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: 2016-10-13

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: 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: 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.


Ma M.,Peking Union Medical College | Ma M.,China National Institute of Biological Sciences | Luo M.,China National Institute of Biological Sciences | Luo M.,Tsinghua University
Journal of Neuroscience | Year: 2012

The main olfactory bulb (MOB) in mammals receives massive centrifugal input from cholinergic neurons in the horizontal limb of the diagonal band of Broca (HDB)in the basal forebrain, the activity of which is thought to be correlated with animal behaving states, such as attention. Cholinergic signals in the bulb facilitate olfactory discrimination and learning, but it has remained controversial how the activity of HDB cholinergic neurons modulates neuronal excitability and olfactory responses in the MOB. In this study, we used an optogenetic approach to selectively activate HDB cholinergic neurons and recorded the effect of this activation on the spontaneous firing activity and odor-evoked responses of mouse MOB neurons. Cells were juxtacellularly labeled and their specific types were morphologically determined. We find that light stimulation of HDB cholinergic neurons inhibits the spontaneous firing activity of all major cell types, including mitral/tufted (M/T) cells, periglomerular (PG) cells, and GAB Aergic granule cells. Inhibitions are significantly produced by stimulation at 10 Hz and further enhanced at higher frequencies. In addition, cholinergic activation sharpens the olfactory tuning curves of a majority of M/T cells but broadly potentiates odor-evoked responses of PG cells and granule cells. These results demonstrate strong effects of the basal forebrain cholinergic system on modulating neuronal excitability in the MOB and support the hypothesis that cholinergic activity increases olfactory discrimination capability. © 2012 the authors.


Ge J.,China National Institute of Biological Sciences | Gong Y.-N.,China National Institute of Biological Sciences | Xu Y.,China National Institute of Biological Sciences | Shao F.,China National Institute of Biological Sciences
Proceedings of the National Academy of Sciences of the United States of America | Year: 2012

Legionella pneumophila, the causative agent of Legionnaires' pneumonia, resides in a distinct vacuole structure called Legionella-containing vacuole (LCV). The LCV resists fusion with the lysosome and permits efficient bacterial replication in host macrophages, which requires a Dot/Icm type IVB secretion system. Dot/Icm-translocated effector SdhA is critical for L. pneumophila intracellular growth and functions to prevent host cell death. Here, we show that the absence of SdhA resulted in elevated caspase-1 activation and IL-1β secretion as well as macrophage pyroptosis during Legionella infection. These inflammasome activation phenotypes were independent of the established flagellin-NAIP5-NLRC4 axis, but relied on the DNA-sensing AIM2 inflammasome. We further demonstrate that Legionella DNA was released into macrophage cytosol, and this effect was significantly exaggerated by the absence of SdhA. SdhA bears a functional Golgi-targeting GRIP domain that is required for preventing AIM2 inflammasome activation. Ectopically expressed SdhA formed a unique ring-shape membrane structure, further indicating a role in membrane trafficking and maintaining LCV membrane integrity. Our data together suggest a possible link, mediated by the function of SdhA, between LCV trafficking/maturation and suppression of host innate immune detection.


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.


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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