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981.
Elmarakby AA Faulkner J Al-Shabrawey M Wang MH Maddipati KR Imig JD 《American journal of physiology. Regulatory, integrative and comparative physiology》2011,301(5):R1307-R1317
Studies suggest that soluble epoxide hydrolase (sEH) inhibition reduces end-organ damage in cardiovascular diseases. We hypothesize that sEH gene (Ephx2) knockout (KO) improves endothelial function and reduces renal injury in streptozotocin-induced diabetes. After 6 wk of diabetes, afferent arteriolar relaxation to acetylcholine was impaired in diabetic wild-type (WT) mice, as the maximum relaxation was 72% of baseline diameter in the WT but only 31% in the diabetic mice. Ephx2 KO improved afferent arteriolar relaxation to acetylcholine in diabetes as maximum relaxation was 58%. Urinary monocyte chemoattractant protein-1 (MCP-1) excretion significantly increased in diabetic WT mice compared with control (868 ± 195 vs. 31.5 ± 7 pg/day), and this increase was attenuated in diabetic Ephx2 KO mice (420 ± 98 pg/day). The renal phospho-IKK-to-IKK ratio and nuclear factor-κB were significantly decreased, and hemeoxygenase-1 (HO-1) expression increased in diabetic Ephx2 KO compared with diabetic WT mice. Renal NADPH oxidase and urinary thiobarbituric acid reactive substances excretion were reduced in diabetic Ephx2 KO compared with diabetic WT mice. Albuminuria was also elevated in diabetic WT mice compared with control (170 ± 43 vs. 37 ± 13 μg/day), and Ephx2 KO reduced this elevation (50 ± 15 μg/day). Inhibition of sEH using trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (tAUCB) also reduced renal inflammation and injury in diabetic WT mice. Furthermore, inhibition of HO with stannous mesoporphyrin negated the reno-protective effects of tAUCB or Ephx2 KO during diabetes. These data demonstrate that Ephx2 KO improves endothelial function and reduces renal injury during diabetes. Additionally, our data also suggest that activation of HO-1 contributes to improved renal injury in diabetic Ephx2 KO mice. 相似文献
982.
Kotipatruni RR Dasari VR Veeravalli KK Dinh DH Fassett D Rao JS 《Neurochemical research》2011,36(11):2063-2074
Spinal cord injury (SCI) induces a series of endogenous biochemical changes that lead to secondary degeneration, including
apoptosis. p53-mediated mitochondrial apoptosis is likely to be an important mechanism of cell death in spinal cord injury.
However, the signaling cascades that are activated before DNA fragmentation have not yet been determined. DNA damage-induced,
p53-activated neuronal cell death has already been identified in several neurodegenerative diseases. To determine DNA damage-induced,
p53-mediated apoptosis in spinal cord injury, we performed RT-PCR microarray and analyzed 84 DNA damaging and apoptotic genes.
Genes involved in DNA damage and apoptosis were upregulated whereas anti-apoptotic genes were downregulated in injured spinal
cords. Western blot analysis showed the upregulation of DNA damage-inducing protein such as ATM, cell cycle checkpoint kinases,
8-hydroxy-2′-deoxyguanosine (8-OHdG), BRCA2 and H2AX in injured spinal cord tissues. Detection of phospho-H2AX in the nucleus
and release of 8-OHdG in cytosol were demonstrated by immunohistochemistry. Expression of p53 was observed in the neurons,
oligodendrocytes and astrocytes after spinal cord injury. Upregulation of phospho-p53, Bax and downregulation of Bcl2 were
detected after spinal cord injury. Sub-cellular distribution of Bax and cytochrome c indicated mitochondrial-mediated apoptosis
taking place after spinal cord injury. In addition, we carried out immunohistochemical analysis to confirm Bax translocation
into the mitochondria and activated p53 at Ser392. Expression of APAF1, caspase 9 and caspase 3 activities confirmed the intrinsic apoptotic pathway after SCI. Activated p53
and Bax mitochondrial translocation were detected in injured spinal neurons. Taken together, the in vitro data strengthened
the in vivo observations of DNA damage-induced p53-mediated mitochondrial apoptosis in the injured spinal cord. 相似文献
983.
Hsp31 of Escherichia coli K-12 is glyoxalase III 总被引:1,自引:0,他引:1
Hsp31 encoded by hchA is known as a heat‐inducible molecular chaperone. Although structure studies revealed that Hsp31 has a putative catalytic triad consisting of Asp‐214, His‐186 and Cys‐185, its enzymatic function, besides weak amino‐peptidase activity, is still unknown. We found that Hsp31 displays glyoxalase activity that catalyses the conversion of methylglyoxal (MG) to d ‐lactate without an additional cofactor. The glyoxalase activity was completely abolished in the hchA‐deficient strain, confirming the relationship between the hchA gene and its enzymatic activity in vivo. Hsp31 exhibits Michaelis–Menten kinetics for substrates MG with Km and kcat of 1.43 ± 0.12 mM and 156.9 ± 5.5 min?1 respectively. The highest glyoxalase activity was found at 35–40°C and pH of 6.0–8.0, and the activity was significantly inhibited by Cu2+, Fe3+ and Zn2+. Mutagenesis studies based on our evaluation of conserved catalytic residues revealed that the Cys‐185 and Glu‐77 were essential for catalysis, whereas His‐186 was less crucial for enzymatic function, although it participates in the catalytic process. The stationary‐phase Escherichia coli cells became more susceptible to MG when hchA was deleted, which was complemented by an expression of plasmid‐encoded hchA. Furthermore, an accumulation of intracellular MG was observed in hchA‐deficient strains. 相似文献
984.
C.V. Chandrasekaran H.B. DeepakP. Thiyagarajan S. KathiresanGopal Krishna Sangli M. DeepakAmit Agarwal 《Phytomedicine》2011,18(4):278-284
Glycyrrhiza glabra and its phytoconstituents have been known to possess widespread pharmacological properties as an anti-inflammatory, anti-viral, antitumour and hepatoprotective drug. In this study, we examined the inhibitory potential of extract of G. glabra (GutGard™) root and its phytoconstituents (glabridin, glycyrrhizin, and isoliquiritigenin) on both cyclooxygenase (COX) and lipoxygenase (LOX) products in order to understand the mechanism of its anti-inflammatory action. Inhibitory effect of GutGard™ and its phytoconstituents on lipopolysaccharide (LPS) induced prostaglandin E2 (PGE2), calcimycin (A23187) induced thromboxane (TXB2), and leukotriene (LTB4) release was studied using murine macrophages (J774A.1) and human neutrophil (HL-60) cells. Results revealed that, G. glabra and glabridin significantly inhibited PGE2, TXB2 (COX) and LTB4 (LOX), while, isoliquiritigenin exerted inhibitory effect only against COX products but failed to suppress LOX product. However, glycyrrhizin at the tested concentrations failed to exhibit inhibitory effect on both COX and LOX products. Here, we report for the first time that G. glabra (almost devoid of glycyrrhizin) exhibits anti-inflammatory property likely through the inhibition of PGE2, TXB2 and LTB4 in mammalian cell assay system, which could be influenced in part by glabridin and isoliquiritigenin. 相似文献
985.
Krishna Kumar Natarajan Amaresan Someshwar Bhagat Kutthum Madhuri Ramesh Chandra Srivastava 《World journal of microbiology & biotechnology》2011,27(7):1625-1632
In this study, a total of 80 rhizobacteria was isolated from coastal agricultural ecosystem of cultivated vegetable rhizosphere
soils. The isolates were screened for antagonistic activity against Sclerotium
rolfsii and Colletotrichum
capsici and plant growth promoting traits. The results revealed that 15.0 and 43.7% isolates showed statistically significant inhibition
of mycelial growth of S. rolfsii and C. capsici respectively, while 48.7% isolates produced siderophore, 57.5% isolates solubilized phosphate and 21.1% isolates produced
indole-3-acetic acid more than 20 μg/mL. However, only three isolates PfS1, PfR2 and BL5 were found positive to all properties
tested. The identification of potential bacterial isolates through Microbial Identification System (BIOLOG) and 16S rDNA sequencing
of the isolates revealed Bacillus species were dominant in the cultivated vegetable rhizosphere soil of Neil and Havelock Islands, India. 相似文献
986.
The sludge exchange process using two anaerobic digesters (CSTRs) in series was investigated under the mesophilic condition (36-38 °C). At first, the digesting sludge of the CSTRs in series with different TVFA/alkalinity ratios was tested in the laboratory by mixing the digesting sludge of two CSTRs from 6.5% to 50% based on volume. The sludge exchange test was then performed using the same CSTRs under batch and continuous processes. The change in the TVFA/alkalinity ratio was found to be linear with the digesting sludge exchange volume. The CSTR of TVFA/alkalinity ratio 1.970 recovered completely failed within 11 days for the batch process and the CSTR of TVFA/alkalinity ratio 1.514 within 3 weeks for the continuous feeding process at a sludge exchange volume of 13%. The reactor operation was stable when the TVFA/alkalinity ratio was less than 1.0 and when the TVFA concentration was lower than 10,000 mg L−1. 相似文献
987.
988.
Vlahov IR You F Santhapuram HK Wang Y Vaughn JF Hahn SJ Kleindl PJ Fan M Leamon CP 《Bioorganic & medicinal chemistry letters》2011,21(4):1202-1205
Efficient syntheses of folate receptor (FR) targeting conjugates of the anti-inflammatory, aminopterin hydrazide, are described. 2-{4-Benzoylamino}-5-oxo-5-{N′-[2-(pyridin-2-yldisulfanyl)-ethoxycarbonyl]-hydrazino}-pentanoic acid is synthesized from commercially available 4-[(2-amino-4-imino-3,4-dihydro-pteridin-6-yl-methyl)-amino]-benzoic acid. Conjugation of this novel, activated aminopterin hydrazide to folic acid through cysteine-terminating (C-terminus), peptide/carbohydrate spacers results in highly water soluble conjugates which allow for the release of free aminopterin hydrazide within the endosomes of targeted cells. 相似文献
989.
Salcedo-Sora JE Ochong E Beveridge S Johnson D Nzila A Biagini GA Stocks PA O'Neill PM Krishna S Bray PG Ward SA 《The Journal of biological chemistry》2011,286(52):44659-44668
Tetrahydrofolates are essential cofactors for DNA synthesis and methionine metabolism. Malaria parasites are capable both of synthesizing tetrahydrofolates and precursors de novo and of salvaging them from the environment. The biosynthetic route has been studied in some detail over decades, whereas the molecular mechanisms that underpin the salvage pathway lag behind. Here we identify two functional folate transporters (named PfFT1 and PfFT2) and delineate unexpected substrate preferences of the folate salvage pathway in Plasmodium falciparum. Both proteins are localized in the plasma membrane and internal membranes of the parasite intra-erythrocytic stages. Transport substrates include folic acid, folinic acid, the folate precursor p-amino benzoic acid (pABA), and the human folate catabolite pABAG(n). Intriguingly, the major circulating plasma folate, 5-methyltetrahydrofolate, was a poor substrate for transport via PfFT2 and was not transported by PfFT1. Transport of all folates studied was inhibited by probenecid and methotrexate. Growth rescue in Escherichia coli and antifolate antagonism experiments in P. falciparum indicate that functional salvage of 5-methyltetrahydrofolate is detectable but trivial. In fact pABA was the only effective salvage substrate at normal physiological levels. Because pABA is neither synthesized nor required by the human host, pABA metabolism may offer opportunities for chemotherapeutic intervention. 相似文献
990.
Banerjee A Lang JY Hung MC Sengupta K Banerjee SK Baksi K Banerjee DK 《The Journal of biological chemistry》2011,286(33):29127-29138
Up-regulation of the dolichol pathway, a "hallmark" of asparagine-linked protein glycosylation, enhances angiogenesis in vitro. The dynamic relationship between these two processes is now evaluated with tunicamycin. Capillary endothelial cells treated with tunicamycin were growth inhibited and could not be reversed with exogenous VEGF(165). Inhibition of angiogenesis is supported by down-regulation of (i) phosphorylated VEGFR1 and VEGFR2 receptors; (ii) VEGF(165)-specific phosphotyrosine kinase activity; and (iii) Matrigel(TM) invasion and chemotaxis. In vivo, tunicamycin prevented the vessel development in Matrigel(TM) implants in athymic Balb/c (nu/nu) mice. Immunohistochemical analysis of CD34 (p < 0.001) and CD144 (p < 0.001) exhibited reduced vascularization. A 3.8-fold increased expression of TSP-1, an endogenous angiogenesis inhibitor in Matrigel(TM) implants correlated with that in tunicamycin (32 h)-treated capillary endothelial cells. Intravenous injection of tunicamycin (0.5 mg/kg to 1.0 mg/kg) per week slowed down a double negative (MDA-MB-435) grade III breast adenocarcinoma growth by ~50-60% in 3 weeks. Histopathological analysis of the paraffin sections indicated significant reduction in vessel size, the microvascular density and tumor mitotic index. Ki-67 and VEGF expression in tumor tissue were also reduced. A significant reduction of N-glycan expression in tumor microvessel was also observed. High expression of GRP-78 in CD144-positive cells supported unfolded protein response-mediated ER stress in tumor microvasculature. ~65% reduction of a triple negative (MDA-MB-231) breast tumor xenograft in 1 week with tunicamycin (0.25 mg/kg) given orally and the absence of systemic and/or organ failure strongly supported tunicamycin's potential for a powerful glycotherapeutic treatment of breast cancer in the clinic. 相似文献