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Biomedical subjects

Z Zhong

Publications and source records attributed to Z Zhong.

At least 127 records · Page 7Linked to original sources
PubMed1995

Role of Kupffer cells in reperfusion injury in fat-loaded livers from ethanol-treated rats.

Reperfusion injury was studied in blood-free perfused livers from fat-loaded, ethanol-treated rats. Rats were pair-fed a modified Lieber-DeCarli liquid diet containing 36% calories as ethanol or isocaloric maltose-dextrin for 4 to 5 weeks. Reperfusion injury to the liver, which occurs in previously hypoxic regions upon reintroduction of oxygen, was studied in a low-flow, reflow perfusion model. Lactate dehydrogenase in effluent perfusate increased from basal levels of < 1 to 17 IU/g/h in livers from controls, whereas prior alcohol treatment elevated values to 37 IU/g/h. Pretreatment of rats with gadolinium chloride (GdCl3, 20 mg/kg i.v.), a selective Kupffer cell toxicant, minimized lactate dehydrogenase release during reperfusion to 7 to 8 IU/g/h in livers from both groups. Rates of malondialdehyde production were 144 and 166 nmol/g/h during reperfusion in control and alcohol-treated rats, respectively, but values reached only 54 and 79 nmol/g/h after GdCl3 treatment. Interestingly, a typical PBN/carbon-centered free radical adduct signal was detected in bile of livers from ethanol-treated rats, but not in controls or ethanol-treated rats given GdCl3. Portal pressure increased during the reperfusion period in livers from alcohol-treated rats, although not in controls, and GdCl3 reduced it significantly. Taken together, these data indicate that reperfusion injury is greater in fatty livers from alcohol-treated rats in a blood-free model. Inactivation of Kupffer cells minimized reperfusion injury in both control and alcohol-treated rats, most likely by diminishing lipid peroxidation thereby improving hepatic microcirculation.

Animals↗
PubMed1994

Epidermal growth factor and lipopolysaccharide activate Stat3 transcription factor in mouse liver.

Previous studies demonstrated that the intraperitoneal injection of epidermal growth factor (EGF) into mice resulted in the appearance, within minutes, of several tyrosine-phosphorylated proteins in liver nuclei. Two of these proteins have been identified as the transcription factors p91/p84 (Stat1 alpha/1 beta) (Ruff-Jamison, S., Chen, K., and Cohen, S. (1993) Science 261, 1733-1736). We have now identified, by Western blotting and immunoprecipitation, an additional EGF-modulated transcription factor, Stat3. We find that Stat3 is tyrosine-phosphorylated and present in mouse liver nuclei following either EGF or lipopolysaccharide administration. Gel shift analyses show that Stat3 is capable of specifically binding the SIE (a DNA sequence present in the c-fos promoter). Three active SIE binding complexes (SIF A, B, and C) exist in the nucleus after the administration of EGF: one complex that contains Stat3, one that contains Stat1, and a third complex that appears to contain both proteins. Only one active SIE binding complex, containing Stat3, was detected after the administration of lipopolysaccharide.

Animals↗
PubMed1994

Stat3 and Stat4: members of the family of signal transducers and activators of transcription.

The deduced amino acid sequence of two members of the signal transducers and activators of transcription (STAT) family from the mouse are described. Comparison with the deduced protein sequence of the two previously described genes (Stat91 and Stat113), discovered because of their activation as transcription factors after interferon-induced tyrosine phosphorylation, shows several highly conserved regions, including the putative SH3 and SH2 domains. The conserved amino acid stretches likely point to conserved domains that enable these proteins to carry out the several required functions they are known and proposed to carry out. While Stat1 and Stat3 are widely expressed, Stat4 expression is restricted to testis, thymus, and spleen. Antiserum to Stat3 detects a major approximately 92-kDa protein and a minor approximately 89-kDa protein, while antiserum to Stat4 precipitates one major protein of approximately 89 kDa.

Amino Acid Sequence↗
PubMed1994

Increased amyloid production from aberrant beta-amyloid precursor proteins.

The 4-kDa beta-amyloid protein that forms fibrillar deposits in Alzheimer's diseased brains is derived from a large precursor, the beta-amyloid precursor protein (beta-APP). Recently, it has been reported that beta-amyloid is normally produced and secreted by cultured mammalian cells. In our studies involving recombinant expression of beta-APP, increased yields of beta-amyloid were associated with expression of aberrant beta-APP molecules. Deletion mutations within the beta-amyloid domain, incorrect beta-APP isoform expression in fibroblasts or neuronal cells, or excess amounts of beta-APP all led to increases in beta-amyloid production. Aberrant beta-APP appears to be diverted from the secretory pathway and then degraded to beta-amyloid.

Amyloid beta-Peptides↗
PubMed1994

Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6.

The STAT family of proteins carries out a dual function: signal transduction and activation of transcription. A new family member, Stat3, becomes activated through phosphorylation on tyrosine as a DNA binding protein in response to epidermal growth factor (EGF) and interleukin-6 (IL-6) but not interferon gamma (IFN-gamma). It is likely that this phosphoprotein forms homodimers as well as heterodimers with the first described member of the STAT family, Stat91 (renamed Stat1 alpha), which is activated by the IFNs and EGF. Differential activation of different STAT proteins in response to different ligands should help to explain specificity in nuclear signaling from the cell surface.

Amino Acid Sequence↗
PubMed1994

Secretion of beta-amyloid precursor protein involves multiple cleavage sites.

A major histopathological feature of Alzheimer's disease is deposits of a approximately 4-kDa beta-amyloid peptide derived by proteolytic processing from a precursor, the beta-amyloid precursor protein (beta-APP). Proteolytic cleavage of beta-APP within the approximately 4-kDa beta-amyloid domain permits the secretion of the amino-terminal portion of beta-APP while concomitantly producing a membrane bound approximately 9-kDa carboxyl-terminal fragment. We have characterized the proteolytic cleavage site for beta-APP secretion by amino acid sequence analysis of the approximately 9-kDa beta-APP carboxyl-terminal cleavage product produced by recombinant and native expression systems. Recombinant beta-APP was generated by a vaccinia virus expression system in CV-1 monkey fibroblasts; endogenous beta-APP was obtained using a fibroblast line derived from an individual with Down's syndrome. The sequences of both unlabeled and metabolically radiolabeled approximately 9-kDa fragment from CV-1 cells reveal that the major (60%) secretory cleavage site is after Lys16 of the beta-amyloid domain as reported previously; however, an additional cleavage site is seen after Phe19 (40%). Radiosequence analysis of the carboxyl-terminal fragment purified from Down's syndrome fibroblasts indicates cleavage sites after Phe19, Glu22, and Gly25 and not after Lys16. CV-1 cells expressing beta-APP mutants lacking 4 and 6 amino acids adjacent to Lys16 yielded approximately 9-kDa fragments with two identical cleavage sites, neither of which occurred after the retained Lys16 but were after Glu11 and His13. These data suggest that secretion of beta-APP involves multiple proteinases and that the composition of these proteinases may vary within different cell backgrounds.

Amino Acid Sequence↗
PubMed1993

A study and analysis of the deaths due to advanced Schistosoma japonicum infection in the Dongting Lake area of China.

This study collected records of 245 cases of death due to advanced schistosomiasis japonica in the eastern Dongting Lake area between 1985 and 1990. The mean survival of the patients was 5.16 years. The patients with ascitic type had a shorter expected life while the life span of splenomegalic type patient markedly improved after splenectomy. The HBsAg positive rate was 43.64%; the rate of those complicated with carcinoma of liver was 19.18%. The latter group had a HBV infection rate as high as 61.70%.

Adolescent↗
PubMed1992

A mammalian factor that binds telomeric TTAGGG repeats in vitro.

We have identified a DNA-binding activity with specificity for the TTAGGG repeat arrays found at mammalian telomeres. This factor, called TTAGGG repeat factor (TRF), is present in nuclear extracts of human, mouse, and monkey cells. TRF from HeLa cells was characterized in detail by electrophoretic mobility shift assays. It binds double-stranded TTAGGG repeats in linear and circular DNAs. Single-stranded repeats are not recognized. The optimal site for TRF appears to contain more than six contiguous TTAGGG repeats. Tandem arrays of TAGGG, TTTAGGG, TTTTAGGG, TTGGGG, and TTAGGC repeats do not bind TRF well, indicating that TRF preferentially recognizes the telomeric repeat sequence present at mammalian chromosome ends. The apparent molecular mass of this factor, based on recovery of TRF from sodium dodecyl sulfate-polyacrylamide gels, is approximately 50 kDa. We suggest that TRF binds along the length of mammalian telomeres.

Animals↗
PubMed1991

Inhibition of glucuronidation of benzo(a)pyrene phenols by long-chain fatty acids.

Long-chain fatty acids inhibit glucuronidation of benzo(a)pyrene phenols in perfused liver; therefore, this study was designed to investigate interactions of fatty acids with beta-glucuronidase, glucuronosyl transferase, and energy supply. In beta-glucuronidase-deficient C3H/He mice, infusion of oleate (250 microM) increased the release of free benzo(a)pyrene phenols from 14 to 33 nmol/g/h and decreased release of glucuronides into the perfusate from 25 to 17 nmol/g/h. Rates of accumulation of glucuronides in the liver were also diminished from 11 to 4 nmol/g/h after infusion of oleate (250 microM). Fatty acids did not affect the release of benzo(a)pyrene metabolites into bile, and the ratio of free phenol to glucuronide production was increased from 0.57 to 1.30. A similar trend was observed in livers from DBA/2 mice that have beta-glucuronidase. Rates of hydrolysis of benzo(a)pyrene-O-glucuronide were not altered in isolated microsomes by addition of oleoyl coenzyme A (CoA) or octanoyl CoA (10- approximately 100 microM). Thus, we conclude that fatty acids do not alter glucuronidation by acting on beta-glucuronidase. The concentration of cofactors (UDP-glucuronic acid, UDP-glucose, and adenine nucleotides) involved in hepatic conjugation was not altered by infusion of concentrations of oleate (300 microM) that inhibited glucuronidation in perfused livers. When oleate concentrations were increased to 600 microM, UDP-glucuronic acid and UDP-glucose decreased 44 and 49%, respectively, and the ATP:ADP ratio declined concomitantly. Oleoyl CoA inhibited UDP-glucuronosyl transferase noncompetitively (half-maximal inhibition, 10 microM) in microsomes with 3-hydroxy-benzo(a)pyrene or p-nitrophenol as substrate. In contrast, octanoyl CoA was a very poor inhibitor of transferase activity. Inhibition of the transferase by oleoyl CoA was increased markedly by treatment with detergents (Triton X-100), i.e., half-inhibition of glucuronosyl transferase was obtained with about 2 microM oleoyl CoA. Inhibition of UDP-glucuronosyl transferase by oleoyl CoA was also increased in a dose-dependent manner by albumin, possibly due to increasing access of the CoA derivative to the enzyme. Collectively, these data indicate that fatty acids diminish glucuronidation via the formation of acyl CoA compounds that inhibit UDP-glucuronosyl transferase noncompetitively.

Animals↗
PubMed1989

Effect of fatty acids on formation, distribution, storage, and release of benzo(a)pyrene phenols and glucuronides in the isolated perfused rat liver.

The hydroxylation of benzo(a)pyrene and conjugation, storage, and release of benzo(a)pyrene phenols and glucuronides by the perfused rat liver were studied in the presence and absence of acute addition of physiological concentrations of common dietary fatty acids. The actions of fatty acids on the oxidation and conjugation of benzo(a)pyrene in the intact liver were compared with their actions on microsomes isolated from rat liver. Rats were treated with beta-naphthoflavone to stimulate polycyclic aromatic hydrocarbon metabolism. Long-chain fatty acyl CoA compounds (palmitoyl CoA, oleoyl CoA, linolenoyl CoA; 50 microM) inhibited hydroxylation of benzo(a)pyrene by isolated microsomes by about 45%; however, long-chain fatty acids did not affect overall rates of hydroxylation of benzo(a)pyrene by the perfused liver at concentrations ranging up to 300 microM. The medium-chain acyl CoA compound, octanoyl CoA, also did not affect benzo(a)pyrene hydroxylation in microsomes or liver. Although fatty acids did not alter rates of hydroxylation, the ratio of free benzo(a)pyrene phenols to glucuronides (F/G ratio) increased about 60% (P less than 0.05) in livers perfused with long-chain fatty acids (palmitate, oleate, linolenate). Inhibition of glucuronidation was not observed with the medium-chain fatty acid, octanoate. Benzo(a)pyrene phenols and glucuronides accumulated linearly in the liver at rates of approximately 40 nmol/g/h. A second action of both long- and medium-chain length fatty acids was to increase rates of release of benzopyrene phenols into the perfusate by 50 to 80%. Fatty acids did not effect release of benzo(a)pyrene phenols and glucuronides into bile. Taken together, these data support the hypothesis that fatty acids displace carcinogenic metabolites of benzo(a)pyrene from binding sites in the liver which enter the circulation and travel to target tissues.

Acyl Coenzyme A↗
PubMed1989

Evidence that graft survival is not related to parenchymal cell viability in rat liver transplantation. The importance of nonparenchymal cells.

Injury to parenchymal and nonparenchymal cells of livers stored in cold Euro-Collins solution was assessed following reperfusion and compared with graft survival following orthotopic rat liver transplantation. Parenchymal cells maintained their viability nearly completely after up to 24 hr of cold storage as assessed by trypan blue exclusion (97% of cells) and LDH release (4% of total) from livers reperfused for 20 min following storage. Furthermore, hepatic glycolysis (rates of lactate plus pyruvate production), oxygen uptake and NADH redox state (lactate:pyruvate ratio) were in the normal range at all time points studied up to 24 hr of cold storage. In contrast, nonparenchymal cells lost viability as assessed from trypan blue staining beginning after 8 hr of storage: 40% were nonviable after 24 hr of storage. Since injury to nonparenchymal cells occurs only upon reperfusion, oxygen radicals may be involved. Accordingly, xanthine and hypoxanthine, substrates for oxygen radical formation, were measured in perfusate upon reperfusion. Both purines accumulated (up to 80 microM) with time of storage and were washed out rapidly (less than 10 min) upon reperfusion. Although parenchymal cell function was in the normal range in livers stored in the cold for 24 hr, liver grafts stored for 6 hr and longer in Euro-Collins solution could not be transplanted successfully. Thus, we conclude that viability of parenchymal cells in liver grafts prior to transplantation is a poor parameter to predict the outcome of transplantation. Therefore, assessment of parenchymal cell energy state (e.g., with 31P NMR and other methods) most likely will not predict survival reliably. On the other hand, nonparenchymal cells lose their viability significantly earlier following storage and reperfusion. These data suggest that preservation of nonparenchymal cell viability is critical for successful liver transplantation.

Animals↗
PubMed1989

Role of purines and xanthine oxidase in reperfusion injury in perfused rat liver.

The purpose of this study was to evaluate the possible involvement of xanthine and xanthine oxidase in reperfusion injury in a low-flow, reflow model of liver perfusion. Livers were perfused at flow rates around 25% of normal for 90 min and then at normal flow rates (4 ml/g/min) for 30 min. When flow was restored to normal, malondialdehyde and lactic dehydrogenase (LDH) were released into the effluent perfusate. Malondialdehyde production rapidly reached values of 300 nmol/g/hr whereas LDH increased from basal levels of 100 to 600 U/l upon reperfusion. Trypan blue was taken up exclusively in cells in pericentral regions of the liver lobule under these conditions. Xanthine and hypoxanthine in the effluent perfusate increased steadily during the low-flow period reaching values around 5 and 10 microM, respectively, and decreased rapidly after the flow was restored to normal. Perfusion with nitrogen-saturated buffer for 3 min before restoration of normal flow rates or infusion of the radical scavenger catechin (400 microM) reduced cell damage by about 50%. Infusion of allopurinol (2-6 mM), an inhibitor of xanthine oxidase, prevented reperfusion injury in a dose-dependent manner. Taken together, these data indicate that a reperfusion injury occurs in liver upon reintroduction of oxygen which is initiated by oxidation of xanthine and hypoxanthine via xanthine oxidase and ultimately leads to production of lipid peroxides. Surprisingly, infusion of xanthine (4 mM), substrate for xanthine oxidase, reduced hepatocellular injury on reperfusion. LDH release was decreased from values around 700 to less than 200 U/l and trypan blue uptake in pericentral region was prevented totally by xanthine.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗