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Z Mi

Publications and source records attributed to Z Mi.

81 records · Page 5Linked to original sources
PubMed1994

Differential interactions of camptothecin lactone and carboxylate forms with human blood components.

The intrinsic fluorescent emissions from the lactone and carboxylate forms of camptothecin have been exploited in order to elucidate their markedly different interactions with the various components of human blood. In phosphate-buffered saline (PBS) at pH 7.4, human serum albumin (HSA) preferentially binds the carboxylate form with a 150-fold higher affinity than the lactone form; these interactions result in camptothecin opening more rapidly and completely in the presence of HSA than in the protein's absence [Burke, T.G., & Mi, Z. (1993) Anal. Biochem. 212, 285-287]. In human plasma, at pH 7.4 and 37 degrees C, we have observed camptothecin lactone to open rapidly and fully to the carboxylate form (t1/2 = 11 min; % lactone at equilibrium, 0.2%). Substitution of a 10-hydroxy moiety into the camptothecin fluorophore makes the agent's emission spectrum highly sensitive to microenvironment polarity; we have observed pronounced blue shifting (from 530 to 430 nm) in the emission spectra of the hydroxy-substituted carboxylate both upon HSA association as well as upon drug dissolution in organic solvents of low dielectric strength. Hence, it appears that camptothecin carboxylate's fluorophore locates in a hydrophobic binding pocket in native HSA. Ionic interactions also appear to strongly affect binding between camptothecin carboxylate and the HSA binding pocket, since a 6-fold increase in solution salt concentration diminished camptothecin carboxylate binding by 10-fold. Our findings that HSA denaturation abolishes high-affinity binding indicate that interactions of the carboxylate drug form are specific for the native HSA conformation. Interestingly, high-affinity binding of the carboxylate appeared not to occur in the presence of other blood proteins, such as gamma-globulin, alpha 1-acid glycoprotein, fibrinogen, and the oxy and deoxy forms of hemoglobin. In whole blood versus plasma, camptothecin was found to display enhanced stability (t1/2 value of 22 min and a lactone concentration at equilibrium value of 5.3%). The enhanced stability of camptothecin in human blood was found to be due to drug associations with the lipid bilayers of red blood cells. Camptothecin lactone partitions into the lipid bilayers of erythrocytes, with the drug locating in a hydrophobic environment protected from hydrolysis.

Binding Sites↗
PubMed1994

The structural basis of camptothecin interactions with human serum albumin: impact on drug stability.

The intense intrinsic fluorescence emissions from several clinically relevant camptothecin drugs have been exploited in order to study the structural basis of drug binding to human serum albumin. Both HPLC and time-resolved fluorescence spectroscopic methodologies were employed to characterize the associations of camptothecins with HSA in phosphate-buffered saline (pH 7.4) at 37 degrees C. The alpha-hydroxy delta-lactone ring moiety of camptothecin (C), 10-hydroxycamptothecin (HC), 10,11-(methylenedioxy)camptothecin (MC) and 9-chloro-10,11-(methylenedioxy)camptothecin (CMC) was in each case observed to hydrolyze more rapidly and completely in the presence of HSA than in the protein's absence. Binding isotherms constructed by the method of fluorescence lifetime titration showed that HSA bound preferentially the carboxylate forms of C, HC, MC, and CMC over their lactone forms, thereby providing an explanation for the shift to the right in the lactone-carboxylate equilibrium observed for each compound upon HSA addition. In marked contrast, three analogues (SN-38, CPT-11, and topotecan) all displayed enhanced stabilities in the presence of HSA. While the lifetimes of CPT-11, topotecan, and the carboxylate forms of both drugs were insensitive to the addition of HSA, the lifetimes of both SN-38 and its carboxylate form did titrate upon HSA addition. Analysis of binding isotherms constructed for the albumin interactions of SN-38 and its carboxylate form demonstrated a higher overall association constant for the lactone form [640 (M amino acid (aa) residues)-1] relative to the carboxylate form [150 (M aa)-1]. Our studies indicate that specific modifications at the 7- and 9-positions of the quinoline nucleus, such as those contained in CPT-11, topotecan, and SN-38, enhance drug stability in the presence of HSA. In the case of SN-38, the enhanced stability was shown to be due to preferential associations between the drug's lactone form and the blood protein.

Camptothecin↗
PubMed1994

3-isobutyl-1-methylxanthine decreases renal cortical interstitial levels of adenosine and inosine.

The purpose of this study was to test the hypothesis that endogenous cyclic AMP, via metabolism by phosphodiesterase, contributes to interstitial levels of adenosine in the renal cortex in vivo. This hypothesis was tested by determining the effects of 3-isobutyl-1-methylxanthine, a phosphodiesterase inhibitor, on renal cortical interstitial levels of adenosine and inosine. Changes in renal cortical interstitial adenosine and inosine levels were assessed in rats by implanting microdialysis probes into the renal cortex and measuring adenosine and inosine levels in the dialysate exiting the kidney using high performance liquid chromatography. When added to the dialysate entering the kidney at concentrations of 0.5, 1 and 2.5 mM, 3-isobutyl-1-methylxanthine significantly and dose-dependently decreased interstitial levels of both adenosine and inosine. The percentage changes from baseline of interstitial levels of adenosine and inosine were: -39 +/- 6% and -19 +/- 6%, respectively, with 0.5 mM 3-isobutyl-1-methylxanthine; -45 +/- 7% and -24 +/- 8%, respectively, with 1 mM 3-isobutyl-1-methylxanthine; and -56 +/- 12% and -38 +/- 8%, respectively, with 2.5 mM 3-isobutyl-1-methylxanthine. These data suggest that in the renal cortex, cyclic AMP metabolism via phosphodiesterase is an important source of renal interstitial adenosine.

1-Methyl-3-isobutylxanthine↗
PubMed1994

Estimates of trace element intakes in Chinese farmers.

Epidemiologic data on the average daily human dietary intake of the trace elements nickel, cadmium, molybdenum and silicon are scarce, worldwide, primarily because foods consumed vary widely over days and seasons. Available full year food allocation records for farmers in rural areas of China provide an unique opportunity to estimate dietary trace elements. In 1988, we measured the concentration of zinc, copper, iron, cadmium, nickel, molybdenum, silicon and selenium in different foods by using food samples collected from 232 villages (distributed among 21 communes). These measurements, combined with the food consumption information from existing food allocation records in each commune for an entire year, allowed us to estimate the average daily consumption of these trace elements by Chinese farmers. With one exception (an association of zinc and esophageal cancer), the variation of dietary trace elements did not show any association with mortality from several common diseases. The estimates for some of the dietary trace elements from some subpopulations were either less or more than current recommendations. No increases in mortality were found, however, from diseases normally associated with either dietary deficiencies or excesses of these elements.

Adult↗
PubMed1993

Corn and wheat-flour consumption and mortality from esophageal cancer in Shanxi, China.

In order to identify factors that may explain the great variation in mortality from esophageal cancer in Shanxi Province, China, an ecological study was carried out in 21 communes in that province. Mortality data were obtained from the registration records of the population of 148,928 during 1983 to 1988, which provided 744,640 person-years of observation. The data regarding average consumption of each kind of grain, potatoes and sweet potatoes were from food allocation records. The data regarding consumption of meat, eggs, fruit, vegetables and the data regarding alcohol drinking were from interviews. The concentrations of nitrite and of nitrate in pickled vegetables and in drinking water were measured. A significant positive relation was found between mortality rate and the consumption of dietary corn and wheat flour. Also, a significant inverse relation was found between the mortality rate and the dietary sorghum and millet level. The age- and sex-adjusted mortality-rate ratio of esophageal cancer for residents in the third and highest quartiles of corn- and wheat-flour consumption are 1.4 (95% CI: 1.1-2.0) and 3.2 (2.5-4.2), respectively, compared with those in the lowest quartile. Other factors studied did not contribute to the great variation in esophageal cancer mortality in the areas studied.

Adult↗
PubMed1992

Dietary trace elements and esophageal cancer mortality in Shanxi, China.

To explore the relation between esophageal cancer and dietary trace elements in humans, we estimated the average daily intake of zinc, copper, iron, selenium, molybdenum, silicon, cadmium, and nickel in 21 Chinese communes, where the annual mortality rate from esophageal cancer among the population 30 years of age and over ranged from 0 to 495/100,000 person-years. We also estimated the relative level of calcium consumption. Zinc and copper intake were inversely related to esophageal cancer mortality, and calcium intake levels was positively related to esophageal cancer mortality. The predicted esophageal cancer mortality among a vegetarian population with a high level of dietary calcium and a low level of dietary zinc was 5.3 times as high as that in a vegetarian population with a low level of dietary calcium and a high level of dietary zinc. The influence of a high level of dietary calcium in a vegetarian population may be explained by a reduction in the absorption of dietary zinc.

Adult↗
PubMedDate not supplied

Transfer of proalpha2(I) cDNA into cells of a murine model of human Osteogenesis Imperfecta restores synthesis of type I collagen comprised of alpha1(I) and alpha2(I) heterotrimers in vitro and in vivo.

The oim mouse is a model of human Osteogenesis Imperfecta (OI) that has deficient synthesis of proalpha2(I) chains. Cells isolated from oim mice synthesize alpha1(I) collagen homotrimers that accumulate in tissues. To explore the feasibility of gene therapy for OI, a murine proalpha2(I) cDNA was inserted into an adenovirus vector and transferred into bone marrow stromal cells isolated from oim mice femurs. The murine cDNA under the control of the cytomegalovirus early promoter was expressed by the transduced cells. Analysis of the collagens synthesized by the transduced cells demonstrated that the cells synthesized stable type I collagen comprised of alpha1(I) and alpha2(I) heterotrimers in the correct ratio of 2:1. The collagen was efficiently secreted and also the cells retained the osteogenic potential as indicated by the expression of alkaline phosphatase activity when the transduced cells were treated with recombinant human bone morphogenetic protein 2. Injection of the virus carrying the murine proalpha2(I) cDNA into oim skin demonstrated synthesis of type I collagen comprised of alpha1 and alpha2 chains at the injection site. These preliminary data demonstrate that collagen genes can be transferred into bone marrow stromal cells as well as fibroblasts in vivo and that the genes are efficiently expressed. These data encourage further studies in gene replacement for some forms of OI and use of bone marrow stromal cells as vehicles to deliver therapeutic genes to bone.

Adenoviridae↗