Biomedical subjects

Hongfeng Gao

Publications and source records attributed to Hongfeng Gao.

5 recordsLinked to original sources

PubMed2006

Design, synthesis, and biological evaluation of semicarbazide-sensitive amine oxidase (SSAO) inhibitors with anti-inflammatory activity.

In an attempt to examine the effect of inhibition of semicarbazide-sensitive amine oxidase (SSAO; EC 1.4.3.6, also known as VAP-1) as a novel anti-inflammatory target, the structure/mechanism based design and synthesis of a series of novel hydrazino-containing small molecules are described. The in vitro biological results show that compounds 4a,c are highly potent SSAO inhibitors with notable selectivity toward SSAO over monoamine oxidases A and B (MAO-A and MAO-B). SAR studies based on compound 4c were performed, and the results are discussed. The most potent and selective compound, 4a (IC(50) = 2 nM), is an orally active, competitive, and apparently irreversible inhibitor of SSAO that is effective at reducing disease incidence and severity in an in vivo animal disease model of multiple sclerosis.

Acute Disease↗

PubMed2005

Anti-inflammatory effects of inhibiting the amine oxidase activity of semicarbazide-sensitive amine oxidase.

Human semicarbazide-sensitive amine oxidase (SSAO) or vascular adhesion protein-1 (VAP-1) is a copper-containing amine oxidase (AOC3, EC 1.4.3.6) that has both enzymatic and adhesive function. SSAO catalyzes the oxidative deamination of primary amines, resulting in the formation of the corresponding aldehyde and release of hydrogen peroxide and ammonia. Membrane-bound SSAO is an inflammation-inducible endothelial cell adhesion molecule that mediates the interaction between leukocytes and activated endothelial cells in inflamed vessels. Both the direct adhesive and enzymatic functions seem to be involved in the adhesion cascade. LJP 1207 [N'-(2-phenyl-allyl)-hydrazine hydrochloride] is a potent (human SSAO IC(50) = 17 nM), selective, and orally available SSAO inhibitor that blocks both the enzymatic and adhesion functions of SSAO/VAP-1. In a mouse model of ulcerative colitis, LJP 1207 significantly reduces mortality, loss of body weight, and colonic cytokine levels. Quantitative histopathological assessment of colitis activity in this model showed a highly significant suppression of inflammation, injury, and ulceration scores in the animals treated with the SSAO/VAP-1 inhibitor. LJP 1207 also reduced serum levels of tumor necrosis factor-alpha and interleukin 6 in lipopolysaccharide (LPS)-challenged mice and prolonged survival post-LPS-induced endotoxemia. Therapeutic and prophylactic administration of LJP 1207 in the rat carrageenan footpad model also markedly inhibited swelling and inflammation. Overall, the data suggest that small molecule SSAO/VAP-1 inhibitors may provide clinical benefit in the treatment of acute and chronic inflammatory diseases.

Amine Oxidase (Copper-Containing)↗

PubMed2004

Asymmetry in visual cortical circuits underlying motion-induced perceptual mislocalization.

Motion signals in the visual field can cause strong biases in the perceived positions of stationary objects. Local motion signal within an object induces a shift in the perceived object position in the direction of motion, whereas adaptation to motion stimuli causes a perceptual shift in the opposite direction. The neural mechanisms underlying these illusions are poorly understood. Here we report two novel receptive field (RF) properties in cat primary visual cortex that may account for these motion-position illusions. First, motion signal in a stationary test stimulus causes a displacement of the RF in the direction opposite to motion. Second, motion adaptation induces a shift of the RF in the direction of adaptation. Comparison with human psychophysical measurements under similar conditions indicates that these RF properties can primarily account for the motion-position illusions. Importantly, both RF properties indicate a spatial asymmetry in the synaptic connections from direction-selective cells, and this circuit feature can be predicted by spike-timing-dependent synaptic plasticity, a widespread phenomenon in the nervous system. Thus, motion-induced perceptual mislocalization may be mediated by asymmetric cortical circuits, as a natural consequence of experience-dependent synaptic modification during circuit development.

Action Potentials↗

PubMed2002

Temporal specificity in the cortical plasticity of visual space representation.

The circuitry and function of mammalian visual cortex are shaped by patterns of visual stimuli, a plasticity likely mediated by synaptic modifications. In the adult cat, asynchronous visual stimuli in two adjacent retinal regions controlled the relative spike timing of two groups of cortical neurons with high precision. This asynchronous pairing induced rapid modifications of intracortical connections and shifts in receptive fields. These changes depended on the temporal order and interval between visual stimuli in a manner consistent with spike timing-dependent synaptic plasticity. Parallel to the cortical modifications found in the cat, such asynchronous visual stimuli also induced shifts in human spatial perception.

Action Potentials↗

PubMedDate not supplied

Spike timing-dependent synaptic plasticity in visual cortex: a modeling study.

Recent studies show that synaptic modification depends critically on the relative spike timing of pre- and postsynaptic neurons. Here we explore the functional implications of spike timing-dependent synaptic plasticity in the visual cortex using a model circuit with modifiable intracortical excitatory connections. First we simulated the experiments using two-point stimuli, in which two visual stimuli in a topographically represented feature space were repeatedly presented in quick succession, and found that tuning of the cortical neurons was modified in a manner similar to that observed experimentally. We then explored the dependence of results on the model parameter and identified the intracortical parameters that were critical for the magnitude of the shifts and obtained a simple relationship between the amount of shift and (S=(sigmaEXTCrec_exc)/sigmaINHCrec_inh). Finally we investigated the effects of moving stimuli in a topographically represented visual space and found that they can effectively induce spike timing-dependent modification of the intracortical connections. It suggests the importance of moving stimuli in dynamic modification of the cortical maps through spike timing-dependent synaptic plasticity.

Action Potentials↗