China National Institute of Biological Sciences

Beijing, China

China National Institute of Biological Sciences

Beijing, China

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Patent
China National Institute of Biological Sciences | Date: 2016-10-24

The invention provides novel compounds and compositions for inhibiting IKK/, including treating disorders associated with IKK/ activity, including cancer, autoimmune and inflammatory disorders, with a compound of structure:


Patent
China National Institute of Biological Sciences | Date: 2016-10-13

The invention provides novel compounds and compositions comprising a 5-HT_(2B )antagonist of formula I: and related methods for treating a person having a disorder characterized by undesirable 5-HT_(2B )receptor signaling, such as migraine, irritable bowel syndrome (IBS), pulmonary arterial hypertension (PAH), fibrosis, hepatocellular cancer, a small intestinal neuroendocrine tumor, cardiovascular disorders, and gastrointestinal (GI) tract disorders.


Patent
China National Institute of Biological Sciences | Date: 2017-02-22

The invention provides novel compounds and compositions comprising a 5-HT2B antagonist of formula I and related methods for treating a person having a disorder characterized by undesirable 5-HT2B receptor signaling, such as migraine, irritable bowel syndrome (IBS), pulmonary arterial hypertension (PAH), fibrosis, hepatocellular cancer, a small intestinal neuroendocrine tumor, cardiovascular disorders, and gastrointestinal (GI) tract disorders.


Sun L.,CAS Shanghai Institutes for Biological Sciences | Wang X.,China National Institute of Biological Sciences
Trends in Biochemical Sciences | Year: 2014

Classically, there are two major forms of cell death: necrosis, an unregulated digestion of cellular components; and apoptosis, a programmed mechanism that is promoted by caspases. However, another form of cell death has recently been identified that is inhibited by caspases, and yet occurs through a regulated mechanism, termed programmed necrosis or necroptosis. The biochemical basis of this program has begun to emerge, with the discovery of the receptor-interacting kinase RIP3 and its substrate, the pseudokinase mixed lineage kinase domain-like protein (MLKL), as core components. Furthermore, animal models have revealed significant functions for RIP3/MLKL-mediated necrotic cell death in immune responses against microbial infection and in the etiology of diseases involving tissue damage. This review discusses recent advances in our understanding of the mechanistic details and physiological functions of programmed necrosis. © 2014 Elsevier Ltd.


Zhao Y.,China National Institute of Biological Sciences | Shao F.,China National Institute of Biological Sciences
Immunological Reviews | Year: 2015

Bacterial flagella and type III secretion system (T3SS) are evolutionarily related molecular transport machineries. Flagella mediate bacterial motility; the T3SS delivers virulence effectors to block host defenses. The inflammasome is a cytosolic multi-protein complex that activates caspase-1. Active caspase-1 triggers interleukin-1β (IL-1β)/IL-18 maturation and macrophage pyroptotic death to mount an inflammatory response. Central to the inflammasome is a pattern recognition receptor that activates caspase-1 either directly or through an adapter protein. Studies in the past 10 years have established a NAIP-NLRC4 inflammasome, in which NAIPs are cytosolic receptors for bacterial flagellin and T3SS rod/needle proteins, while NLRC4 acts as an adapter for caspase-1 activation. Given the wide presence of flagella and the T3SS in bacteria, the NAIP-NLRC4 inflammasome plays a critical role in anti-bacteria defenses. Here, we review the discovery of the NAIP-NLRC4 inflammasome and further discuss recent advances related to its biochemical mechanism and biological function as well as its connection to human autoinflammatory disease. © 2015 John Wiley & Sons A/S.


Wang Z.,University of Texas Southwestern Medical Center | Jiang H.,University of Texas Southwestern Medical Center | Jiang H.,China National Institute of Biological Sciences | Chen S.,China National Institute of Biological Sciences | And 3 more authors.
Cell | Year: 2012

The programmed necrosis induced by TNF-α requires the activities of the receptor-interacting serine-threonine kinases RIP1 and RIP3 and their interaction with the mixed lineage kinase domain-like protein MLKL. We report the identification of RIP1- and RIP3-containing protein complexes that form specifically in response to necrosis induction. One component of these complexes is the mitochondrial protein phosphatase PGAM5, which presents as two splice variants, PGAM5L (long form) and PGAM5S (short form). Knockdown of either form attenuated necrosis induced by TNF-α as well as reactive oxygen species (ROS) and calcium ionophore, whereas knockdown of RIP3 and MLKL blocked only TNF-α-mediated necrosis. Upon necrosis induction, PGAM5S recruited the mitochondrial fission factor Drp1 and activated its GTPase activity by dephosphorylating the serine 637 site of Drp1. Drp1 activation caused mitochondrial fragmentation, an early and obligatory step for necrosis execution. These data defined PGAM5 as the convergent point for multiple necrosis pathways. © 2012 Elsevier Inc.


Li J.,China National Institute of Biological Sciences
G3 (Bethesda, Md.) | Year: 2014

Nonhomologous end joining (NHEJ) is the main means for repairing DNA double-strand breaks (DSBs) in human cells. Molecular understanding of NHEJ has benefited from analyses in the budding yeast Saccharomyces cerevisiae and the fission yeast Schizosaccharomyces pombe. In human cells, the DNA ligation reaction of the classical NHEJ pathway is carried out by a protein complex composed of DNA ligase IV (LigIV) and XRCC4. In S. cerevisiae, this reaction is catalyzed by a homologous complex composed of Dnl4 and Lif1. Intriguingly, no homolog of XRCC4 has been found in S. pombe, raising the possibility that such a factor may not always be required for classical NHEJ. Here, through screening the ionizing radiation (IR) sensitivity phenotype of a genome-wide fission yeast deletion collection in both the vegetative growth state and the spore state, we identify Xrc4, a highly divergent homolog of human XRCC4. Like other fission yeast NHEJ factors, Xrc4 is critically important for IR resistance of spores, in which no homologous recombination templates are available. Using both extrachromosomal and chromosomal DSB repair assays, we show that Xrc4 is essential for classical NHEJ. Exogenously expressed Xrc4 colocalizes with the LigIV homolog Lig4 at the chromatin region of the nucleus in a mutually dependent manner. Furthermore, like their human counterparts, Xrc4 and Lig4 interact with each other and this interaction requires the inter-BRCT linker and the second BRCT domain of Lig4. Our discovery of Xrc4 suggests that an XRCC4 family protein is universally required for classical NHEJ in eukaryotes. Copyright © 2014 Li et al.


Li W.,China National Institute of Biological Sciences
Annual Review of Cell and Developmental Biology | Year: 2015

Hepatitis B virus (HBV) infection affects 240 million people worldwide. A liver-specific bile acid transporter named the sodium taurocholate cotransporting polypeptide (NTCP) has been identified as the cellular receptor for HBV and its satellite, the hepatitis D virus (HDV). NTCP likely acts as a major determinant for the liver tropism and species specificity of HBV and HDV at the entry level. NTCP-mediated HBV entry interferes with bile acid transport in cell cultures and has been linked with alterations in bile acid and cholesterol metabolism in vivo. The human liver carcinoma cell line HepG2, complemented with NTCP, now provides a valuable platform for studying the basic biology of the viruses and developing treatments for HBV infection. This review summarizes critical findings regarding NTCP's role as a viral receptor for HBV and HDV and discusses important questions that remain unanswered. © 2015 by Annual Reviews. All rights reserved.


Zhao Y.,China National Institute of Biological Sciences | Shao F.,China National Institute of Biological Sciences
Current Opinion in Microbiology | Year: 2016

The inflammasomes are emerging cytosolic defenses against bacterial infections. The inflammasomes converge on inflammatory caspases activation that triggers pyroptosis, and interleukin-1β/18 maturation in the case of caspase-1 activation. The inflammasomes not only detect major bacterial molecules but also sense bacterial virulence activity. Among the canonical caspase-1-activating inflammasomes, the NAIP subfamily of NLR proteins serves as the receptors for bacterial flagellin and type III secretion apparatus; Pyrin indirectly senses Rho modification/inactivation by various bacterial agents; NLRP1 in mice/rats detects the protease activity of anthrax lethal toxin by serving as its substrate. Caspase-11 and caspase-4/5 directly recognize bacterial LPS and then become activated. Inflammasome sensing of cytosolic bacteria employs much more diversified biochemical mechanisms, compared with Toll-like receptors-mediated recognition on the membrane. © 2015 Elsevier Ltd.


Patent
China National Institute of Biological Sciences | Date: 2014-01-04

Obesity is inhibited by administering to a person in need thereof an effective amount of entacapone ((2E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethylprop-2-enamide), or a pharmaceutically-acceptable salt thereof, particularly in conjunction with a second, different anti-obesity medicament. Pharmaceutical compositions comprise entacapone copackaged or coformulated with a second, different anti-obesity medicament.

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