Biomedical subjects
Publications and source records attributed to Jun Xu.
Potent and selective TACE and MMP inhibitors utilizing the diazepine and thiazepine ring systems were synthesized and evaluated for biological activity in in vitro and in vivo models of TNF-alpha release. Oral activity in the mouse LPS model of TNF-alpha release was seen. Efficacy in the mouse collagen induced arthritis model was achieved with diazepine 20.
(15)N spin relaxation data have provided a wealth of information on protein dynamics in solution. Standard R(1), R(1)(rho), and NOE experiments aimed at (15)N[(1)H] amide moieties are complemented in this work by HA(CACO)N-type experiments allowing the measurement of nitrogen R(1) and R(1)(rho) rates at deuterated (15)N[(2)D] sites. Difference rates obtained using this approach, R(1)((15)N[(1)H]) - R(1)((15)N[(2)D]) and R(2)((15)N[(1)H]) - R(2)((15)N[(2)D]), depend exclusively on dipolar interactions and are insensitive to (15)N CSA and R(ex) relaxation mechanisms. The methodology has been tested on a sample of peptostreptococcal protein L (63 residues) prepared in 50% H(2)O-50% D(2)O solvent. The results from the new and conventional experiments are found to be consistent, with respect to both local backbone dynamics and overall protein tumbling. Combining several data sets permits evaluation of the spectral density J(omega(D) + omega(N)) for each amide site. This spectral density samples a uniquely low frequency (26 MHz at a 500 MHz field) and, therefore, is expected to be highly useful for characterizing nanosecond time scale local motions. The spectral density mapping demonstrates that, in the case of protein L, J(omega(D) + omega(N)) values are compatible with the Lipari-Szabo interpretation of backbone dynamics based on the conventional (15)N relaxation data.
The efficiency of neural circuits is enhanced not only by increasing synaptic strength but also by increasing intrinsic excitability. In contrast to the detailed analysis of long-term potentiation (LTP), less attention has been given to activity-dependent changes in the intrinsic neuronal excitability. By stimulating hippocampal CA1 pyramidal neurons with synaptic inputs correlating with postsynaptic neuronal spikes, we elicited an LTP of intrinsic excitability (LTP-IE) concurring with synaptic LTP. LTP-IE was manifested as a decrease in the action potential threshold that was attributable to a hyperpolarized shift in the activation curve of voltage-gated sodium channels (VGSCs) rather than activity-dependent changes in synaptic inputs or A-type K+ channels. Cell-attached patch recording of VGSC activities indicated such an activity-dependent change in VGSCs. Induction of LTP-IE was blocked by the NMDA receptor antagonist APV, intracellular BAPTA, the CaM kinase inhibitors KN-62 and autocamtide-2-related inhibitory peptide, and the protein synthesis inhibitors emetine and anisomycin. The results suggest that induction of LTP-IE shares a similar signaling pathway with the late phase of synaptic LTP and requires activation of the NMDA glutamate receptor subtype, Ca2+ influx, activity of CaM kinase II, and function of the protein synthesis. This new form of hippocampal neuronal plasticity could be a cellular correlate of learning and memory besides synaptic LTP.
Large-area ZnO nanorod arrays have been synthesized successfully on a stainless steel grid at a mild growth temperature of around 400 degrees C. The as-grown ZnO nanorods have uniform diameters of about 30-50 nm with approximately 5 nm tips. Patterned growth can be realized by engineering the shape of the grid in the growth. Photoluminescence demonstrates a sharp strong UV peak and a broad green band. The growth method provides a promising way of producing nanorod arrays with good controllability in patterns and morphologies, which will be critical in potential application such as high-efficiency filtering and catalysts.
The effect of external-cavity length on self-mixing signals in a multilongitudinal-mode Fabry-Perot laser diode (FP-LD) was investigated experimentally. It has been shown that the output waveforms of self-mixing signals vary periodically when the length of the external cavity changes. This result agrees well with our theoretical calculations for the self-mixing effect of two adjacent longitudinal modes in a FP-LD. Moreover, the time-averaged output intensities of self-mixing signals has also been measured and compared with theoretical analysis.
AIM: To observe the effect of resveratrol on nuclear factor Kappa-B (NF-kappaB) activation and the inflammatory response in sodium taurocholate-induced pancreatitis in rats. METHODS: Seventy-two male SD rats were randomly divided into three groups: sham operation group (control), severe acute pancreatitis (SAP) group, and severe acute pancreatitis group treated with resveratrol (RES). A SAP model was established by injecting 4% sodium taurocholate 1 mL/kg through puncturing the pancreatic duct. In Res group, Res was given at 30 mg/kg b.m. intraperitoneally after the SAP model was successfully established. Eight animals from each group were sacrificed at 3, 6 and 12 h after modeling. The expression of NF-kappaB activation of pancreas was detected by immunohistochemical staining, whereas the levels of TNF-alpha and IL-8 in pancreatic tissues were estimated by radioimmunoassay. The pathological changes of pancreas and lungs were examined microscopically. RESULTS: Much less hyperemia, edema, dust-colored necrotic focus and soaps were noticed in pancreas in RES group than in SAP group. In RES group, hemorrhage, exudates and infiltration of inflammatory cells in pancreas and interstitial edema, destruction of alveolar wall in lung were significantly less than in SAP group. In the SAP group, the activation of NF-kappaB in pancreatic tissues was enhanced significantly at any measure point compared with control group (64.23+/-10.72% vs 2.56+/-0.65%, 55.86+/-11.34% vs 2.32+/-0.42%, 36.23+/-2.30% vs 2.40+/-0.36%,P<0.01), TNF-alpha,IL-8 were also increased and reached their peak at 6 h and then declined. The activation of NF-kappaB and the levels of TNF-alpha and IL-8 in RES group were significantly lower than those in SAP group (P<0.01): activation (52.63+/-9.45% vs 64.23+/-10.72%, 40.52+/-8.40% vs 55.86+/-11.34%, 29.83+/-5.37% vs 36.23+/-2.30%), TNF-alpha (132.76+/-15.68 pg/mL vs 158.36+/-12.58 pg/mL, 220.32+/-23.57 pg/mL vs 247.67+/- 11.62 pg/mL, 175.68+/-18.43 pg/mL vs 197.35+/-12.57 pg/mL) and IL-8 (0.62+/-0.21 microg/L vs 0.83+/-0.10 microg/L, 1.10+/-0.124 microg/L vs 1.32+/-0.18 microg/L, 0.98+/-0.16 microg/L vs 1.27+/-0.23 microg/L). CONCLUSION: The activation of NF-kappaB is involved in the inflammatory response of rats with SAP. Resveratrol could effectively inhibit the expression of NF-kappaB activation, alleviate the severity of SAP through its anti-inflammatory effects and regulate the inflammatory mediators.
AIM: To investigate the mechanism of resveratrol underlying the microcirculation disorder and lung injury following severe acute pancreatitis (SAP). METHODS: Twenty-four rats were divided into 3 groups (SAP, sham and resveratrol groups) randomly. SAP model was established by injecting 4% sodium taurocholate 1 mL/kg through puncturing pancreatic ducts. Sham (control) group (8 rats) was established by turning over the duodenum. Resveratrol was given at 0.1 mg/kg b.m. intraperitoneally. Rats were sacrificed 9 h after SAP was induced. Blood samples were obtained for hemorrheological examination. Lung tissues were used for pathological observation, and examination of microvascular permeability, dry/wet ratio and myeloperoxidase (MPO) activity. Gene expression of intercellular adhesion molecule-1 (ICAM-1) was detected by RT-PCR. RESULTS: Compared with SAP group, resveratrol relieved the edema and infiltration of leukocytes in the lungs. Resveratrol improved markers of hemorrheology: high VTB (5.77+/-1.18 mPas vs 9.49+/-1.34 mPas), low VTB (16.12+/-3.20 mPas vs 30.91+/-7.28 mPas), PV (4.69+/-1.68 mPas vs 8.00+/-1.34 mPas), BSR (1.25+/-0.42 mm/h vs 0.03+/-0.03 mm/h), VPC (54.67+/-3.08% vs 62.17+/-3.39%), fibrinogen (203.2+/-87.8 g/ L vs 51.3+/-19.1 g/L), original hemolysis (0.45+/-0.02 vs 0.49+/-0.02), and complete hemolysis (0.41+/-0.02 vs 0.43+/-0.02) (P<0.05). Resveratrol decreased the OD ratio of ICAM-1 gene (0.800+/-0.03 vs 1.188+/-0.10), dry/wet ratio (0.74+/-0.02 vs 0.77+/-0.03), microvascular permeability (0.079+/-0.006 vs 0.112+/-0.004) and MPO activity (4.42+/-0.32 vs 5.03+/-0.51) significantly (P<0.05). CONCLUSION: Resveratrol can improve the microcirculation disorder of the lung by decreasing leukocyte-endothelial interaction, reducing blood viscosity, improving the decrease of blood flow, and stabilizing erythrocytes in SAP rats. It may be a potential candidate to treat SAP and its severe complications (ALI).
RATIONALE: There is currently no optimal treatment or effective drug for severe acute respiratory syndrome (SARS), because the immunopathologic mechanism is poorly understood. OBJECTIVES: To explore the immune mechanism underlying the pathogenesis of SARS, we studied the expression profile of cytokines/chemokines in the blood and the immunopathology of the lung and lymphoid tissues. METHODS: Fourteen cytokines/chemokines in the blood of 23 patients with SARS were dynamically screened, using a bead-based multiassay system. Reverse transcription-polymerase chain reaction was performed to amplify mRNA. Histopathology of the lung and lymphoid tissues at autopsy was examined, using methods of immunohistochemistry and double immunofluorescence staining. MAIN RESULTS: Interferon-inducible protein-10 (IP-10) was markedly elevated in the blood during the early stage of SARS, and remained at a high level until convalescence. Moreover, IP-10 was highly expressed in both lung and lymphoid tissues, where monocyte-macrophage infiltration and depletion of lymphocytes were observed. The levels of interleukin-6, interleukin-8, and monocyte chemoattractant protein-1 were concomitantly increased in the blood of the patients with superinfection, and the mRNAs for these cytokines were also increased in lung tissues. CONCLUSIONS: Induction of IP-10 is a critical event in the initiation of immune-mediated acute lung injury and lymphocyte apoptosis during the development of SARS. Superinfection after the immune injury is the main cause of death. The prompt elevation of interleukin-6, interleukin-8, and monocyte chemoattractant protein-1 is a sign of superinfection, indicating a high risk of death.
OBJECTIVE: RNA interference is a process in which genes can be silenced sequence-specifically. In mammals, RNA interference can be invoked by introduction of small (19-21-nucleotide) double-stranded RNA molecules known as small interfering RNA (siRNA) into cells. Thereby, siRNA offers promise as a novel therapeutic modality. However, siRNA is a relatively large, highly charged molecule and does not readily enter cells. This study was undertaken to investigate the use of electroporation for in vivo transfection of siRNA into joint tissue in arthritic mice to achieve local RNA interference. METHODS: Proof of principle that siRNA is able to inhibit gene expression in vivo in the mouse joint was studied by local injection and electroporation of siRNA designed to silence reporter genes. In mice with collagen-induced arthritis (CIA), the disease-modulating activity of siRNA designed to silence tumor necrosis factor alpha (TNFalpha) was investigated. RESULTS: Luciferase activity could be reduced by >90% with luciferase-specific siRNA as compared with the activity measured after electroporation without siRNA or with irrelevant siRNA. The effect was observed only locally. In mice with CIA, electroporation of siRNA designed to inhibit TNFalpha strongly inhibited joint inflammation, whereas electroporation of irrelevant siRNA or injection of siRNA against TNFalpha without electroporation failed to produce therapeutic effects. CONCLUSION: Local electroporation of siRNA in joint tissue can inhibit CIA in mice. These results offer promise for the use of siRNA as a new strategy for therapeutic intervention in rheumatoid arthritis and may serve as a tool to study arthritis disease pathways through loss-of-function phenotypes.
It has been commonly recognized that residual dipolar coupling data provide a measure of quality for protein structures. To quantify this observation, a database of 100 single-domain proteins has been compiled where each protein was represented by two independently solved structures. Backbone 1H-15N dipolar couplings were simulated for the target structures and then fitted to the model structures. The fits were characterized by an R-factor which was corrected for the effects of non-uniform distribution of dipolar vectors on a unit sphere. The analyses show that favorable R values virtually guarantee high accuracy of the model structure (where accuracy is defined as the backbone coordinate rms deviation). On the other hand, unfavorable R values do not necessarily suggest low accuracy. Based on the simulated data, a simple empirical formula is proposed to estimate the accuracy of protein structures. The method is illustrated with a number of examples, including PDZ2 domain of human phosphatase hPTP1E.
In a retrospective study, levels of LH in the midfollicular phase had a significant impact on ovarian response and pregnancy outcome. High LH levels were associated with reduced implantation and clinical pregnancy rates.
Effects of docosahexaenoic acid (DHA) on survival and neurite outgrowth were investigated in primary cultures of rat cortical neurons. Cell cultures were prepared from cortex on embryonic day 18 (E-18) for treatment with a series of DHA concentrations (12.5, 25, 50, 75, 100 and 200 microM). Docosahexaenoic acid (25-50 microM) significantly enhanced neuronal viability, but lower concentration of DHA (12.5 microM) did not show an obvious effect. In contrast, higher concentrations of DHA (100-200 microM) exerted the significant opposite effects by decreasing neuronal viability. Furthermore, treatment with 25 microM DHA significantly prevented the neurons from death after different culture days in vitro (DIV). Moreover, measurements from the cultures exposed to 25 microM DHA immediately after plating showed significant increases in the percentage of cells with neurites, the mean number of neurite branches, the total neuritic length per cell and the length of the longest neurite in each cell after 24 and 48 h in vitro (HIV). The DHA-treated neurons had greater growth-associated protein-43 (GAP-43) immunoactivity and higher phosphatidylserine (PS) and phosphatidylethanolamine (PE) contents, but lower phosphatidylcholine (PC) content than control neurons. The significant increased DHA contents were also observed in both PE and PS in the treated neurons. These findings suggest that optimal DHA (25 microM) may have positive effects on the survival and the neurite outgrowth of the cultured fetal rat cortical neurons, and the effects probably are related to DHA-stimulating neuron-specific protein synthesis and its enhancing the discrete phospholipid (PL) content through enrichment of DHA in the PL species.
Infrared (1.2-1.6 microm) luminescence in a ytterbium aluminium garnet (YbAG) crystal, doped with Cr (0.05at.%) ions, was investigated under CW laser diode pumping (lambda=940 nm). The Cr4+ emission band was observed with its peak at 1.34 microm and measured to be about 1.3 times with respect to Yb3+ IR luminescence (lambda=1.03 microm). We demonstrate that for the excitation wavelength of 940 nm Yb3+ ions act as sensitizers of the 3B2(3T2)-3B1(3A2) emission of Cr4+ ions. This crystal is promising as a high-efficient system for tunable laser (1.2-1.6 microm) output.
Yb(3)Al(5)O(12) single crystal has been grown by Czochralski (CZ) method. The absorption spectrum was investigated at low temperature and the electronic energy levels for (2)F(5/2) multiplet of Yb(3+) in YbAG was proposed. The up-conversion emission of the crystal under 940 nm diode pumping and the X-ray excited luminescence (XEL) features of the crystal were also studied.
Six novel 4,5-seco-rearranged abietane diterpenoids, including one tetracyclic diterpenoid, prionoid A (1), two tricyclic diterpenoids, prionoids B (2) and C (3), and three dicyclic diterpenoids, prionoids D (4), E (5), and F (6), were isolated from the roots of Salvia prionitis Hance (Labiatae). Their structures were elucidated using spectroscopic analysis. The structure of 1 was further confirmed by a single-crystal X-ray diffraction determination. Moreover, it was found that 4 (IC50 = 0.41 microM) and 5 (IC50 = 0.72 microM) showed significant cytotoxic activity against P-388 and A-549 cell lines, respectively.
Using Western blot analysis we found transcriptional co-repressor Sin3A to be expressed at a higher level in male mouse kidney than in females. HDAC1 (histone deacetylase 1) protein, another co-repressor forming complexes with Sin3A, was not higher in males. No sex differences in Sin3A expression were found after gonadectomy, suggesting that gonadal secretions in adulthood cause the sex difference in kidney expression of Sin3A. In contrast, HDAC1 levels were higher in castrated gonadal males than in females, which presumably reflects a long-lasting differentiating effect of testicular secretions in early development on this protein in kidneys. In gonadectomized mice in which sex chromosome complement (XX vs. XY) is independent of gonadal type (testes vs. ovaries), there was no difference in the level of Sin3A or HDAC1 expression in kidney in XX or XY mice of the same gonadal sex.
Information about the world is often represented in the brain in the form of topographic maps. A paradigm example is the topographic representation of the visual world in the optic tectum/superior colliculus. This map initially forms during neural development using activity-independent molecular cues, most notably some type of chemospecific matching between molecular gradients in the retina and corresponding gradients in the tectum/superior colliculus. Exactly how this process might work has been studied both experimentally and theoretically for several decades. This review discusses the experimental data briefly, and then in more detail the theoretical models proposed. The principal conclusions are that (1) theoretical models have helped clarify several important ideas in the field, (2) earlier models were often more sophisticated than more recent models, and (3) substantial revisions to current modelling approaches are probably required to account for more than isolated subsets of the experimental data.
Rifamycin B biosynthesis by Amycolatopsis mediterranei S699 involves a number of unusual modification reactions in the formation of the unique polyketide backbone and decoration of the molecule. A number of genes believed to be involved in the tailoring of rifamycin B were investigated and the results confirmed that the formation of the naphthalene ring moiety of rifamycin takes place during the polyketide chain extension and is catalysed by Rif-Orf19, a 3-(3-hydroxyphenyl)propionate hydroxylase-like protein. The cytochrome P450-dependent monooxygenase encoded by rif-orf5 is required for the conversion of the Delta12, 29 olefinic bond in the polyketide backbone of rifamycin W into the ketal moiety of rifamycin B. Furthermore, Rif-Orf3 may be involved in the regulation of rifamycin B production, as its knock-out mutant produced about 40 % more rifamycin B than the wild-type. The work also revealed that many of the genes located in the cluster are not involved in rifamycin biosynthesis, but might be evolutionary remnants carried over from an ancestral lineage.