Biomedical subjects
Publications and source records attributed to J Xu.
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.
High expression of epidermal growth factor receptor (EGFR) is found in a variety of solid tumors, including colorectal cancer. EGFR has been identified as a rational target for anticancer therapy. Curcumin, the yellow pigment of turmeric in curry, has received attention as a promising dietary supplement for cancer prevention and treatment. We recently reported that curcumin inhibited the growth of human colon cancer-derived Moser cells by suppressing gene expression of cyclinD1 and EGFR. The aim of the present study was to explore the molecular mechanisms underlying curcumin inhibition of gene expression of EGFR in colon cancer cells. The generality of the inhibitory effect of curcumin on gene expression of EGFR was verified in other human colon cancer-derived cell lines, including Caco-2 and HT-29 cells. Promoter deletion assays and site-directed mutageneses identified a binding site for the transcription factor early growth response-1 (Egr-1) in egfr promoter as a putative curcumin response element in regulating the promoter activity of the gene in Moser cells. Electrophoretic mobility shift assays demonstrated that curcumin significantly reduced the DNA-binding activity of the transcription factor Egr-1 to the curcumin response element. In addition, curcumin reduced the trans-activation activity of Egr-1 by suppressing egr-1 gene expression, which required interruption of the ERK signal pathway and reduction of the level of phosphorylation of Elk-1 and its activity. Taken together, our results demonstrated that curcumin inhibited human colon cancer cell growth by suppressing gene expression of EGFR through reducing the trans-activation activity of Egr-1. These results provided novel insights into the mechanisms of curcumin inhibition of colon cancer cell growth and potential therapeutic strategies for treatment of colon cancer.
The results of studying angular dependent spectral parameters in a magnetic field are reported in the chiral smectic C phases of a smectogen 1-methylheptyl -(4-n-decyloxybenzoyloxy)-biphenyl-4-carboxylate. Our data provide direct evidence of a phase transition between two ferrielectric phases in this compound, viz. three-layer (SmC*(FiI)) and four-layer (SmC*(FiII)) superlattices. Simulation of spectral patterns of the methyl (C10) deuterons obtained after an aligned sample is rotated by 90 degrees in the magnetic field rules out the "clock model" for the three-layer and four-layer structures in these ferriphases. Instead, our data obtained under a magnetic field (9.4 T) seem to favor an "asymmetric clock model" for the interlayer packing. Interlayer jump rate is also obtained from the simulation of angular dependent spectra in these ferrielectric phases, and compared with those in the antiferroelectric SmC*(A) phase.
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OBJECTIVE: Cardiac ischemia/reperfusion (I/R) injury, a necessary consequence of transplantation, is probably related to the formation of reactive oxygen species (ROS). The ROS burst within the first moments of reperfusion is associated with injury, continuously generate O2- at about 3% to 5% of total O2 consumption owing to electron leak by mitochondrial oxidoreductases, especially complexes I and III. 3-nitro-N-methyl-salicylamide (NNMS) displays inhibitory effects on succinate-cytochrome C reductase, but also reduces effects on creation of O2- radical and H2O2 by isolated rat mitochondria. Presumably NNMS inhibits electron leakage from the mitochondrial respiratory chain. We investigated effect of NNMS on heart protection after hypothermic ischemia. METHODS: A Langendorff-prepared rat heart model was employed after the heart had been preserved for 4 hours under hypothermic conditions of ischemia with subsequent reperfusion/rewarming for 60 minutes. RESULTS: The group of hearts treated with NNMS showed increased recovery of heart function compared with a group of mEC. The lactate dehydrogenase (LDH) activity in coronary flow (CF) by hearts treated with NNMS was lower than that with mECs, as was the content of malonedialdehyde (MDA) and conjugated diene (CD). CONCLUSIONS: NNMS improved heart physiology after reperfusion following 4 hours of hypothermic ischemia.
AIM: Six cases of hemophilia A treated with living related donated splenic transplantation (LRDST) were performed over 10 years. METHODS: We reviewed the six consecutive cases of LRDST from 1992 to 2002. Three patients received whole spleen allografts and the other three, partial spleen allografts. All allografts were transplanted to the extraperitoneal space in the right iliac fossa by an end-to-end anastomosis between the splenic artery and the internal iliac artery and an end-to-side anastomosis between the splenic vein and the external (or common) iliac vein. After the operation, a combined regimen with cyclosporine, azathioprine, anti-lymphocyte globulin, OKT3, was administered to suppress the immune reaction. RESULTS: The functional period of the allografts varied between 30 days to 4 years. Patient factor-VIII (F-VIII) levels rose from less than 5% before operation to 15% to 56% postoperatively. One patient died from central nervous system complications. Another lost his graft because exogenous F-VIII was not supplemented in timely fashion at the onset of rejection. And the third could no longer afford the expensive immunosuppressive drugs at 2 years after the operation and eventually lost the spleen. The remaining three patients presently have regained self-support, among whom one has survived for 4 years. CONCLUSION: Though the sample pool is relatively small, our clinical observations tend to confirm LRDST as a feasible, effective treatment for hemophilia A.
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A new beta-dihydroagarofuran sesquiterpene ester, 1beta,2beta,6alpha, 13-tetraacetoxy-9alpha-cinnamoyloxy-beta-dihydroagarofuran (1), and the known compound 1beta,6alpha,13-triacetoxy-9alpha-benzoyloxy-beta-dihydroagarofuran (2), have been isolated from the fruits of Celastrus orbiculatus Thunb. Their structures have been elucidated on the basis of spectroscopic methods. Compound 1 shows moderate activity of inhibiting LPS-induced nitric oxide production in murine macrophage RAW264.7 cells, with an IC50 of 55.4 microM.
Dilated cardiomyopathy (DCM), a heart disease, affects many vertebrates including humans and poultry. The disease can be either idiopathic (IDCM) or toxin-induced (TIDCM). Although genetic and other studies of IDCM are extensive, the specific etiology of TIDCM is still unknown. In this study, we compared mRNA levels of cardiac troponin T (cTnT) and phospholamban (PLN) in turkeys affected and unaffected by TIDCM. Cardiac TnT and PLN were chosen because their altered expression has been observed in IDCM-affected birds. A total of 72 birds, 44 affected and 28 unaffected with TIDCM, were used. Differences in the mRNA levels of cTnT and PLN between affected and unaffected turkeys were significant only for cTnT. The sequence of the turkey PLN showed significant similarity at the nucleotide level to the reference chicken sequence and to those of other species. In addition to implicating cTnT in TIDCM, the present work describes a partial turkey PLN coding sequence that could be useful for future studies.
BACKGROUND: Systemic lupus erytematosus (SLE) is characterized by the presence of various autoantibodies and the deposition of immune complexes which are cleared by Fcgamma receptors. OBJECTIVES: Family-based association analysis was performed to investigate whether the FCGR3A-72S/R and FCGR3A-270T/R polymorphisms are risk factors for SLE in a Chinese population. METHODS: In total, 119 patients with SLE from 95 nuclear families, aged 14-78 years, who met the American College of Rheumatology 1997 criteria were recruited, as were 316 family members of these patients. We studied two single-nucleotide polymorphisms (SNPs) encoding nonsynonymous substitution in the FCGR3A gene with respect to genetic susceptibility to SLE in a collection of 435 subjects from 95 nuclear families. We performed the genotyping using PCR restriction fragment length polymorphism. RESULTS: Our results showed that FCGR3A-72R/S have an excess of transmission of the R allele from heterozygous parents to affected offspring (transmission disequilibrium test chi2 = 9.30, P = 0.0032). Univariate (single-marker) family-based association tests demonstrated that a variant allele at SNP rs403016 of the FCGR3A gene was significantly associated with genetic susceptibility to SLE (exon 3, Z = 2.5444, P = 0.01097) in an additive model. The R and S allele frequencies were 39.4% and 60.6%, respectively. The frequencies of FCGR3A 72R/R, R/S and SS genotypes were 9.1%, 60.6% and 30.3%, respectively. However, the FCGR3A-270T/S SNP was not found in this Chinese population. CONCLUSION: This study suggests a linkage disequilibrium of the FCGR3A-72R/S SNP with SLE, and supports the notion that a novel polymorphism of the FCGR3A-72R/S SNP is associated with genetic susceptibility to SLE in Chinese populations.
Mesangial cell proliferation is a common cellular response to a variety of different types of glomerular injury. Complement C5b-9 is a prime candidate to mediate mesangial cell proliferation, especially sublytic C5b-9, which can induce the production of multiple inflammatory factors and cytokines. Transforming growth factor (TGF)-beta1 plays a major role in the accumulation of extracellular matrix (ECM), while thrombospondin (TSP)-1 has been identified as an activator of latent TGF-beta1 in an in vitro system. Using rat glomerular mesangial cells (GMCs) as a model system, we assessed the effect of sublytic C5b-9 on the expression of TSP-1 and TGF-beta1 and explored the relevant pathway of signal transduction. First, we ensured the concentrations of anti-Thy1 antibody and complement, which were regarded as a sublytic C5b-9 dose, and examined whether the sublytic C5b-9 induced expression of TSP-1 in rat GMCs which, in turn, activated latent TGF-beta1 by real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA), respectively. Then, we investigated the role of the PI3-k/Akt pathway in sublytic C5b-9-induced TSP-1 production in rat GMCs by Western blot analysis. The addition of sublytic C5b-9 (5% anti-Thy1 antibody and 4% normal serum) to rat GMCs induced activation of latent TGF-beta1 via TSP-1. The addition of sublytic C5b-9 apparently increased the protein of Akt phosphorylation, whereas PI3-k inhibitor LY294002 could clearly reduce the increase of TSP-1 induced by sublytic C5b-9. These results indicate that TSP-1 is an activator of latent TGF-beta1 in sublytic C5b-9-induced rat GMCs; furthermore, the PI3-k/Akt signal transduction pathway may play a key role in sublytic C5b-9-induced TSP-1 production.
To understand virus and host interactions and host responses to rotavirus infection in children, we analysed by real-time polymerase chain reaction (PCR) the expression of mRNA for five Toll-like receptors (TLRs) (TLR2, TLR3, TLR4, TLR7 and TLR8) and four T helper (Th)1 and Th2 cytokines [interleukin (IL)-2, IL-12, interferon (IFN)-gamma and IL-4) in peripheral blood mononuclear cells (PBMC) of children with acute rotavirus diarrhoea. We observed significantly higher expression of genes encoding TLR2, TLR3, TLR4, TLR7 and TLR8 in PBMC of 41% (31/75) patients within 3 days of illness onset than those in healthy children. After 3 days of illness onset, only TLR3 and TLR8 mRNA expressions were still significantly (P<0.05) increased in 59% (44/75) children with diarrhoea. We also observed significantly (P<0.05) elevated expression of IL-12p40 and IFN-gamma in PBMC of patients during the entire period of illness and the first 3 days of illness, respectively. We further demonstrated a weak but significant association between elevated levels of gene expression of four TLRs (TLR2, TLR3, TLR4 and TLR8) and IFN-gamma. Our results suggest that multiple TLRs may modulate the immune response in the acute phase of rotavirus infection and play a role in the activation of IFN-gamma.