against MCF7, U373, and C6 cancer cell lines. Thus, the present study highlights the synthesized P1C in P1C-Tit*CAgNPs as a target PLA2-specific anti-inflammatory candidate, and further tuning of small and development-functionalized nanoparticles has a great future in medicine; hence, their clinical applications are warranted.
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PMID:Development of piperazine-1-carbothioamide chitosan silver nanoparticles (P1C-Tit*CAgNPs) as a promising anti-inflammatory candidate: a molecular docking validation. 3010 62