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Biomedical subjects

Guohua Zhao

Publications and source records attributed to Guohua Zhao.

29 records · Page 2Linked to original sources
PubMed2004

Synthesis of potent and selective 2-azepanone inhibitors of human tryptase.

The serine protease tryptase has been associated with a broad range of allergic and inflammatory diseases and, in particular, has been implicated as a critical mediator of asthma. The inhibition of tryptase therefore has the potential to be a valuable therapy for asthma. The synthesis, employing solution phase parallel methods, and SAR of a series of novel 2-azepanone tryptase inhibitors are presented. A member of this series, 8t, was identified as a potent inhibitor of human tryptase (IC(50)=38 nM) with selectivity >/=330-fold versus related serine proteases (trypsin, plasmin, uPA, tPA, APC, alpha-thrombin, and FXa) [corrected].

Azepines↗
PubMed2004

Three novel mutations of the spastin gene in Chinese patients with hereditary spastic paraplegia.

BACKGROUND: Hereditary spastic paraplegia is a group of genetically heterogeneous neurodegenerative disorders characterized by progressive spasticity of the lower limbs. The most common form of hereditary spastic paraplegia is caused by mutations in the spastin gene (SPG4), which encodes spastin, an adenosine triphosphatase associated with various cellular activities protein. OBJECTIVE: To investigate the Chinese patients with hereditary spastic paraplegia for mutations in SPG4. METHODS: DNA samples from 31 unrelated patients were analyzed for mutations in SPG4 by single-strand conformation polymorphism analysis and direct sequencing. All DNA samples were screened for mutations by the polymerase chain reaction, followed by electrophoresis and silver staining. Each new variant identified was analyzed in 50 control subjects to determine whether it is a polymorphism or a mutation. RESULTS: Three novel mutations were detected in 4 affected individuals, including 2 missense mutations (T1258A and A1293G) and 1 deletion mutation (1668-1670delCTA). CONCLUSIONS: To our knowledge, this is the first report of SPG4 mutations in the People's Republic of China. The percentage of involved Chinese families with autosomal dominant hereditary spastic paraplegia with an SPG4 mutation is 18% (4/22), lower than the estimated 40% linked to this locus.

Adenosine Triphosphatases↗
PubMed2003

Simvastatin rescues rats from fatal pulmonary hypertension by inducing apoptosis of neointimal smooth muscle cells.

BACKGROUND: Pulmonary vascular injury by toxins can induce neointimal formation, pulmonary arterial hypertension (PAH), right ventricular failure, and death. We showed previously that simvastatin attenuates smooth muscle neointimal proliferation and pulmonary hypertension in pneumonectomized rats injected with the alkaloid toxin monocrotaline. The present study was undertaken to investigate the efficacy of simvastatin and its mechanism of reversing established neointimal vascular occlusion and pulmonary hypertension. METHODS AND RESULTS: Pneumonectomized rats injected with monocrotaline at 4 weeks demonstrated severe PAH at 11 weeks (mean pulmonary artery pressure [mPAP]=42 versus 17 mm Hg in normal rats) and death by 15 weeks. When rats with severe PAH received simvastatin (2 mg x kg(-1) x d(-1) by gavage) from week 11, there was 100% survival and reversal of PAH after 2 weeks (mPAP=36 mm Hg) and 6 weeks (mPAP=24 mm Hg) of therapy. Simvastatin treatment reduced right ventricular hypertrophy and reduced proliferation and increased apoptosis of pathological smooth muscle cells in the neointima and medial walls of pulmonary arteries. Longitudinal transcriptional profiling revealed that simvastatin downregulated the inflammatory genes fos, jun, and tumor necrosis factor-alpha and upregulated the cell cycle inhibitor p27Kip1, endothelial nitric oxide synthase, and bone morphogenetic protein receptor type 1a. CONCLUSIONS: Simvastatin reverses pulmonary arterial neointimal formation and PAH after toxic injury.

Animals↗
PubMed2003

[Mutation analysis of neurofilament-light gene in Chinese Charcot-Marie-Tooth disease].

OBJECTIVE: To study the characteristic of the mutation of neurofilament-light (NF-L) gene in Chinese Charcot-Marie-Tooth disease (CMT) patients. METHODS: Mutation analysis of NF-L gene was made by use of polymerase chain reaction-single strand conformation polymorphsim combined with DNA direct sequencing in 32 CMT probands from the Hans of five provinces in China who had been diagnosed by clinical feature and electromyography and/or biopsy of sural nerve. RESULTS: In 32 CMT probands, only one sporadic case was found to display variant banding pattern, and this case was confirmed as 1329C to T (Tyr443Tyr) single nucleotide polymorphism by sequencing. CONCLUSION: Mutation of NF-L gene may be rare in Chinese CMT patients.

Adolescent↗
PubMed2003

[Eletrocatalytic oxidation for organic pollutant on the nanoparticle platinum coated titanium electrode].

The nanoparticle platinum coated titanium electrode was prepared using the method of electrochemical cathodic reduction followed by anodic oxidation. The surface microstructure of electrode has demonstrated that platinum particles dispersed in the three-dimensional network of channels of the titanium oxide film were in the supper-fine and well-distributed state. The nanoparticle platinum electrode owned plenty of active points and well electrocatalytic property based on the exposed platinum particles with very small diameters. Electrochemical behaviors of two kinds of platinum electrode for methanol has been performed through Cyclic Voltammetry. The results have showed that the nanoparticle platinum electrode had a much better electrocatalytic property for methanol than smooth platinum electrode in acidic, neutral or alkaline medium. The oxidation current densities on nanoparticle platinum electrode are over 100 times of that on smooth platinum electrode. Furthermore, the values of average current efficiency on nanoparticle platinum electrode are several times of that on smooth platinum electrode when degrading three kinds of organics methanol, phenol and methyl orange. This clearly revealed that the nanoparticle platinum electrode had stronger ability to degrade organic pollutants.

Catalysis↗
PubMed2002

Molecular characterization of NikD, a new flavoenzyme important in the biosynthesis of nikkomycin antibiotics.

Nikkomycin antibiotics are potent inhibitors of chitin synthase, effective as therapeutic antifungal agents in humans and easily degradable insecticides in agriculture. NikD is a novel flavoprotein that catalyzes the oxidation of Delta(1)- or Delta(2)-piperideine-2-carboxylate, a key step in the biosynthesis of nikkomycin antibiotics. The resulting dihydropicolinate product may be further oxidized by nikD or converted to picolinate in a nonenzymic reaction. Saturated nitrogen heterocycles (L-pipecolate, L-proline) and 3,4-dehydro-L-proline act as alternate substrates. The ability of nikD to oxidize 3,4-dehydro-L-proline, but not 1-cyclohexenoate, suggests that the enzyme is specific for the oxidation of a carbon-nitrogen bond. An equivalent reaction is possible with the enamine (Delta(2)), but not the imine (Delta(1)), form of the natural piperideine-2-carboxylate substrate. Apparent steady-state kinetic parameters for the reaction of nikD with Delta(1)- or Delta(2)-piperideine-2-carboxylate (k(cat) = 64 min(-1); K(m) = 5.2 microM) or 3,4-dehydro-L-proline (k(cat) = 18 min(-1); K(m) = 13 mM) were determined in air-saturated buffer by measuring hydrogen peroxide formation in a coupled assay. NikD appears to be a new member of the monomeric sarcosine oxidase (MSOX) family of amine oxidizing enzymes. The enzyme contains 1 mol of flavin adenine dinucleotide (FAD) covalently linked to Cys321. The covalent flavin attachment site and two residues that bind substrate carboxylate in MSOX are conserved in nikD. NikD, however, exhibits an unusual long-wavelength absorption band, attributed to charge-transfer interaction between FAD and an ionizable (pK(a) = 7.3) active-site residue. Similar long-wavelength absorption bands have been observed for flavoproteins containing an active site cysteine or cysteine sulfenic acid. Interestingly, Cys273 in nikD aligns with an active-site histidine in MSOX (His269) that is, otherwise, a highly conserved residue within the MSOX family.

Amino Acid Sequence↗
PubMed2002

Synthesis and SAR of 4-carboxy-2-azetidinone mechanism-based tryptase inhibitors.

A series of N1-activated C4-carboxy azetidinones was prepared and tested as inhibitors of human tryptase. The key stereochemical and functional features required for potency, serine protease specificity and aqueous stability were determined. From these studies compound 2, BMS-262084, was identified as a potent and selective tryptase inhibitor which, when dosed intratracheally in ovalbumin-sensitized guinea pigs, reduced allergen-induced bronchoconstriction and inflammatory cell infiltration into the lung.

Animals↗
PubMed2002

Synthesis of potent and highly selective inhibitors of human tryptase.

The serine protease tryptase has been implicated in allergic and inflammatory diseases and associated with asthma. The synthesis and SAR of a series of N1-activated-4-carboxy azetidinones are described, resulting in identification of BMS-363131 (2) as a potent inhibitor of human tryptase (IC(50)<1.7 nM) with high selectivity (>3000-fold) for tryptase versus related serine proteases including trypsin.

Animals↗
PubMed2002

[A new mutation in the connexin 32 gene of a Chinese family with Charcot-Marie-Tooth disease associated with central conduction slowing].

OBJECTIVE: To report a Chinese Charcot-Marie-Tooth disease (CMT) family whose proband had abnormal brainstem auditory evoked potentials (BAEPs) and to study its relationship with connexin 32 (Cx32) gene mutation. METHODS: All family members were studied through clinical examinations, out of them, the proband was subjected to electromyography and BAEPs examination. Mutation analysis of Cx32 was screened by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) combined with DNA direct sequencing in the proband, 8 family members and 50 unrelated normal individuals. RESULTS: The proband had highly decreased nerve conduction velocities and delayed BAEPs. Leu131Pro mutation was found in the proband and 3 family members, not found in 50 normal controls. CONCLUSION: This mutation has not been reported previously. Central nervous system can be affected in CMT patients.

Asian People↗
PubMed1996

Direct Synthesis of G-2N.

The synthesis of angularly fused quinone natural products has been achieved using a photoenolization reaction and a Diels-Alder reaction in the key carbon-carbon bond forming steps.

Journal Article↗