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
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
Anika Prabhu, Insung Kang, Raffaella De Pace, Christopher A. Wassif, Hideji Fujiwara, Pamela Kell, Xuntian Jiang, Daniel S. Ory, Juan S. Bonifacino, Michael E. Ward, Forbes D. Porter
Summary: Niemann-Pick disease type C is a childhood-onset neurodegenerative disorder caused by mutations in NPC1 or NPC2 genes. A novel human iPSC-derived neuronal model of NPC1 has been developed, recapitulating key pathological features and showing potential for high-throughput drug screening.
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
Pharmacology & Pharmacy
Shiqian Han, Huiwen Zhang, Mengni Yi, Xiaoqing Liu, Gustavo H. B. Maegawa, Yunding Zou, Qijun Wang, Dianqing Wu, Zhijia Ye
Summary: This study evaluated the safety and feasibility of lithium carbonate in NP-C1 patients and found that lithium treatment significantly reduced plasma 7-ketocholesterol concentrations, improved NPC Neurological Severity Scores, and enhanced swallowing capacity. Patients tolerated lithium well with no serious adverse events recorded.
FRONTIERS IN PHARMACOLOGY
(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)
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)
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
Niamh X. Cawley, Anna T. Lyons, Daniel Abebe, Rachel Luke, Julia Yerger, Rebecca Telese, Christopher A. Wassif, Joan E. Bailey-Wilson, Forbes D. Porter
Summary: Complex asparagine-linked glycosylation plays a critical role in cellular functions. The deficiency of MGAT5, a key enzyme involved in this process, leads to increased severity of NPC1 disease in mice. The reduction in asparagine-linked glycosylation is associated with the progression of NPC1 disease.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
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)
Article
Genetics & Heredity
Beth I. Solomon, Andrea M. Munoz, Ninet Sinaii, Nicole M. Farhat, Andrew C. Smith, Simona Bianconi, An Dang Do, Michael C. Backman, Leonza Machielse, Forbes D. Porter
Summary: This study provides a comprehensive characterization of phenotypic spectrum and progression of swallowing dysfunction in NPC1, serving as a foundation for clinical management and future therapeutics.
ORPHANET JOURNAL OF RARE DISEASES
(2022)
Article
Biology
Toru Yasuda, Toru Uchiyama, Nobuyuki Watanabe, Noriko Ito, Kazuhiko Nakabayashi, Hideki Mochizuki, Masafumi Onodera
Summary: Niemann-Pick disease type C1 (NPC1) is a fatal lysosomal storage disorder characterized by progressive neuronal degeneration. Cell transplantation and manipulation of the immune system have been found to ameliorate NPC1 phenotypes in mice, highlighting the role of the peripheral immune system in neuropathogenesis. Specifically, regulatory T cells have a neuroprotective effect, while circulating inflammatory monocytes contribute to the progression of neuronal degeneration.
LIFE SCIENCE ALLIANCE
(2023)
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.
Article
Medicine, Research & Experimental
Anna Scotto Rosato, Einar K. Krogsaeter, Dawid Jaslan, Carla Abrahamian, Sandro Montefusco, Chiara Soldati, Barbara Spix, Maria Teresa Pizzo, Giuseppina Grieco, Julia Boeck, Amanda Wyatt, Daniela Wuenkhaus, Marcel Passon, Marc Stieglitz, Marco Keller, Guido Hermey, Sandra Markmann, Doris Gruber-Schoffnegger, Susan Cotman, Ludger Johannes, Dennis Crusius, Ulrich Boehm, Christian Wahl-Schott, Martin Biel, Franz Bracher, Elvira De Leonibus, Elena Polishchuk, Diego L. Medina, Dominik Paquet, Christian Grimm
Summary: This study found that TPC2 activation can improve cellular phenotypes associated with LSDs, including cholesterol or lipofuscin accumulation and abnormal vacuole formation. Validation in patient cells and mouse models suggests that TPC2 is a promising target for the treatment of different types of LSDs.
EMBO MOLECULAR MEDICINE
(2022)
Article
Multidisciplinary Sciences
Yuzhe Weng, Dawn Shepherd, Yi Liu, Nitya Krishnan, Brian D. Robertson, Nick Platt, Gerald Larrouy-Maumus, Frances M. Platt
Summary: Lipids shed by pathogenic mycobacteria inhibit the NPC1 pathway, which is crucial for the evolution of pathogenicity and disease progression.
NATURE COMMUNICATIONS
(2022)
Article
Cell Biology
Xiaojie Liu, Minnan Zhao, Xue Sun, Zhenzhen Meng, Xiaojing Bai, Yanchao Gong, Limei Xu, Xiaohe Hao, Tingting Yang, Zhao Wei, Xiyu Zhang, Haiyang Guo, Peishan Li, Qiao Liu, Yaoqin Gong, Yufang Shi, Changshun Shao
Summary: Solid tumors are often associated with extracellular acidosis, causing cancer cells to become more aggressive in acidic microenvironment. Antioxidant supplementation can abolish the increased sensitivity of NF-kappa B inhibition in CRC-AA. Secretory factors from cancer cells adapted to acidic stress, like soluble ICAM-1, also have cytoprotective effects.
OXIDATIVE MEDICINE AND CELLULAR LONGEVITY
(2021)
Article
Cell Biology
Liping Chu, Yuxiu Qu, Yang An, Linjun Hou, Juewan Li, Weijia Li, Gaofeng Fan, Bao-Liang Song, En Li, Liye Zhang, Wei Qi
Summary: This study investigates the pharmacological mechanism of the PRC2 inhibitor MAK683 and identifies a group of senescence-associated genes that are derepressed upon PRC2 inhibition, leading to tumor regression and improved therapeutic efficacy. Furthermore, the combination of PRC2 inhibitors and CDK4/6 inhibitors shows even better effects, providing a novel strategy for clinical treatment.
CELL DEATH & DISEASE
(2022)
Article
Endocrinology & Metabolism
Yu Song, Wenying Zan, Liping Qin, Shuang Han, Lili Ye, Molin Wang, Baichun Jiang, Pan Fang, Qiji Liu, Changshun Shao, Yaoqin Gong, Peishan Li
Summary: The study reveals that ORMDL3 plays an important role in the regulation of brown adipose tissue thermogenesis, white adipose tissue browning, and insulin resistance.
MOLECULAR METABOLISM
(2022)
Review
Biochemistry & Molecular Biology
Qing Li, Ying Wang, Qiang Sun, Jasmin Knopf, Martin Herrmann, Liangyu Lin, Jingting Jiang, Changshun Shao, Peishan Li, Xiaozhou He, Fei Hua, Zubiao Niu, Chaobing Ma, Yichao Zhu, Giuseppe Ippolito, Mauro Piacentini, Jerome Estaquier, Sonia Melino, Felix Daniel Weiss, Emanuele Andreano, Eicke Latz, Joachim L. Schultze, Rino Rappuoli, Alberto Mantovani, Tak Wah Mak, Gerry Melino, Yufang Shi
Summary: This article reviews the unprecedented impact of COVID-19 on our daily lives and quality of life over a period of more than two years, focusing on the changes in immune response, virus mutations, vaccines, and treatment strategies. The authors predict that with the use of existing and emerging technologies, we will be able to control the COVID-19 pandemic.
CELL DEATH AND DIFFERENTIATION
(2022)
Article
Cell Biology
Junjie Jiang, Haiyue Tu, Peishan Li
Summary: This article reviews the dynamic regulation of lipid metabolism in neutrophils, with a focus on the key regulators involved. It describes how alterations in lipid metabolism are intertwined with different signaling pathways orchestrating neutrophil functions during pathogen defense, tissue repair and tumor metastasis.
CELLULAR IMMUNOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Zhi-Ping Qiu, Zi-Cun Lin, Ao Hu, Yuan-Bin Liu, Wan-Er Zeng, Xiaolu Zhao, Xiong-Jie Shi, Jie Luo, Bao-Liang Song
Summary: The Hedgehog (Hh) signaling pathway is important for embryonic development. The interaction between Hh and PTCH1 regulates the activity of SMO, a key protein in the pathway. Cholesterol modification of SMO in the endoplasmic reticulum (ER) is regulated by Hh and PTCH1, and it affects the localization and function of SMO. The transport of cholesterol by GRAMD1/ASTER proteins plays a role in SMO maturation and Hh signaling.
Article
Cell Biology
Yayun Ding, Pixia Gong, Junjie Jiang, Chao Feng, Yanan Li, Xiao Su, Xiaojing Bai, Chenchang Xu, Chunxiao Liu, Jianxin Yang, Jiankai Fang, Xiaocao Ji, Yongjing Chen, Peishan Li, Lingchuan Guo, Changshun Shao, Yufang Shi
Summary: Subcutaneous application of MSCs-IT primed by IFN-gamma and TNF-alpha exhibits remarkable therapeutic efficacy on IMQ-induced psoriasis-like inflammation in mice, possibly by reducing neutrophil infiltration and CXCL1 expression mediated by TSG-6.
CELL DEATH & DISEASE
(2022)
Article
Cell Biology
Pixia Gong, Yayun Ding, Rongrong Sun, Zishan Jiang, Wen Li, Xiao Su, Ruifeng Tian, Yipeng Zhou, Tingting Wang, Junjie Jiang, Peishan Li, Changshun Shao, Yufang Shi
Summary: The study found that MSCs pretreated with IFN-γ and TNF-α can effectively alleviate skin fibrosis in a bleomycin-induced SSc model, reduce macrophage accumulation, and decrease the number of mature macrophages expressing CCR2 by inhibiting the generation of CCL2.
CELL DEATH DISCOVERY
(2022)
Article
Cell Biology
Yu-Xia Zhou, Jian Wei, Gang Deng, Ao Hu, Pu-Yu Sun, Xiaolu Zhao, Bao-Liang Song, Jie Luo
Summary: This study identifies an intracellular transport pathway of LDL-LDL receptor that bypasses lysosomes and delivers cholesterol to mitochondria for steroidogenesis.
NATURE CELL BIOLOGY
(2023)
Review
Biochemistry & Molecular Biology
Jiankai Fang, Wangwang Chen, Pengbo Hou, Zhanhong Liu, Muqiu Zuo, Shisong Liu, Chao Feng, Yuyi Han, Peishan Li, Yufang Shi, Changshun Shao
Summary: Nicotinamide adenine dinucleotide (NAD(+)) is an essential molecule in energy metabolism, and it also plays a role in immune response and inflammatory diseases. This review explores the biochemistry of NAD(+) and its impact on the immune system, as well as the potential of NAD(+) research in developing therapeutics for inflammatory diseases, including COVID-19.
CELL AND BIOSCIENCE
(2023)
Article
Biochemistry & Molecular Biology
Nan Zhao, Gang Deng, Pei-Xin Yuan, Ya-Fen Zhang, Lu-Yi Jiang, Xiaolu Zhao, Bao-Liang Song
Summary: The previously unannotated protein TMEM241 is found to play a crucial role in cholesterol egress from lysosomes. It transports UDP-N-acetylglucosamine (UDP-GlcNAc) into the Golgi lumen, which is used for the modification of proteins like NPC2. Loss of TMEM241 leads to cholesterol accumulation in lysosomes due to impaired lysosomal targeting of NPC2.
JOURNAL OF LIPID RESEARCH
(2023)
Article
Biochemistry & Molecular Biology
Zhanhong Liu, Pengbo Hou, Jiankai Fang, Jingyu Zhu, Juanmin Zha, Rui Liu, Yayun Ding, Muqiu Zuo, Peishan Li, Lijuan Cao, Chao Feng, Gerry Melino, Changshun Shao, Yufang Shi
Summary: Chemotherapy resistance in breast cancer can be induced by mesenchymal stromal cells (MSCs) through reducing the intratumoral accumulation of doxorubicin. This resistance is mediated by hyaluronan (HA), a major extracellular matrix (ECM) product of MSCs, which can bind with doxorubicin and inhibit its entry into breast cancer cells. High levels of HA in the serum are positively associated with chemoresistance in breast cancer patients.
Review
Biochemistry & Molecular Biology
Yanan Li, Sara Giovannini, Tingting Wang, Jiankai Fang, Peishan Li, Changshun Shao, Ying Wang, Yufang TOR Ctr, Yufang Shi, Eleonora Candi, Gerry Melino, Francesca Bernassola
Summary: Epithelial tissue homeostasis is closely associated with the self-renewal and differentiation behaviors of epithelial stem cells (ESCs). p63, a well-known marker of ESCs, regulates the transcription of genes involved in cell survival, stem cell self-renewal, migration, differentiation, and epithelial-to-mesenchymal transition. p63 plays a crucial role in normal epithelial development and epithelium-derived cancer pathogenesis.
Article
Cell Biology
Muqiu Zuo, Jiankai Fang, Peiqing Huang, Shisong Liu, Pengbo Hou, Shiqing Wang, Zhanhong Liu, Chao Feng, Lijuan Cao, Peishan Li, Yufang Shi, Changshun Shao
Summary: Muscle stem cells (MuSCs) exhibit therapeutic efficacy by regulating inflammatory microenvironments, but the mechanism underlying their immunoregulatory property is not well characterized. This study demonstrated that IL4I1, an essential enzyme in indole metabolism, was highly expressed in human MuSCs treated with IFN-γ and TNF-α. MuSCs inhibited neutrophil infiltration and ameliorated acute lung injury in mice through an IL4I1-dependent manner. Mechanistically, IL4I1-produced indole metabolites acted as ligands to activate aryl hydrocarbon receptor (AHR), increasing the expression of TNF-stimulated gene 6 (TSG-6) in inflammatory cytokine-primed MuSCs. Additionally, administration of indole-3-pyruvic acid (I3P) alone suppressed neutrophil infiltration and reduced reactive oxygen species levels in neutrophils. This study reveals a novel mechanism by which MuSCs acquire their immunoregulatory property and provides insights for developing MuSC-based therapies for inflammatory diseases.
CELL DEATH DISCOVERY
(2023)
Review
Immunology
Peishan Li, Qianmin Ou, Songtao Shi, Changshun Shao
Summary: Mesenchymal stem/stromal cells (MSCs) are widely distributed in the body and can be used for the treatment of autoimmune diseases and other chronic disorders. Dental stem cells (DSCs) have remarkable immunomodulatory properties and have therapeutic effects on systemic inflammatory diseases. MSCs derived from nondental tissues, such as the umbilical cord, also show benefits in the management of periodontitis in preclinical studies.
CELLULAR & MOLECULAR IMMUNOLOGY
(2023)