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W Jiang

Publications and source records attributed to W Jiang.

At least 19 recordsLinked to original sources
PubMed2006

JNJ-10280205 and JNJ-10287069: Novel PDE5 inhibitors as clinical candidates for erectile dysfunction.

Phosphodiesterase 5 (PDE5) inhibitors are efficacious in treating patients with erectile dysfunction. New PDE5 inhibitors with different selectivity and pharmacokinetic profiles have been vigorously pursued. Here we report two novel, potent, and selective PDE5 inhibitors, JNJ-10280205 and JNJ-10287069, with Ki values of 0.05 and 0.12 nM, respectively. Both compounds displayed superior selectivity against PDE1-4 and -6 when compared to sildenafil. In the anesthetized dogs, JNJ-10280205 and JNJ-10287069 exhibited similar efficacy as sildenafil in enhancing erectile functions, with no significant effect on cardiovascular parameters. Pharmacokinetic studies showed that JNJ-10287069 had better oral bioavailability than JNJ-10280205 in several animal species. In vitro study suggested that cytochrome P450 (CYP) 3A4 played a major role in the metabolism of both compounds. The compounds inhibited some of the CYP450 enzymes and the human ether-a-go-go (HERG) channel at much higher concentrations than that required to inhibit PDE5, thus, no cross inhibition would be expected at therapeutic doses. Both compounds are suitable clinical candidates.

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

Potentiated response to adrenomedullin in myocardia and aortas in spontaneously hypertensive rat.

Adrenomedullin (AM) is a multifunctional regulatory peptide, and endogenous AM is an important factor in regulating cardiovascular and renal homeostasis as a potent cardio-reno-protective factor. To illustrate the protective mechanism of adrenomedullin (AM) on the cardiovascular system by observing (1) the changes in mRNA and protein levels of AM and its receptor-calcitonin receptor-like receptor (CL) and receptor activity-modifying proteins (RAMPs)-in myocardia and aortas of spontaneously hypertensive rats (SHRs) and (2) the response of cardiovascular tissue to AM. The AM content and cyclic adenosine monophosphate (cAMP) production in myocardia and aortas were measured in SHRs and Wistar Kyoto (WKY) rats (11-week-old) by radioimmunoassay (RIA). The mRNA levels of brain natriuretic peptide (BNP), AM, CL, RAMP1, -2, -3 were determined by semi-quantitative RTPCR. Protein levels of CL, RAMP1, -2, -3 were assayed by Western blotting. SHRs had severe hypertension, and the tail-blood pressure was 76.7% higher, the ratio of heart weight to body weight (heart coefficient) 45.5% higher, and the BNP gene expression 4.5-fold higher than that of WKY rats (all p < 0.01). The AM-ir content in plasma, myocardia and aortas of SHRs increased by 42.5%, 68.3% and 80.4%, respectively (all p < 0.01) compared with WKY rats. Furthermore, the mRNA levels of AM, CL, RAMP1, RAMP2 and RAMP3 were elevated by 46% (p < 0.01), 62% (p < 0.05), 51.2% (p < 0.01), 41% (p < 0.01) and 54% (p < 0.01), respectively, in myocardia and by 72%, 87%, 155%, 53% and 74% (all p < 0.01), respectively, in aortas. The elevated mRNA level of CL, RAMP1 RAMP2 and RAMP3 correlated positively with that of AM mRNA in hypertrophic myocardia (r= 0.943, 0.621, 0.688 and 0.633, respectively, all p < 0.01) and aortas (r = 0.762, 0.892, 0.828 and 0.736, respectively, all p < 0.01). The protein levels of CL, RAMP1, RAMP2 and RAMP3 in myocardia and aortas of SHRs were increased compared with that of WKY rats. The response to AM was potentiated in myocardia and aortas in SHRs, and the production of cAMP was increased by 47% and 65% (both p < 0.01), respectively. AM-stimulated cAMP generation in myocardia and aortas was blocked by both AM(22-52), the specific antagonist of AM, and calcitonin gene-related peptide (CGRP)(8-37), the antagonist of the CGRP1 receptor. In myocardia and aortas of SHRs, the gene expressions and protein levels of AM, CL, RAMP1, RAMP2 and RAMP3 were increased, and the response to AM was potentiated. AM-stimulated cAMP generation in myocardia and aortas was blocked by both AM(22-52) and CGRP(8-37). The results suggest that the changes of AM and its receptors in cardiovascular tissue, and the increased response of cardiovascular tissue to AM might importantly impact the pathogenesis of hypertension.

Adrenomedullin↗
PubMed2006

Birt-Hogg-Dubé gene mutations in human endometrial carcinomas with microsatellite instability.

Birt-Hogg-Dubé (BHD) syndrome is a rare form of autosomal dominantly inherited genodermatosis characterized by benign hamartomatous skin lesions named fibrofolliculomas, and an increased risk for developing pulmonary cyst/pneumothorax and various forms of renal cell carcinoma. Many of the patients harbour insertion/deletion mutations in the hypermutable poly(C)8 tract in exon 11 of the BHD gene. This mutational hot spot is also reported to be a target of mutation in microsatellite instability (MSI) sporadic colorectal cancer. To test the hypothesis that the BHD gene is also a mutational target in sporadic endometrial carcinoma with microsatellite instability, 139 cases of sporadic endometrial carcinoma were screened for MSI status, and mutations of the poly(C)8 tract in exon 11 as well as other coding exons of the BHD gene. The poly(G)8 tract of the BAX gene, the poly(C)8 tract of MSH6, and methylation status of hMLH1 were also assessed. Thirty-nine of 139 cases (28%) showed MSI. Mutations in the poly(C)8 tract of BHD were detected in five of the 39 MSI cases (12.8%). Of these, one showed additional mutation in exon 4, possibly satisfying the two-hit hypothesis of tumour suppressor genes. BAX gene mutation was detected in ten of the 39 MSI cases (25.6%). Four tumours showed both BAX and BHD mutations, and a significant positive association was found between mutations of the two genes. No association was found between BHD status and MSH6 mutation or hMLH1 methylation. When multiple foci were microdissected and individually screened for mutation, BHD mutations were shown to have been acquired during tumour progression, after mutation of the BAX gene, in three of five cases. Taken together, these findings show that the BHD gene is a target gene in MSI endometrial carcinoma. However, its mutational frequency is lower than that of BAX, and BHD mutation tends to occur during neoplastic progression after the acquisition of mutations in another MSI target gene, BAX.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Characterization of SSU and LSU rRNA genes of three Trypanosoma (Herpetosoma) grosi isolates maintained in Mongolian jirds.

Trypanosoma (Herpetosoma) grosi, which naturally parasitizes Apodemus spp., can experimentally infect Mongolian jirds (Meriones unguiculatus). Three isolates from A. agrarius, A. peninsulae, and A. speciosus (named SESUJI, HANTO, and AKHA isolates, respectively) of different geographical origin (AKHA from Japan, and the others from Vladivostok), exhibited different durations of parasitaemia in laboratory jirds (2 weeks for HANTO, and 3 weeks for the others). To assess the genetic background of these T. grosi isolates, their small (SSU) and large subunit (LSU) ribosomal RNA genes (rDNA) were sequenced along with those of 2 other Herpetosoma species from squirrels. The SSU rDNA sequences of these 3 species along with available sequences of 3 other Herpetosoma trypanosomes (T. lewisi, T. musculi and T. microti) seemed to reflect well the phylogenetic relationship of their hosts. Three isolates of T. grosi exhibited base changes at 2-6 positions of 2019-base 18S rDNA, at 5-29 positions of 1817/1818-base 28Salpha rDNA, or 1-5 positions of 1557-1559-base 28Sbeta rDNA, and none was separated from the other 2 isolates by rDNA nucleotide sequences. Since base changes of Herpetosoma trypanosomes at the level of inter- and intra-species might occur frequently in specified rDNA regions, the molecular analysis on these regions of rodent trypanosomes could help species/strain differentiation and systematic revision of Herpetosoma trypanosome species, which must be more abundant than presently known.

Animals↗
PubMed2005

Sensitization of mesenteric afferents to chemical and mechanical stimuli following systemic bacterial lipopolysaccharide.

BACKGROUNDS AND AIMS: The mechanisms underlying endotoxin-induced hyperalgesia remain unknown. We aimed to study the mechanisms underlying the sensitizing action of lipopolysaccharide (LPS) on intestinal afferent responses to mechanical and chemical stimuli. METHODS: Extracellular recordings of jejunal afferent nerve discharge were obtained from pentobarbitone-anaesthetized rats. RESULTS: Lipopolysaccharide (6 mg kg(-1), i.v.) stimulated a short-term, transient (<30 min) increase in chemosensitivity to systemic 5-HT (6 microg kg(-1)) and responses to mechanical distension and a delayed but maintained (>30 min) increase in spontaneous afferent discharge. Naproxen (10 mg kg(-1)) and the prostaglandin receptor antagonist AH6809 (1 mg kg(-1)) significantly attenuated both the short-term sensitization to mechanical distension and 5-HT and the long-term increase in baseline afferent firing following LPS. In contrast, the iNOS inhibitor aminoguanidine (15 mg kg(-1)) and the L-type calcium channel antagonist nifedipine (1 mg kg(-1)) both prolonged the period of afferent sensitization to distension and 5-HT without influencing the augmented baseline-firing rate. omega-Conotoxin GVIA attenuated the increase in afferent discharge to LPS, without any change in mechano- and chemosensitivity. CONCLUSIONS: The long-term (>30 min) increase in afferent firing following systemic LPS involves neurogenic release of prostanoids. The short-term (<30 min) sensitization also appears to depend on prostanoid release, while nitric oxide production may serve to down-regulate LPS-induced afferent hypersensitivity.

Action Potentials↗
PubMed2005

Vagal selective effects of ruthenium red on the jejunal afferent fibre response to ischaemia in the rat.

A variety of inflammatory mediators and local metabolites, have been implicated in the sensitivity of intestinal afferent fibres to brief periods of ischaemia and reperfusion. As yet, the contribution of the vanilloid transient receptor potential (TRPV)1 receptor to the response to intestinal ischaemia remains undetermined. In the present study, the effect of pretreatment with the competitive TRPV1 antagonist capsazepine and the non-selective TRPV channel antagonist ruthenium red, on the mesenteric afferent fibre response to ischaemia was examined. In control animals there was a reproducible biphasic increase in whole nerve afferent fibre activity during two brief periods of ischaemia. Treatment with ruthenium red significantly attenuated the early phase increase in afferent fibre activity during ischaemia. However, capsazepine treatment did not significantly alter the afferent fibre response to either ischaemia or reperfusion. Further experiments in chronically vagotomized animals indicated that the early phase response to ischaemia was mediated via vagal afferent fibres. The mechanism via which ruthenium red selectively inhibited vagal afferent fibres during ischaemia is unknown, but it does not appear to involve blockade of the TRPV1 receptor.

Animals↗
PubMed2004

The role of adrenomedullin and its receptor system in cardiovascular calcification of rat induced by Vitamin D(3) plus nicotine.

Adrenomedullin (ADM) is a potent vasodilatory peptide which regulates blood pressure, cell growth and bone formation. Our work was aimed to explore the production of ADM, changes and pathophysiological significance of ADM mRNA and ADM receptor components--calcitonin receptor like receptor (CRLR) and receptor activity modifying proteins (RAMPs) mRNA in calcified myocardium and aorta of rats induced by Vitamin D3 plus nicotine. Contents of ADM in plasma, myocardium and aorta were measured by radioimmunoassay (RIA). The amount of ADM, CRLR and RAMPs mRNA was determined by semi-quantitative RT-PCR. The calcium content and alkaline phosphatase activity in myocardium and aorta of rats were measured. The results showed that the contents of calcium in calcified myocardium and aorta were increased by 3.5- and 6-fold (all P < 0.01), respectively, and alkaline phosphatases activity in calcified myocardium and aorta were increased by 66.5 and 82.7% (all P < 0.01 ), respectively, compared with control. Contents of ADM in plasma, myocardium and aorta were increased by 58% (P < 0.01), 14.3% (P < 0.01) and 27.8% P < 0.05). Furthermore, it was found that the amount of ADM, CRLR and RAMP2 mRNA in calcified myocardium was elevated by 90.6, 157.5 and 119.6% (all P < 0.01), RAMP3 mRNA was decreased by 14.1% (P < 0.01), respectively, compared with control. The amount of ADM, CRLR, RAMP2 and RAMP3 mRNA in calcified aorta was elevated by 37.7% (P < 0.01), 41.4% (P < 0.01), 60.1% (P < 0.05) and 13% P < 0.01), respectively, compared with control. The elevated level of CRLR and RAMP2 mRNA were in positive correlation with that of ADM mRNA (r = 0.992 and 0.882, respectively, P < 0.01) in calcified myocardium. The elevated level of CRLR and RAMP3 mRNA were also in positive correlation with that of ADM mRNA (r = 0.727, P < 0.05 and 0.816, P < 0.01, respectively) in calcified aorta. These results demonstrated that calcified myocardium and aorta generated an increased amount of ADM, up-regulated gene expressions of ADM, CRLR and RAMP2 mRNA. While the alteration of RAMP3 mRNA in calcified myocardium and aorta was different. These suggested that ADM and its receptor system might involve in the regulation of calcification in heart and aorta.

Adrenomedullin↗
PubMed2004

Characterization of the distinct orthotopic bone-forming activity of 14 BMPs using recombinant adenovirus-mediated gene delivery.

Efficacious bone regeneration could revolutionize the clinical management of bone and musculoskeletal disorders. Although several bone morphogenetic proteins (BMPs) (mostly BMP-2 and BMP-7) have been shown to induce bone formation, it is unclear whether the currently used BMPs represent the most osteogenic ones. Until recently, comprehensive analysis of osteogenic activity of all BMPs has been hampered by the fact that recombinant proteins are either not biologically active or not available for all BMPs. In this study, we used recombinant adenoviruses expressing the 14 types of BMPs (AdBMPs), and demonstrated that, in addition to currently used BMP-2 and BMP-7, BMP-6 and BMP-9 effectively induced orthotopic ossification when either AdBMP-transduced osteoblast progenitors or the viral vectors were injected into the quadriceps of athymic mice. Radiographic and histological evaluation demonstrated that BMP-6 and BMP-9 induced the most robust and mature ossification at multiple time points. BMP-3, a negative regulator of bone formation, was shown to effectively inhibit orthotopic ossification induced by BMP-2, BMP-6, and BMP-7. However, BMP-3 exerted no inhibitory effect on BMP-9-induced bone formation, suggesting that BMP-9 may transduce osteogenic signaling differently. Our findings suggest that BMP-6 and BMP-9 may represent more effective osteogenic factors for bone regeneration.

Adenoviridae↗
PubMed2004

Implantation of BM cells transfected with phVEGF165 enhances functional improvement of the infarcted heart.

BACKGROUND: Experimental data have suggested that BM-cell implantation can improve infarcted cardiac function. However, the number of implanted cells that survive is still unknown. The present study was performed to investigate whether implantation of autologous BM mononuclear cells (BM-MNCs) transfected with phVEGF165 can increase the number of surviving implanted cells, and enhance functional improvement of infarcted hearts in rabbits. METHODS: Acute myocardial infarction (AMI) in rabbits was replicated by ligating the left anterior descending coronary artery, and animals were randomly divided into the following three groups: I AMI control group (n=7); II BM-MNCs transfected with phVEGF165 implantation group (n=7); III BM-MNCs implantation group (n=7). In addition, sham-operated (n=5) rabbits were randomly selected to serve as a non-infarction control group (VI). Animals for cell implantation received intramyocardial injections of autologous BM-MNCs 14 days after AMI. Echocardiography and hemodynamic studies were performed to evaluate cardiac structure and function 28 days after implantation. The implanted sites were examined using immunofluorescence to identify the phenotypes and number of the labelled cells. Reverse transcriptase (RT)-PCR and Western blot analysis were performed to detect the expression of hVEGF165 gene and VEGF165 protein respectively. RESULTS: Failed cardiac function produced by AMI was significantly improved in Groups II and III 28 days after cell implantation. BM-MNCs transfected with phVEGF165 implantation conferred a further improvement of cardiac function, with significant changes of all assessed parameters when compared with BM-MNCs implantation alone (all P<0.05). The implanted cells demonstrated myogenic differentiation with the expression of Troponin T and organized contractile proteins. The positive staining for Factor VIII-related Ag indicated the induction of angiogenesis in the infarct area. The percentage of Brdu-positive myocyte, endothelial cells was 75+/-%, 34.1+/-4.6% in Group II, significantly higher than that in Group III(51+/-7%, 11.3+/-2.5% respectively, P<0.05). RT-PCR analysis demonstrated exclusive expression of hVEGF165 gene in Group II, and Western blot showed the expression of VEGF165 protein was significantly higher in Group II than in Group III (P<0.05). CONCLUSIONS: Implantation of BM-MNCs transfected with phVEGF165 can increase the number of implanted cells surviving, and enhance the impaired cardiac function after AMI.

Angiogenesis Inducing Agents↗
PubMed2004

Nano silica removal from IC wastewater by pre-coagulation and microfiltration.

Microfiltration (MF) coupled with pretreatment by coagulation was adopted in the treatment of chemical mechanical polishing (CMP) wastewater from IC manufacturing plants, containing high concentrations of silica. Poly-aluminium chloride (PACl) was the coagulant, while the cationic polyacrylamide (PAA) was the flocculant aid. Preliminary tests were performed with the raw CMP wastewater in order to determine the optimal coagulation condition for subsequent microfiltration. Analysis of the particle size distribution shows that nearly all silica particles were enlarged from nano scale to at least 4 microm in diameter after the pre-treatment. The pre-treated wastewater was then filtered through a polytetrafluoroethylene (PTFE) membrane with a pore size 0.5 microm at a constant vacuum pressure. Trace amounts of PAA in addition to the PACl coagulation can effectively increases the permeate flux.

Acrylic Resins↗
PubMed2003

Enhanced second-harmonic generation from planar photonic crystals.

Strongly enhanced second-harmonic generation is observed from a two-dimensional square lattice GaAs/AlGaAs photonic crystal waveguide when the fundamental beam, the second-harmonic beam, or both beams resonantly couple to a leaky eigenmode. P-polarized second-harmonic spectra are obtained for s-polarized, 150-fs pump pulses that are tuned from 5000 to 5600 cm(-1) and directed along the gamma-chi direction of the crystal for various angles of incidence. Compared with off-resonant conditions, enhancements of >1200x in the second-harmonic conversion are observed for resonant coupling of both the fundamental and the second-harmonic fields to leaky eigenmnodes. The angular and spectral positions of the peaks are in good agreement with simulations.

Journal Article↗
PubMed2002

MoeA, an enzyme in the molybdopterin synthesis pathway, is required for rifamycin SV production in Amycolatopsis mediterranei U32.

Rifamycin SV contains one amide nitrogen atom at its C(7)N moiety. Earlier labeling studies suggested that nitrogen might be incorporated from a pathway involved in a molybdenum-dependent nitrate reductase. However, no genetic evidence is available thus far. The structural gene moeA, which is involved in molybdopterin synthesis in various organisms, has been cloned from rifamycin SV-producing Amycolatopsis mediterranei strain U32. The amino acid sequence deduced from the moeA gene showed significant similarity to members of the MoeA protein family and contains all the structural features that are highly conserved in the putative functional domains of MoeA proteins. Southern hybridization showed that there is only one moeA gene in the A. mediterranei genome. To further investigate the possible physiological function of the moeA gene, a double crossover gene replacement was achieved by inserting an aparmycin resistance gene into moeA in the A. mediterranei U32 chromosome. Phenotype analysis showed that the moeA gene is required for A. mediterranei growth in a minimal medium with nitrate as sole nitrogen source, possibly because nitrate reductase activity is diminished due to disruption of the moeA gene. Compared to the wild type strain, moeA-disrupted mutants lost 95% of their rifamycin SV production capacity in complex fermentation media. The results demonstrate that the moeA gene is necessary for rifamycin SV production in A. mediterranei, and that the nitrogen assimilation pathway involved in nitrate reductase is the major pathway for the genesis of the amide nitrogen atom in the rifamycin SV molecule.

Actinomycetales↗
PubMed2002

Reynolds number dependence of streamwise velocity spectra in turbulent pipe flow.

Spectra of the streamwise velocity component in fully developed turbulent pipe flow are presented for Reynolds numbers up to 5.7x10(6). Even at the highest Reynolds number, streamwise velocity spectra exhibit incomplete similarity only: while spectra collapse with both classical inner and outer scaling for limited ranges of wave number, these ranges do not overlap. Thus similarity may not be described as complete, and a region varying with the inverse of the streamwise wave number, k(1), is not expected, and any apparent k(-1)(1) range does not attract any special significance and does not involve a universal constant. Reasons for this are suggested.

Journal Article↗
PubMed2002

Cosensitivity of vagal mucosal afferents to histamine and 5-HT in the rat jejunum.

A complex sensitivity of afferent nerves in the mesentery of the rat jejunum to systemic administration of histamine has recently been demonstrated. In the present study, we aimed to characterize subpopulations of mesenteric afferents that mediate this afferent nerve response. Multiunit afferent discharge was recorded from mesenteric nerves supplying the proximal jejunum in anesthetized rats. The majority of mesenteric bundles (84%) exhibited biphasic responses to histamine (8 micromol/kg), and these bundles also responded to 2-methyl-5-HT (2m5HT). In contrast, monophasic responses lacked a short-latency component, and these bundles failed to respond to 2m5HT. Single-unit analysis revealed a population of afferents that possessed cosensitivity for 2m5HT and histamine. This population of afferents was absent in chronically vagotomized animals, whereas mucosal anesthesia with luminal lidocaine reversibly converted the biphasic profile to a monophasic one. Ondansetron (500 microg/kg) blocked the response to 2m5HT with no effect on the profile of the histamine response, whereas pyrilamine (5 mg/kg) blocked the histamine response without affecting the response to 2m5HT. We conclude that histamine-sensitive afferents exist in the rat proximal jejunum that also respond to 5-HT via the 5-HT3 receptor. These fibers appear to be vagal afferents originating in the intestinal mucosa and may be involved in the organization of mast cell-mediated responses.

Anesthetics, Local↗
PubMed2002

Fluorescence-based functional assay for Wnt/beta-catenin signaling activity.

Aberrant activation of beta-catenin signaling has been implicated in the development of human cancers. As a Wnt signal transducer, beta-catenin forms a complex with the lymphocyte enhancer-binding factor/T cell factor transcription factor and activates downstream targets that promote cell proliferation. Here we developed a Wnt-dependent beta-catenin-mediated heterologous transactivation system, which consisted of a chimeric transcription factor constructed by fusing the GAL4 DNA-binding domain with the full-length beta-catenin, and a GAL4-responsive reporter expressing GFP. The chimeric transcription factor was highly unstable and exerted no detectable transactivating effect on the GAL4-responsive reporter. However, lithium and Wnt1 significantly stabilized this chimeric transactivator, indicating that this transactivation system is regulated by beta-catenin in a Wnt-responsive fashion. Thus, this transactivation system could be used as a functional reporter to identify potential upstream factors that deregulate beta-catenin signaling during tumorigenesis, as well as to screen for potential anti-cancer agents that specifically inhibit beta-catenin signaling in human tumors.

Adenocarcinoma↗