Article
Chemistry, Medicinal
Renshuai Zhang, Wenjing Liu, Jun Zeng, Jingsen Meng, Hongfei Jiang, Jie Wang, Dongming Xing
Summary: Cholesterol is a critical component of cell membranes, but elevated serum cholesterol levels are a major risk factor for heart disease. Understanding and developing NPC1L1 inhibitors, which can decrease cholesterol absorption, is an important research direction that presents both challenges and exciting therapeutic opportunities.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Multidisciplinary Sciences
Shiqian Han, Qijun Wang, Yongfeng Song, Mao Pang, Chunguang Ren, Jing Wang, Dongwei Guan, Wei Xu, Fangyong Li, Fengchao Wang, Xinyuan Zhou, Carlos Fernandez-Hernando, Huiwen Zhang, Dianqing Wu, Zhijia Ye
Summary: Niemann-Pick disease type C (NP-C) is a genetic lysosomal disorder with limited therapeutic options. This study demonstrates that lithium treatment improves phenotypes and extends survival in NP-C mouse models by suppressing STING activation, SREBP2 processing, and target gene expression. Lithium impedes STING/SREBP2 transport, providing a mechanistic explanation for its effects. This reveals a potential therapeutic option for NP-C patients and a strategy to reduce active STING/SREBP2 pathway.
Article
Biochemistry & Molecular Biology
Jun Zeng, Wenjing Liu, Bing Liang, Lingyu Shi, Shanbo Yang, Jingsen Meng, Jing Chang, Xiaokun Hu, Renshuai Zhang, Dongming Xing
Summary: This study found that isoliquiritigenin (ISL) can lower cholesterol levels by downregulating NPC1L1 expression and competitively inhibiting cellular cholesterol uptake. This provides a theoretical basis for further investigating the molecular mechanisms of its cholesterol-lowering effect and inspires new drug research for cholesterol-lowering purposes through NPC1L1 inhibition.
Review
Chemistry, Medicinal
Marcos Morales-Tenorio, Tiziana Ginex, Miguel Angel Cuesta-Geijo, Nuria E. Campillo, Cesar Munoz-Fontela, Covadonga Alonso, Rafael Delgado, Carmen Gil
Summary: The Niemann-Pick C1 (NPC1) receptor plays a crucial role in regulating intracellular cholesterol trafficking and facilitating the entry of Ebola virus into host cells. Disruption of the NPC1/EBOV-GP interaction could be a promising strategy for developing drugs to inhibit viral entry and infection, although further research is needed to understand the molecular and structural details of this interaction.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Nina H. Pipalia, Syed Z. Saad, Kanagaraj Subramanian, Abigail Cross, Aisha Al-Motawa, Kunal Garg, Brian S. J. Blagg, Len Neckers, Paul Helquist, Olaf Wiest, Daniel S. Ory, Frederick R. Maxfield
Summary: Inhibition of HSP90 clears cholesterol from LE/Ly in NPC1(I1061T) fibroblasts and enhances delivery of mutant NPC1(I1061T) protein. Additionally, HSP90 inhibition increases HSP70 expression, and overexpression of HSP70 reduces cholesterol storage in NPC1(I1061T) fibroblasts. This suggests that HSP90 inhibitors may improve NPC1 protein folding and relieve cholesterol accumulation in NPC1 mutant fibroblasts by increasing other chaperones.
JOURNAL OF LIPID RESEARCH
(2021)
Article
Oncology
Kiersten Campbell, Niamh X. Cawley, Rachel Luke, Katelin E. J. Scott, Nicholas Johnson, Nicole Y. Farhat, Derek Alexander, Christopher A. Wassif, Wenping Li, Stephanie M. Cologna, Elizabeth Berry-Kravis, An Dang Do, Ryan K. Dale, Forbes D. Porter
Summary: This study compared cerebrospinal fluid samples from individuals with NPC1 and non-NPC1 samples, and identified multiple proteins with altered levels in CSF from individuals with NPC1. Correlations between these proteins and clinically relevant phenotypic parameters were also observed. These findings may provide useful data for therapeutic trials of NPC1.
BIOMARKER RESEARCH
(2023)
Review
Biochemistry & Molecular Biology
Christin Voelkner, Maik Liedtke, Andreas Hermann, Moritz J. Frech
Summary: Niemann-Pick disease Type C1 and C2 are rare disorders caused by mutations in the NPC1 or NPC2 gene, leading to cholesterol accumulation in late endosomes and lysosomes. Clinical manifestations include neurological and systemic symptoms. iPSCs are a valuable tool for disease modeling and drug discovery in NPC1 research.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Review
Neurosciences
Maria Teresa Fiorenza, Piergiorgio La Rosa, Sonia Canterini, Robert P. Erickson
Summary: Selective neuronal vulnerability is a common feature in degenerative disorders. This article focuses on the vulnerability of the cerebellum in Niemann-Pick C (NPC), discussing the impact of altered intracellular cholesterol trafficking on the development and functional maturation of cerebellar cells. The article also addresses the progression of cerebellar defects and the persistence of these defects in mouse models despite genetic manipulations.
Article
Biochemistry & Molecular Biology
Anouk G. Groenen, Anouk M. La Rose, Mengying Li, Venetia Bazioti, Arthur F. Svendsen, Niels J. Kloosterhuis, Albertina Ausema, Alle Pranger, M. Rebecca Heiner-Fokkema, Klary E. Niezen-Koning, Tom Houben, Ronit Shiri-Sverdlov, Marit Westerterp
Summary: This study found that elevated G-CSF levels and HSC mobilization may contribute to splenomegaly in patients with NPC1 disease.
JOURNAL OF LIPID RESEARCH
(2022)
Article
Medicine, Research & Experimental
Denzil Furtado, Christina Cortez-Jugo, Ya Hui Hung, Ashley I. Bush, Frank Caruso
Summary: Researchers successfully used NPC1-encoded mRNA to combat protein insufficiency and pathogenic phenotype caused by biallelic NPC1 mutations, achieving treatment for the rare disease NP-C1. The gene engineering strategies greatly improved the expression efficiency of the mRNA.
MOLECULAR PHARMACEUTICS
(2022)
Article
Biology
Cristin D. Davidson, Alana L. Gibson, Tansy Gu, Laura L. Baxter, Benjamin E. Deverman, Keith Beadle, Arturo A. Incao, Jorge L. Rodriguez-Gil, Hideji Fujiwara, Xuntian Jiang, Randy J. Chandler, Daniel S. Ory, Viviana Gradinaru, Charles P. Venditti, William J. Pavan
Summary: Niemann-Pick C1 disease (NPC1) is a rare, fatal neurodegenerative disease caused by mutations in NPC1 gene, resulting in cholesterol accumulation in lysosomes and leading to neurological complications. AAV-PHP.B vector shows greater efficiency in transducing the central nervous system of Npc1 mutant mice compared to AAV9, indicating potential for improved gene therapy in NPC1.
LIFE SCIENCE ALLIANCE
(2021)
Article
Biochemistry & Molecular Biology
Carsten Holzmann, Martin Witt, Arndt Rolfs, Veronica Antipova, Andreas Wree
Summary: In a mouse model of Niemann-Pick disease type C1 (NPC1), combination treatment (COMBI) and individual treatments with MIGLU or HPssCD were beneficial in terms of body and brain weight, with differences observed based on gender. While all treatments had some beneficial effects on evaluated parameters, locomotor activity reduction was not significantly improved.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Multidisciplinary Sciences
Ting-Ting Chu, Xintao Tu, Kun Yang, Jianjun Wu, Joyce J. Repa, Nan Yan
Summary: This study identifies a cGAS- and cGAMP-independent mode of STING activation that affects neuropathology and provides a therapeutic target for the treatment of Niemann-Pick disease type C.
Article
Pharmacology & Pharmacy
Jiang Du, Xinlei Liu, Yan Zhang, Xiaojing Han, Chunya Ma, Yanli Liu, Lihong Guan, Liang Qiao, Juntang Lin
Summary: This study found that combination treatment with HP beta CD and metformin did not prolong survival time or increase body weight in Npc1(-/-) mice, but it reduced inflammatory response.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Medicine, Research & Experimental
Yoshihide Yamanashi, Tappei Takada, Yusuke Tanaka, Yutaka Ogata, Yu Toyoda, Sayo M. Ito, Maiko Kitani, Natsumi Oshida, Kosuke Okada, Junichi Shoda, Hiroshi Suzuki
Summary: This study found that among major dietary oxysterols, 22R-OHC and 25-OHC are particularly potent in promoting the progression of hepatic steatosis, and this effect is dependent on hepatic NPC1L1.
BIOMEDICINE & PHARMACOTHERAPY
(2022)
