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Biomedical subjects

Zheng Huang

Publications and source records attributed to Zheng Huang.

At least 19 recordsLinked to original sources
PubMed2007

Eliminating the longitudinal piston error between tiled gratings by angle tuning.

In a tiled-grating system, it is difficult to make two tiled gratings strictly coplanar. We propose and demonstrate for the first time, as far as we know, a simple method by which the longitudinal piston error between two tiled gratings can be reduced below lambda/10, close to the influence of the environmental factors. The alignment precision of the method increases with the tiled-grating system's stability to environmental factors.

Journal Article↗
PubMed2006

Identification of the proliferation/differentiation switch in the cellular network of multicellular organisms.

The protein-protein interaction networks, or interactome networks, have been shown to have dynamic modular structures, yet the functional connections between and among the modules are less well understood. Here, using a new pipeline to integrate the interactome and the transcriptome, we identified a pair of transcriptionally anticorrelated modules, each consisting of hundreds of genes in multicellular interactome networks across different individuals and populations. The two modules are associated with cellular proliferation and differentiation, respectively. The proliferation module is conserved among eukaryotic organisms, whereas the differentiation module is specific to multicellular organisms. Upon differentiation of various tissues and cell lines from different organisms, the expression of the proliferation module is more uniformly suppressed, while the differentiation module is upregulated in a tissue- and species-specific manner. Our results indicate that even at the tissue and organism levels, proliferation and differentiation modules may correspond to two alternative states of the molecular network and may reflect a universal symbiotic relationship in a multicellular organism. Our analyses further predict that the proteins mediating the interactions between these modules may serve as modulators at the proliferation/differentiation switch.

Animals↗
PubMed2006

Rapid measurement of deuterium-labeled long-chain fatty acids in plasma by HPLC-ESI-MS.

Imbalanced fatty acid metabolism contributes significantly to the increased incidence of metabolic disorders. Isotope-labeled fatty acids (2H, 13C) provide efficient means to trace fatty acid metabolism in vivo. This study reports a new and rapid method for the quantification of deuterium-labeled fatty acids in plasma by HPLC-MS. The sample preparation protocol developed required only hydrolysis, neutralization, and quenching steps followed by high-performance liquid chromatography-electrospray ionization-mass spectrometry analysis in negative ion mode using single ion monitoring. Deuterium-labeled stearic acid (d7-C18:0) was synthesized to reduce matrix interference observed with d5 analog, which improved the limit of detection (LOD) significantly, depending on the products analyzed. Linearity > 0.999 between the LOD (100 nM) and 30 microM, accuracy > 90%, precision > 88%, and adequate recovery in the dynamic range were obtained for d7-C18:0 and d7-oleic acid (C18:1). Upon oral dosing of d7-C18:0 in rats, the parent compound and its desaturation and beta-oxidation products, d7-C18:1 and d7-C16:0, were circulating with a maximal concentration ranging from 0.6 to 2.2 microM, with significant levels of d7-fatty acids detected for up to 72 h.

Chromatography, High Pressure Liquid↗
PubMed2006

Catalytic alkane metathesis by tandem alkane dehydrogenation-olefin metathesis.

With petroleum supplies dwindling, there is increasing interest in selective methods for transforming other carbon feedstocks into hydrocarbons suitable for transportation fuel. We report the development of highly productive, well-defined, tandem catalytic systems for the metathesis of n-alkanes. Each system comprises one molecular catalyst (a "pincer"-ligated iridium complex) that effects alkane dehydrogenation and olefin hydrogenation, plus a second catalyst (molecular or solid-phase) for olefin metathesis. The systems all show complete selectivity for linear (n-alkane) product. We report one example that achieves selectivity with respect to the distribution of product molecular weights, in which n-decane is the predominant high-molecular-weight product of the metathesis of two moles of n-hexane.

Journal Article↗
PubMed2006

Enantiomer discrimination illustrated by the high resolution crystal structures of type 4 phosphodiesterase.

Type 4 phosphodiesterase (PDE4) inhibitors are emerging as new treatments for a number of disorders including asthma and chronic obstructive pulmonary disease. Here we report the biochemical characterization on the second generation inhibitor (+)-1 (L-, IC50=0.4 nM) and its enantiomer (-)-1 (L-, IC50=43 nM) and their cocrystal structures with PDE4D at 2.0 A resolution. Despite the 107-fold affinity difference, both enantiomers interact with the same sets of residues in the rigid active site. The weaker (-)-1 adopts an unfavorable conformation to preserve the pivotal interactions between the Mg-bound waters and the N-oxide of pyridine. These structures support a model in which inhibitors are anchored by the invariant glutamine at one end and the metal-pocket residues at another end. This model provides explanations for most of the observed structure-activity relationship and the metal ion dependency of the catechol-ether based inhibitors and should facilitate their further design.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2006

Nitrogen-bridged substituted 8-arylquinolines as potent PDE IV inhibitors.

Potent inhibitors of the human PDE IV enzyme are described. Substituted 8-arylquinoline analogs bearing nitrogen-linked side chain were identified as potent inhibitors based on the SAR described herein. The pharmacokinetic profile of the best analog and the in vivo efficacy in an ovalbumin-induced bronchoconstriction assay in conscious guinea pigs are reported.

Animals↗
PubMed2006

Magnetic resonance imaging correlated with the histopathological effect of Pd-bacteriopheophorbide (Tookad) photodynamic therapy on the normal canine prostate gland.

BACKGROUND AND OBJECTIVE: To determine the optimal magnetic resonance imaging (MRI) methodology to assess photodynamic therapy (PDT)-induced histopathological responses in the prostate. STUDY DESIGN/MATERIALS AND METHODS: Laparotomy was performed in five healthy dogs. Cylindrical diffuser was placed in the prostates to deliver light of 50-300 J/cm at 150 mW/cm and 763 nm to activate IV-injected Tookad (1 mg/kg b.w.). Fast spin echo (FSE) T2-weighted, post-contrast-enhanced T1-(CE-T1) and diffusion weighted images (DWI) were obtained pre- and 2 days, 7 days, and 1 month post-PDT. Radiological-histopathological correlation was performed at 7 days (n = 4) and 1 month (n = 1) after PDT. A qualitative assessment of signal changes and apparent diffusion coefficient (ADC) mapping was performed. RESULTS: At 2 or 7 days post-PDT, there was good spatial correlation between PDT-induced hemorrhagic necrosis and unenhanced regions on CE-T1 images. There was a rapidly and persistently enhancing rim corresponding to edema and inflammation. FSE T2 and DWI showed altered signal but did not clearly define necrosis in all cases. At 1 month, it was hard to correlate MR images to histopathologic changes as they represented a mixture of necrosis and developing fibrosis, which led to a mixed signal intensity and less demarcated contrast enhancement. CONCLUSIONS: At 7 days after PDT, gadolinium DTPA contrast-enhanced MRI is superior to DWI and T2 imaging in assessing the boundary of Tookad PDT-induced tissue necrosis in the normal canine prostate.

Animals↗
PubMed2006

Photoimmunotherapy for cancer treatment.

Phototherapy, with its effective dose control and light delivery, has become a promising modality for treating malignant and nonmalignant diseases. Photochemical interaction, specifically photodynamic therapy (PDT), and photothermal interaction have been the primary mechanisms for direct cell destruction in the treatment of cancers. Preclinical studies demonstrate that, in addition to direct local cytotoxicity, PDT can also induce systemic immune responses, which may enhance therapeutic effects on primary tumors and on metastases at distant sites. Selective photothermal therapy, using an in situ application of light-absorbing dye, has also proven to be an effective method for local treatment of tumors. When combined with immunotherapy, the effects of phototherapy can be amplified, potentially making the photoimmunotherapy a systemic treatment modality. This phototherapy-immunotherapy combination, particularly in conjunction with immunoadjuvant, has been used in preclinical studies. The efficacy and long-term effects of such a combination are summarized and the recent experimental results are presented. A new immunoadjuvant, glycated chitosan (GC), has been used to enhance photochemical and photothermal therapies. The PDT-GC combination in the treatment of mammary tumors and lung tumors in mice provided significant improvement in the long-term survival of tumor-bearing animals. The use of GC in dye-assisted laser photothermal therapy also provided long-term curative effects and antitumor immune responses in the treatment of metastatic tumors in rats. The immune responses induced by phototherapy and enhanced by immunotherapy could become important mechanism in the control of metastatic tumors.

Adjuvants, Immunologic↗
PubMed2006

Phosphodiesterase 4 inhibitors for the treatment of asthma and COPD.

Type 4 cyclic nucleotide phosphodiesterases (PDE4s) are metallo-hydrolases which specifically hydrolyze cAMP to AMP in various cells types. The catalytic core is a bimetallic ion center composed of a tightly bound Zn(2+) and a loosely bound Mg(2+), which plays a dictating role in eliciting cAMP binding and catalysis activation. An invariant glutamine positioned opposite to the ion center serves as the substrate recognition determinant and synergizes the transient Mg-oxo-phosphate interaction in the substrate complex. The Mg(2+) binding is activated by a PKA-mediated serine phosphorylation and modulated through protein-protein interactions, thus, providing efficient mechanisms in the temporal regulation of cAMP signaling. Several PDE4 inhibitors including roflumilast, cilomilast and rolipram also rely on the interaction with the glutamine and metallic ion center for binding, with their affinity enhanced dramatically by the presence of the Mg(2+) ion. Recent studies have provided new insights into the role of this enzyme in inflammatory settings, CFTR regulation, long term potentiation, and its importance in immune surveillance. The major inflammatory cytokines which are modulated with PDE4 inhibitors include TNFalpha, IL-2, IFNgamma, IL-12, GM-CSF and LTB(4). The role of PDE4 inhibitors in modulating cytokines, lipid mediators and in mucociliary clearance, along with clinical efficacy in asthma and/or COPD demonstrated with roflumilast and cilomilast, suggest a broad anti-inflammatory spectrum for these compounds. Presently, the major impediment to approval of these novel therapies has been the mechanism based gastrointestinal adverse events which has limited the dosing and the ultimate efficacy with these novel therapeutic agents.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2005

Preferential inhibition of human phosphodiesterase 4 by ibudilast.

Ibudilast ophthalmic solution exhibited an improved clinical efficacy over cromoglycate in the treatment of allergic conjunctivitis. To further characterize its principal mode of action, the phosphodiesterase (PDE) inhibitory profile of ibudilast has been examined using human recombinant enzymes. Ibudilast, but not the other commonly used anti-allergic ophthalmic solutions including cromoglycate, ketotifen, tranilast and levocabastine, potently inhibits purified human PDE4A, 4B, 4C and 4D with IC50 values at 54, 65, 239 and 166 nM, respectively. Ibudilast effectively blocks lipopolysaccharide (LPS)-induced tumor necrosis factor (TNFalpha, IC50 = 6.2 microM) and N-formyl-Met-Leu-Phe (fMLP)-induced leukotriene (LT) B4 biosynthesis (IC50 = 2.5 microM) in human whole blood, which are 3 and 6-fold more potent than cilomilast, respectively. The attenuated inflammatory and allergic responses from the potent and preferential PDE4 inhibition of ibudilast may have contributed significantly to its beneficial pharmacological responses and distinguishes ibudilast from the other ophthalmic solutions in the treatment of ocular allergy.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2005

Discovery of a substituted 8-arylquinoline series of PDE4 inhibitors: structure-activity relationship, optimization, and identification of a highly potent, well tolerated, PDE4 inhibitor.

The discovery and SAR of a new series of substituted 8-arylquinoline PDE4 inhibitors are herein described. This work has led to the identification of several compounds with excellent in vitro and in vivo profiles, including a good therapeutic window of emesis to efficacy in several animal models. Typical optimized compounds from this series are potent inhibitors of PDE4 (IC(50)<1nM) and also of LPS-induced TNF-alpha release in human whole blood (IC(50)<0.5microM). The same compounds are potent inhibitors of ovalbumin-induced bronchoconstriction in conscious guinea pigs (EC(50)<0.1mg/kg ip) but require a dose of about 10mg/kg po in the squirrel monkey to produce an emetic response. From this series of compounds, 23a (L-454,560) was identified as an optimized compound.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2005

Dynamic activation of cystic fibrosis transmembrane conductance regulator by type 3 and type 4D phosphodiesterase inhibitors.

The diseases of cystic fibrosis, chronic obstructive pulmonary disease (COPD), and chronic bronchitis are characterized by mucus-congested and inflamed airways. Anti-inflammatory agents that can simultaneously restore or enhance mucociliary clearance through cystic fibrosis transmembrane conductance regulator (CFTR) activation may represent new therapeutics in their treatment. Herein, we report the activation of CFTR-mediated chloride secretion by phosphodiesterase (PDE) 4 inhibitors in T84 monolayer using (125)I anion as tracer. In the absence of forskolin, the iodide secretion was insensitive to PDE4 inhibitor L-826,141 [4-[2-(3,4-bis-difluoromethoxyphenyl)-2-[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl]-ethyl]-3-methylpyridine-1-oxide], roflumilast, or to PDE3 inhibitor trequinsin. However, these inhibitors potently augmented iodide secretion after forskolin stimulation, with efficacy coupled to the activation states of adenylyl cyclase. The iodide secretion from PDE3 or PDE4 inhibition was characterized at first by a prolonged efflux duration, followed by progressively elevated peak efflux rates at higher inhibitor concentrations. Paralleled with an increased phosphor-cAMP response element-binding protein formation, the CFTR activation dissociated from a global cAMP elevation and was blocked by H89 [N-[2-((p-bromocinnamyl)amino)ethyl]-5-isoquinolinesulfonamide]. 2-(4-Fluorophenoxy)-N-[(1S)-1-(4-methoxyphenyl)ethyl]nicotinamide, a stereoselective PDE4D inhibitor, augmented iodide efflux more efficiently than its less potent (R)-isomer. The peak efflux from maximal PDE4 and PDE3 inhibition matched that from full adenylyl cyclase activation. These data suggest that PDE3 and PDE4 (mainly PDE4D) form the major cAMP diffusion barrier in T84 cells to ensure a compartmentalized CFTR signaling. Together with their potent anti-inflammatory properties, the potentially enhanced airway mucociliary clearance from CFTR activation may have contributed to the efficacy of PDE4 inhibitors in COPD and asthmatic patients. PDE4 inhibitors may represent new opportunities to combat cystic fibrosis and other respiratory diseases in future.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2005

Isolation and characterization of Pseudomonas sp. strain HF-1, capable of degrading nicotine.

A nicotine-degrading bacterium, strain HF-1, was isolated from tobacco waste-contaminated soil and identified as a member of Pseudomonas sp. based on morphology, physiological tests, Vitek system (GN+), Biolog GN, 16S rDNA sequence and phylogenetic characteristics. The thermal denaturation test indicated that the G+C content of the DNA of HF-1 was 62.7 mol%. The relationship between growth and nicotine degradation of the isolate suggested that strain HF-1 could utilize nicotine as sole source of carbon, nitrogen and energy. Viridescent pigment was observed during nicotine degradation by strain HF-1. The isolate grew optimally at 30 degrees C, initial pH 6.5-7.5 and 1.3 g l(-1) of nicotine concentration in the nicotine inorganic salt medium, which is basically consistent with degradation of nicotine by the isolate. Strain HF-1 could degrade 99.6% of nicotine under the optimized incubation conditions for 25 h monitored by high-performance liquid chromatography. This study demonstrates that Pseudomonas sp. strain HF-1 had strong ability to degrade nicotine, and may be useful for bioremediation of environments contaminated by tobacco waste.

Bacterial Typing Techniques↗
PubMed2005

Studies of a vascular-acting photosensitizer, Pd-bacteriopheophorbide (Tookad), in normal canine prostate and spontaneous canine prostate cancer.

BACKGROUND AND OBJECTIVES: Photodynamic therapy (PDT) mediated with Tookad (Pd-bacteriopheophorbide, WST09) was investigated pre-clinically as part of a program to develop an alternative modality for treating prostate cancer. STUDY DESIGN/MATERIALS AND METHODS: Spontaneous canine prostate cancer and normal canine prostate were used as the animal models. Interstitial PDT was performed by IV infusion of the photosensitizer and irradiating the prostates with a diode laser (763 nm). The prostates were harvested 1-week post-PDT and subjected to histopathologic examinations. The effects of the drug doses and light doses were studied for one- and two-session PDT. Pharmacokinetics were studied using HPLC assay. The feasibility of using perfusing CT scans for assessing PDT lesions was also evaluated. RESULTS: Tookad is a vascular-acting drug and clears rapidly from the circulation. Tookad-PDT-induced lesions, in both normal and cancerous prostates, were characterized by marked hemorrhagic necrosis. CONCLUSIONS: Tookad-PDT is very effective in ablating prostatic tissue through its vascular effects.

Animals↗
PubMed2005

[Protective effects of losartan against myocardial ischemic reperfusion in intact canine].

OBJECTIVE: To evaluate the protective effect of losartan, an angiotensin II type 1 (AT1) receptor antagonist, against myocardial ischemic reperfusion in intact canine. METHODS: Sixteen dogs were divided into model group(n=8) with left anterior descending coronary artery occlusion for 30 min followed by reperfusion for 30 min and losartan group (n=8) with 5 mg/(kg x d) intragastric losartan administration for 2 weeks before the ischemic-reperfusion model establishment. Monophasic action potential recording technique was employed to observe the incidence of early after depolarization (EAD) and reperfusion arrhythmias. RESULTS: In the model group, 5 dogs (62.5%) developed EAD and reperfusion arrhythmia while 3 (37.5%) developed the symptoms in losartan group, showing significant difference between the two groups (P<0.05). No ventricular tachycardia or ventricular fibrillation was observed in losartan group (P<0.01). CONCLUSION: Losartan can suppress the occurrence of EAD during reperfusion following myocardial ischemia to reduce the incidence of reperfusion arrhythmias, suggesting its protective effect against myocardial ischemic injury.

Angiotensin II Type 1 Receptor Blockers↗