Biomedical subjects
Publications and source records attributed to G Jin.
A series of thiomorpholine sulfonamide hydroxamate TACE inhibitors, all bearing propargylic ether P1' groups, was explored. In particular, compound 5h has excellent in vitro potency against isolated TACE enzyme and in cells, oral activity in a model of TNF-alpha production and a collagen-induced arthritis model, was selected as a clinical candidate for the treatment of RA.
PURPOSE: It is of interest to perform a systematic comparative analysis of the conserved domains in DNA glycosylases and the evolution of DNA base excision repair systems. Furthermore, it is important to characterize the roles and regulation of base excision repair during the development of organisms. To address these issues, we first identified 8-oxo-7,8-dihydroguanine (8-oxoG)-DNA glycosylase (Ogg1) of the ascidian Ciona intestinalis as a good model system. MATERIALS AND METHODS: A cDNA clone coding for a peptide with homology to human Ogg1 was identified in the expressed sequence tag (EST) database from the Ciona cDNA resources. We examined whether CiOgg1 has DNA glycosylase/AP (apurinic/apyrimidinic) lyase activities for 8-oxoG-containing oligonucleotide. Furthermore, the expression level of CiOgg1 was compared in various tissues of Ciona intestinalis. RESULTS: The CiOgg1gene encoded a protein of 351 amino acids, which shows 37% identity of amino acid sequence with human Ogg1. The Helix-hairpin-Helix motif was highly conserved. The ascidian enzyme had functional 8-oxoG-DNA glycosylase/AP lyase activities, which removed 8-oxoG opposite cytosine from DNA. Expression of the CiOgg1 significantly reduced the frequency of spontaneous G:C to T:A transversions in E. coli mutM mutY. The highest expression level was observed in testis in Ciona intestinalis. CONCLUSIONS: The structure and functions of Ogg1 are well conserved in Ciona intestinalis. CiOgg1 is involved in the repair of 8-oxoG in DNA in Ciona intestinalis.
The focus of this paper is on variability concerns in wastewater treatment and approaches to control unacceptable fluctuations in effluent quality. Areas considered include: factors contributing to variability in both waste loads and process technology performance; variability assessment; control of variability employing the process best management practice (BMP); design/operation of biological waste treatment technologies for variability reduction; and modelling to enhance process control.
We investigate pattern formation on a solid substrate of a diblock copolymer-homopolymer mixture containing doping wettable nanoparticles with a preferential attraction for one component of the copolymers, using a three-order-parameter model. The presence of doping nanoparticles under the surface-interaction modulation breaks the isotropy in the process of microphase-separation and macrophase-separation. This leads to the formation of orientational microphase and macrophase structures due to the interplay between the phase separation and wetting particle ordering under a modulated potential at the late stage. Simulations suggest that the microphase morphology and macrophase morphology can be changed through adjustment of the wetting strength, the amplitude as well as the period of the modulated potential. It provides some important insights for changing microphase and macrophase structures in polymer blends by wetting-driven spinodal decomposition.
Sister chromatid exchanges (SCEs) are symmetrical exchanges between newly replicated chromatids and their sisters. While homologous recombination may be one of the principal mechanisms responsible for SCEs, the full details of their molecular basis and biological significance remain to be elucidated. Following exposure to ultraviolet light B (UVB), mitomycin C (MMC) and cisplatin, we analyzed the location of SCEs on metaphase chromosomes in Chinese hamster CHO cells. The frequency of SCEs increased over the spontaneous level in proportion to the agent's dose. UVB-induced SCEs occurred frequently in telomere regions, as cisplatin-induced SCEs did, differing from MMC-induced ones. The remarkable difference of intrachromosomal distribution among the three mutagens may be attributed to the specificity of induced DNA lesions and structures of different chromosome regions. Telomeric DNA at the end of chromosomes is composed of multiple copies of a repeated motif, 5'-TTAGGG-3' in mammalian cells. Telomeric repeats may be potential targets for UVB and cisplatin, which mainly form pyrimidine dimers and intrastrand d(GpG) cross-links, respectively, resulting in SCE formation. UVB irradiation shortened telomeres and augmented the telomerase activity. The possible implications of the frequent occurrence of SCEs in telomere regions are discussed in connection with the maintenance of telomere integrity.
The SAR of a series of potent sulfonamide hydroxamate TACE inhibitors, all bearing a butynyloxy P1' group, was explored. In particular, compound 5j has excellent in vitro potency against isolated TACE enzyme and in cells, good selectivity over MMP-1 and MMP-9, and oral activity in an in vivo model of TNF-alpha production and a collagen-induced arthritis model.
Potent and selective bicyclic heteroaryl hydroxamic acid MMP and TACE inhibitors were synthesized by a novel convergent route. Selectivity and efficacy versus MMPs and TACE could be controlled by appropriate substitution on the scaffolds and by variation of the P1' group. Select compounds were found to be effective in in vivo models of arthritis.
The overall objective of this study was to assess the impact of individual rainfall events on Lake Pontchartrain water quality and risk to swimmers. Indicator organisms in lake water under dry weather conditions, in storm water runoff (prior to dilution with lake water), and in the outfall plume within the lake following storm events were monitored and quantified. Results indicated that drainage canals constitute a significant microbial loading to lake waters. Significant reductions of indicator microbes are observed in the water column following two to three days after storm pumping events into the lake. A mathematical model incorporating advection, dispersion, and bacterial die-off gives fairly good prediction on E. coli, enterococcoi, and fecal coliform titers. The somewhat under estimation by model suggests re-suspension of sediment and re-introduction of the indicator organisms that attached to the sediment back into the water column. Future direction of model development should include the mechanism of re-suspension and survival of indicator organisms in sediment.
To optimize the efficiency of bioremediation, treatability studies are needed to understand the fate of pollutants and environmental conditions under which microorganism growth is promoted and efficient degradation of these pollutants result. This article presents a recommended procedure which may achieve these goals. Results and treatability comparisons for candidate compounds including carbon tetrachloride (CT), methyl-tert-butyl-ether (MTBE) and hexachlorobutadiene (HCBD) are presented and discussed. Culture redox potential (ORP) which is an indicator or free electron activity of a system appeared to have a significant impact on CT biodegradation. Optimum biodegradation of CT by Pseudomonas cepacia was observed between -100 and -200mv. Under the optimum environmental conditions established during the batch-scale biotransformation study, 98 to 99.9% of CT and 70% of MTBE introduced into the continuous fixed-biofilm reactor were degraded. The biphasic model simulating biodegradation of CT and MTBE provided an excellent correlation in the fixed-biofilm study and was simple to apply as compared with other models.
Neuroprotective effects of glial cell line-derived neurotrophic factor (GDNF) on cell survival and death signals were investigated after 90 min of transient middle cerebral artery occlusion (MCAO) in rats. Immunoreactivities of phosphorylated Akt (p-Akt), cleaved caspase-9 (c-cas9), and -3 (c-cas3) increased after the reperfusion in the penumbra in vehicle group with peaks at 3 h, 8 h, and 1 day, respectively. Topical application of GDNF (6.8 micrograms/9 microliters) on brain surface potentiated and prolonged p-Akt activation, but suppressed activation of the caspases, and reduced the number of terminal deoxynucleotidyl transferase-mediated dUDP-biotin in situ nick labeling (TUNEL) positive cells. These results suggest that GDNF plays a protective role against ischemic injury by controlling the balance between Akt pathway and caspase cascades.
To achieve an efficient delivery targeting to post-ischemic cerebral vascular endothelium, PEG-liposome conjugated with transferrin (Tf) (Tf-PEG-liposome) was intravenously administered to the rats after 90 min of transient middle cerebral occlusion. The expression of Tf receptor (TfR) in the cerebral endothelium increased with a peak at 1 day after the reperfusion and returned to the control level by 6 days. The Tf-PEG fluorescence was marginally detectable in sham control brain, but remarkably increased with a peak at 2 days, showing about 70% of TfR positive vascular endothelium double-labeled with Tf-PEG. These results indicate that the Tf-PEG-liposome could be utilized as an efficient drug delivery tool to the brain after stroke.
Functional recovery by the application of electro-acupuncture (EA) on different acupoints was investigated using a transient middle cerebral artery occlusion (MCAO) model in rat. Acupoints were Baihui (D20) plus Renzhong (D26) (MCAO + D group), and Hanyan (G4), Xuanlu (G5), Xuanli (G6), plus Qubin (G7) (MCAP + G group). Animals with EA treatment showed significant functional improvements from 12 days after the reperfusion against those without EA treatment. Among EA treated groups, MCAO + G showed a more significant recovery than MCAO + D. Infarct volume revealed the significant reduction in the EA treated groups especially in MCAO + G at 30 days. Immunohistochemical study showed a remarkable induction of vascular endothelial growth factor (VEGF) in astrocytes of the peri-infarct area at 30 days, more in EA treated groups than in groups treated with MCAO alone. These results suggest that the acupoints applied in this study are effective for the functional recovery, and an enhanced expression of VEGF may play a certain role in recovery process after stroke.
Glial cell line-derived neurotrophic factor (GDNF) activates protein kinase Akt/PKB by phosphorylation (p-Akt) which plays key roles in cell survival. In the current study, we investigated a temporal expression of p-Akt by immunohistochemical analysis after a topical application of GDNF to normal cerebral hemisphere of rats. Although p-Akt immunoreactivity was weakly present in the sham control neural cells, GDNF application greatly enhanced it at 3 h, which lasted until 1 day. These results indicate that p-Akt is expressed in neuronal cells under physiological conditions, and that topical application of GDNF greatly enhanced the phosphorylation of Akt in normal rat brain.
A phosphatase PTEN (phosphatase and tensin homologue deleted on chromosome 10) is a tumor suppressor gene that suppresses cell growth, inhibits cell migration, and induces apoptosis. Phosphorylated form of PTEN (p-PTEN) is a key survival factor relating PI3K-Akt pathway and their downstream effectors. A spatiotemporal profiles of PTEN and p-PTEN expression were immunohistochemically examined after 90 min of transient middle cerebral artery occlusion in rats. In the ischemic core, PTEN progressively decreased by 3 days, whereas a rapid but transient increase of p-PTEN was found with a peak at 1 h after the reperfusion. In contrast, in the ischemic penumbra, PTEN showed a minor change and a gradual but sustained p-PTEN expression was observed in the ischemic penumbra with a peak at 12 h. In addition, the balance of population among strongly, moderately, and weakly stained cells was different between the ischemic core and penumbra at their peak time points. These results suggest an important role of p-PTEN for cell survival after ischemia as an upstream regulator for PI3K-Akt.
The SAR of a series of potent sulfonamide hydroxamate TACE inhibitors bearing novel acetylenic P1' groups was explored. In particular, compound 4t bearing a butynyloxy P1' moiety has excellent in vitro potency against isolated TACE enzyme and in cells, good selectivity over MMP-1 and oral activity in an in vivo model of TNF-alpha production.
Electro-acupuncture (EA) is an effective curative method for various diseases in oriental medicine. To investigate a detailed molecular mechanism of EA stimulation, an induction of phospho-Akt (p-Akt) was examined in normal adult rat brain after 60 min of EA with acupoints of Baihui (D20) and Renzhong (D26). In the sham control brain, strong neuronal p-Akt expression was found in ventral posterolateral thalamic nucleus (VPL) and medial habenular nuclei (MHb), but moderate to weak in cortex, caudate, CA1 sector and dentate gyrus of hippocampus, and ventral posteromedial thalamic nucleus. EA stimulation generally enhanced and sustained p-Akt expression for at least 24 h especially in the regions listed above, except VPL and MHb where no apparent change was found. Western blot analysis of p-Akt confirmed the enhanced signal intensity after EA at 8 and 24 h. These results suggest that the EA on D20 and D26 acupoints activates the survival Akt signal pathway, which may be maintaining the neural functions such as cell survival and memory formation in normal brain.
Anthranilic acid derivatives bearing basic amines were prepared and evaluated in vitro and in vivo as inhibitors of MMP-1, MMP-9, MMP-13, and TACE. Piperazine 4u has been identified as a potent, selective, orally active inhibitor of MMP-9 and MMP-13.
A novel series of anthranilic acid-based inhibitors of MMP-1, MMP-9, MMP-13, and TACE was prepared and evaluated. Selective inhibitors of MMP-9, MMP-13, and TACE were identified, including the potent, orally active MMP-13 inhibitor 4p.