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21.
McNulty J Nair JJ Vurgun N Difrancesco BR Brown CE Tsoi B Crankshaw DJ Holloway AC 《Bioorganic & medicinal chemistry letters》2012,22(1):718-722
The discovery of a novel five-component 1,2,3-triazole-containing pharmacophore that exhibits potent and selective inhibition of aromatase (CYP 450 19A1) is described. All compounds are derived from an initial aldol reaction of a phenylacetate derivative with an aromatic aldehyde. Structure-activity data generated from both syn- and anti-aldol adducts provides initial insights into the requirements for both potency and selectivity. 相似文献
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High affinity Ca-binding to rabbit aortic smooth muscle microsomes was reduced at low pH. To investigate the role of this Ca-binding, aortic strips were briefly exposed either to pH 5.1 or 7.3, subsequently incubated in a Ca-free medium at pH 7.3, and then challenged with 1 μM norepinephrine (NE). Tissues pretreated at pH 5.1 gave smaller contractions. Tissues loaded with 45Ca when exposed to pH 5.1 showed much larger release of 45Ca than those exposed to pH 7.3. Subsequently, all 45Ca-loaded tissues were placed at pH 7.3 and the effect of 100 μM NE on 45Ca-efflux was examined. Tissues exposed previously to pH 7.3 showed a NE-sensitive 45Ca-efflux but those pretreated at pH 5.1 did not. The results are consistent with, but do not prove, the hypothesis that the high affinity pH-sensitive Ca-binding to plasma membranes is a large Ca-pool and that the NE-sensitive Ca-pool is a small component of it. 相似文献
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Berkeley LI Cohen JF Crankshaw DL Shirota FN Nagasawa HT 《Journal of biochemical and molecular toxicology》2003,17(2):95-97
L-Cysteine-glutathione disulfide, a ubiquitous substance present in mammalian cells, was shown to be highly effective in protecting mice against acetaminophen-induced hepatotoxicity. Since the corresponding D-cysteine-glutathione disulfide was totally ineffective in this regard, an enzymatic mechanism that provides glutathione directly to cells is postulated. 相似文献
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The hepatic, microsomal, thiol:protein disulfide oxidoreductase catalyzes the glutathione (GSH) reduction of protein disulfides to sulfhydryl groups. In the presence of physiological concentrations of glucagon this activity increased from 2.3 to 6.4 fold in isolated microsomes. The stimulation had a P50 for glucagon of 7.8 X 10(-10) M which was only observed at microsomal protein concentrations of less than 100 micrograms/ml and in the presence of a GSH reducing system. This latter observation suggests that the stimulation may be inhibited by the presence of oxidized glutathione. These data support the hypothesis that glucagon may act in part by stimulating the reduction of protein disulfides by the thiol:protein disulfide oxidoreductase. 相似文献
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Timothy G. Bromage Yusuf M. Juwayeyi Igor Smolyar Bin Hu Santiago Gomez Vincent J. Scaringi Sydnee Chavis Premsai Bondalapati Khushmit Kaur John Chisi 《Comptes Rendus Palevol》2011,10(5-6):499-507
Of the major contributions to our understanding of the skeleton made by Armand de Ricqlès is the notion that within the microanatomy of bone we may observe “signals”, some relating to phylogeny, and others to aspects of growth, function, and physiology. We are motivated to follow this road, as it were, and read the “signposts” along the way. Incremental structures are such signposts, representing biological rhythms as successive forming fronts in enamel and bone. A long period rhythm in humans, which occurs on average every eight to nine days, is observed in enamel as the stria of Retzius and in bone as the lamella. Because lamellae are formed within defined periods of time, quantitative measures of widths of individual lamellae provide time-resolved growth rate variability. Results obtained on primary incremental lamellar bone from midshaft femur histological sections of sub-Saharan Africans of Bantu origin and known life history reveal environmental effects heretofore unknown. 相似文献
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Clouser CL Holtz CM Mullett M Crankshaw DL Briggs JE Chauhan J VanHoutan IM Patterson SE Mansky LM 《PloS one》2011,6(1):e15840
Replication of retroviral and host genomes requires ribonucleotide reductase to convert rNTPs to dNTPs, which are then used as substrates for DNA synthesis. Inhibition of ribonucleotide reductase by hydroxyurea (HU) has been previously used to treat cancers as well as HIV. However, the use of HU as an antiretroviral is limited by its associated toxicities such as myelosuppression and hepatotoxicity. In this study, we examined the ribonucleotide reductase inhibitor, gemcitabine, both in cell culture and in C57Bl/6 mice infected with LP-BM5 murine leukemia virus (LP-BM5 MuLV, a murine AIDS model). Gemcitabine decreased infectivity of MuLV in cell culture with an EC50 in the low nanomolar range with no detectable cytotoxicity. Similarly, gemcitabine significantly decreased disease progression in mice infected with LP-BM5. Specifically, gemcitabine treatment decreased spleen size, plasma IgM, and provirus levels compared to LP-BM5 MuLV infected, untreated mice. Gemcitabine efficacy was observed at doses as low as 1 mg/kg/day in the absence of toxicity. Higher doses of gemcitabine (3 mg/kg/day and higher) were associated with toxicity as determined by a loss in body mass. In summary, our findings demonstrate that gemcitabine has antiretroviral activity ex vivo and in vivo in the LP-BM5 MuLV model. These observations together with a recent ex vivo study with HIV-1, suggest that gemcitabine has broad antiretroviral activity and could be particularly useful in vivo when used in combination drug therapy. 相似文献
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Crankshaw DL Berkeley LI Cohen JF Shirota FN Nagasawa HT 《Journal of biochemical and molecular toxicology》2002,16(5):235-244
A series of double-prodrugs of L-cysteine, designed to release L-cysteine in vivo and stimulate the biosynthesis of glutathione (GSH), were synthesized. To evaluate the hepatoprotective effectiveness of these double-prodrugs, male Swiss-Webster mice were administered acetaminophen (ACP) (2.45 mmol/kg (360 mg/kg), intraperitoneally (i.p.)). Prodrug (2.50 mmol/kg, i.p. or 1.25 mmol/kg, i.p., depending on the protocol) was administered 1 h before ACP as a priming dose. A supplementary dose of prodrug (2.5 mmol/kg, i.p. or 1.25 mmol/kg, i.p. depending on the protocol) was administered 0.5 h after ACP. The plasma alanine amino transferase (ALT) values, 24 h after ACP administration were transformed to logs and the 95% and 99% confidence intervals of the log values were plotted and compared for each group. Hepatoprotection was assessed by the degree of attenuation of plasma ALT levels. With these multiple dose schedules, the use of 2% carboxymethylcellulose as vehicle for the prodrugs was found to be detrimental; therefore, the prodrugs were dissolved in dilute aqueous base and the pH adjusted for administration. When a priming dose was given 1 h before ACP followed by a supplementary dose 0.5 h after ACP, only N,S-bis-acetyl-L-cysteine, where both the sulfhydryl and amino groups of L-cysteine were functionalized with the acetyl group, was found to be effective in protecting mice against the hepatotoxic effects of ACP. This suggests that these acetyl groups were rapidly hydrolyzed in vivo to liberate L-cysteine. In contrast, N-acetylation of 2(R,S)-methylthiazolidine-4(R)-carboxylic acid (MTCA) and its 2-n-propyl analog (PTCA), or N-acetylation of 2-oxothiazolidine-4-carboxylic acid (OTCA), reduced the hepatoprotective effects relative to the parent MTCA, PTCA, and OTCA, indicating that the release of L-cysteine in vivo from these N-acetylated thiazolidine prodrugs was metabolically unfavorable. The carbethoxy group, whether functionalized on the sulfhydryl or on the amino group of L-cysteine, or on the secondary amino group of MTCA, appears to be a poor "pro-moiety," since these carbethoxylated double-prodrugs of L-cysteine did not protect mice from ACP-induced hepatotoxicity. 相似文献
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Alexander Ochoa Stuart A. Wells Gary West Ma’en Al-Smadi Sergio A. Redondo Sydnee R. Sexton Melanie Culver 《Conservation Genetics》2016,17(5):1145-1155
The Arabian oryx (Oryx leucoryx) historically ranged across the Arabian Peninsula and neighboring countries until its extirpation in 1972. In 1963–1964 a captive breeding program for this species was started at the Phoenix Zoo (PHX); it ultimately consisted of 11 animals that became known as the ‘World Herd’. In 1978–1979 a wild population was established at the Shaumari Wildlife Reserve (SWR), Jordan, with eight descendants from the World Herd and three individuals from Qatar. We described the mtDNA and nuclear genetic diversity and structure of PHX and SWR. We also determined the long-term demographic and genetic viability of these populations under different reciprocal translocation scenarios. PHX displayed a greater number of mtDNA haplotypes (n = 4) than SWR (n = 2). Additionally, PHX and SWR presented nuclear genetic diversities of \(\bar{N}_{\text{A}}\) = 2.88 vs. 2.75, \(\bar{H}_{\text{O}}\) = 0.469 vs. 0.387, and \(\bar{H}_{\text{E}}\) = 0.501 vs. 0.421, respectively. Although these populations showed no signs of inbreeding (\(\bar{F}_{\text{IS}}\) ≈ 0), they were highly differentiated (\(G^{\prime\prime}_{\text{ST}}\) = 0.580; P < 0.001). Migration between PHX and SWR (Nm = 1, 4, and 8 individuals/generation) increased their genetic diversity in the short-term and substantially reduced the probability of extinction in PHX during 25 generations. Under such scenarios, maximum genetic diversities were achieved in the first generations before the effects of genetic drift became predominant. Although captive populations can function as sources of genetic variation for reintroduction programs, we recommend promoting mutual and continuous gene flow with wild populations to ensure the long-term survival of this species. 相似文献