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PubMed2004

c-Jun N-terminal kinase is required for vitamin E succinate-induced apoptosis in human gastric cancer cells.

AIM: To investigate the roles of c-Jun N-terminal kinase (JNK) signaling pathway in vitamin E succinate-induced apoptosis in human gastric cancer SGC-7901 cells. METHODS: Human gastric cancer cell lines (SGC-7901) were treated with vitamin E succinate (VES) at 5, 10, 20 mg/L. Succinic acid and vitamin E were used as vehicle controls and condition medium only as an untreated (UT) control. Apoptosis was observed by 4', 6-diamidine-2'-phenylindole dihydrochloride (DAPI) staining for morphological changes and by DNA fragmentation for biochemical alterations. Western blot analysis was applied to measure the expression of JNK and phosphorylated JNK. After the cells were transiently transfected with dominant negative mutant of JNK (DN-JNK) followed by treatment of VES, the expression of JNK and c-Jun protein was determined. RESULTS: The apoptotic changes were observed after VES treatment by DNA fragmentation. DNA ladder in the 20 mg/L VES group was more clearly seen than that in 10 mg/L VES group and was not detected following treatment of UT control, succinate and vitamin E. VES at 5, 10 and 20 mg/L increased the expression of p-JNK by 2.5-, 2.8- and 4.2-fold, respectively. VES induced the phosphorylation of JNK beginning at 1.5 h and produced a sustained increase for 24 h with the peak level at 12 h. Transient transfection of DN-JNK blocked VES-triggered apoptosis by 52%. DN-JNK significantly increased the level of JNK, while decreasing the expression of VES-induced c-Jun protein. CONCLUSION: VES-induced apoptosis in human gastric cancer SGC-7901 cells involves JNK signaling pathway via c-Jun and its downstream transcription factor.

Apoptosis↗
PubMed1975

[Comparative microspectrophotometric study of the activity of oxidative enzymes in separate types of fibers of the skeletal muscle of rats in the normal state and in experimental ischemia].

Microspectrophotometrical investigation of the activity of oxidative enzymes (glutamatdehydrogenase, cytoplasmic and mitochondrial alpha-glycerol phosphate dehydrogenase, succinic acid dehydrogenase and glucose-6-phosphatedehydrogenase) in certain types of muscular fibres of m. soleus, gastronemius and quadriceps of rats during experimental stenosins of the abdominal part of the aorta has shown the existence of certain cyclic changes in the enzymic activity of different periods after graded constriction which may be associated with arising of adaptational reactions of metabolic systems in striated muscles in response to chronic hypoxia.

Animals↗
PubMed1992

Identification and characterization of neutral endopeptidase in endothelial cells from venous or arterial origins.

Neutral endopeptidase (NEP; enkephalinase, EC 3.4.24.11) is a cell membrane-associated zinc metalloprotease, which cleaves peptides like atrial natriuretic peptide (ANP) on the amino side of hydrophobic amino acids. Although NEP is mainly located in reabsorptive epithelia (kidney proximal tubule), it is also present in non-epithelial cells such as neuronal cells. As the renal NEP cannot account for the entire ANP metabolism, other locations were postulated. The present experiments show its expression in endothelial cells (EC) from arterial (bovine pulmonary, porcine, and human aorta) and venous (human umbilical, rabbit ear marginal) origins. Three different methods were used to demonstrate the presence of the protein and its mRNA. 1) NEP enzymatic activity was estimated using both a synthetic ([D-Ala2,Leu5]enkephalin) and a natural substrate (bradykinin). Using the synthetic substrate, the enzymatic activity in EC was completely blocked by thiorphan, a specific NEP inhibitor with an IC50 value in the nanomolar range. In contrast, captopril, bestatin, [2-guanidinoethylmercapto]succinic acid, inhibitors of angiotensin-converting enzyme, aminopeptidases, and carboxypeptidases, respectively, were 10,000 times less active, revealing an inhibition profile similar to that of the purified enzyme. Bradykinin, a natural substrate of NEP, was in part metabolized by NEP, in the presence of captopril, since 50% of the formation of the major metabolite bradykinin 1-7 was inhibited by thiorphan. 2) Immunoreactive NEP was detected on the plasma membrane of rabbit EC using a monoclonal antibody directed against the homologous renal enzyme. 3) NEP mRNA was detected by Northern blot analysis of rabbit EC as a major transcript of 3.9 kilobases. Reverse transcriptase polymerase chain reaction amplification showed the presence of a specific transcript in all EC tested. Therefore, endothelial NEP may play an important role in the inactivation of ANP, bradykinin, and endothelins by its localization facing the circulating vasoactive peptides.

Animals↗
PubMed2000

Catalytic mechanism of a C-C hydrolase enzyme: evidence for a gem-diol intermediate, not an acyl enzyme.

2-Hydroxy-6-keto-nona-2,4-diene 1,9-dioic acid 5,6-hydrolase (MhpC) from Escherichia coli catalyses the hydrolytic cleavage of the extradiol ring fission product on the phenylpropionate catabolic pathway and is a member of the alpha/beta hydrolase family. The catalytic mechanism of this enzyme has previously been shown to proceed via initial ketonization of the dienol substrate (Henderson, I. M. J., and Bugg, T. D. H. (1997) Biochemistry 36, 12252-12258), followed by stereospecific fragmentation. Despite the implication of an active site serine residue in the alpha/beta hydrolase family, attempts to verify a putative acyl enzyme intermediate by radiochemical trapping methods using a (14)C-labeled substrate yielded a stoichiometry of <1% covalent intermediate, which could be accounted for by nonenzymatic processes. In contrast, incorporation of 5-6% of two atoms of (18)O from H(2)(18)O into succinic acid was observed using the natural substrate, consistent with the reversible formation of a gem-diol intermediate. Furthermore, time-dependent incorporation of (18)O from H(2)(18)O into the carbonyl group of a nonhydrolysable analogue 4-keto-nona-1,9-dioic acid was observed in the presence of MhpC, consistent with enzyme-catalyzed attack of water at the ketone carbonyl. These results favor a catalytic mechanism involving base-catalyzed attack of water, rather than nucleophilic attack of an active site serine. The implication of this work is that the putative active site serine in this enzyme may have an alternative function, for example, as a base.

Carbon Radioisotopes↗
PubMed1995

Leader peptidase from Escherichia coli: overexpression, characterization, and inactivation by modification of tryptophan residues 300 and 310 with N-bromosuccinimide.

We have overproduced the leader peptidase from Escherichia coli in a high yield by using a T7 RNA polymerase/promoter system and purified the enzyme. This leader peptidase showed an apparent pH optimum of about 10 toward a synthetic peptide substrate, and was stable at temperatures below 40 degrees C. Kinetic studies indicated that one of the active site residues in the enzyme has a pKa value of approximately 7.5. The enzyme was rapidly inactivated by reaction with N-bromosuccinimide (NBS). When approximately two tryptophan residues were oxidized with NBS, the activity was almost completely lost and this inactivation was markedly prevented by a substrate. These NBS-reactive tryptophan residues were identified as Trp300 and Trp310 by a peptide mapping analysis. This indicates that Trp300 and/or Trp310 are critically important for the activity of the leader peptidase. On the other hand, the enzyme was scarcely inhibited by treatment with N-acetylimidazole, iodoacetic acid, 5,5'-dithiobis(2-nitrobenzoic acid), succinic anhydride, or 2,4,6-trinitrobenzenesulfonate. Diethylpyrocarbonate inhibited the enzyme; however, this inhibition did not seem to result from the modification of histidine residues. Thus, there seem to be no functionally important tyrosine, cysteine, or histidine residues or amino groups among the residues which readily react with these reagents. However, the enzyme was inactivated significantly by treatment with phenylglyoxal or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide. Therefore, some of the arginine residues and the carboxyl groups appear to be important for the enzyme activity.

Amino Acid Sequence↗
PubMed1987

Mutagenicity of chloroaniline/lignin metabolites in the Salmonella/microsome assay.

Chloroanilines are constituents of many agrochemicals and have been found to be metabolized to succinic acid conjugates, e.g., succinamides and succinimides. The mutagenic potential of five chloroanilines and their succinamides and succinimide derivatives have been tested with two strains of Salmonella typhimurium (TA98 and TA100) with and without rat hepatic microsomal fraction. None of the compounds produced a dose response effect with a two-fold increase in revertants indicating that these compounds are not mutagens or promutagens in these assays.

Aniline Compounds↗
PubMed2006

Directing the growth of highly aligned gold nanorods through a surface chemical amidation reaction.

This paper describes the seed-mediated growth of highly aligned gold nanorods (Au NRs) over large areas directly on a Si(100) surface. The Si(100) surface is NH2-functionalized with (aminopropyl)triethoxysilane (APTES) followed by a DCC-catalyzed surface amidation reaction with acetic acid. After exposure to a gold nanoparticle (Au NP) "seed" solution, chemical seed-mediated growth of the surface-bound seeds via reduction of AuCl4- by ascorbic acid in the presence of cetyltrimethylammonium bromide leads to the growth of highly aligned Au NRs on the surface. About 80% of the NRs are aligned in the same direction within a +/-30 degrees range. Au NRs account for 19% of the nanostructures with average aspect ratio (AR) of approximately 20. The alignment direction did not correlate with the atomic arrangement of the Si(100) crystal since it varied over different regions of the sample, rotating by 90 degrees from top to bottom of an approximately 5 mm sample. Si crystallinity may still be important since alignment is not observed on amorphous glass. Surface functionalization is the key since alignment is only observed following the amidation reaction and not on NH2-functionalized, SH-functionalized, or bare Si(100) surfaces. Alignment also occurred for Au NRs grown on Si(100)/APTES reacted with succinic acid and on Ag NRs grown on Si(100)/APTES/acetic acid surfaces. This unique alignment of metal NRs promoted by a surface amidation chemical reaction may find use in nanoelectronics, chemical sensing, and plasmonics applications.

Journal Article↗
PubMed1977

Synthesis and testing of glucose derivatives for feeding to ruminants.

Glucose compounds were synthesized and tested for resistance in a 48-h in vitro rumen fermentation. Glucose complexed with formaldehyde, acetaldehyde, and acetone was resistant. When complexed with propionic and succinic acids, the products readily fermented. The resistant compounds also withstood acid hydrolysis at a pH similar to that of the abomasum. This suggests that these products would have little value as a dietary source of glucose for ruminants if the release of glucose to the animal depended on acid hydrolysis in the abomasum. The possibility of enzymatic hydrolysis of glucose-formaldehyde compound was studied in a feeding trial with sheep. Eight Finncross wethers were fed the formaldehyde product in three quantities in their diet. Blood and urine glucose plus blood, urine, and fecal total soluble carbohydrate were measured. It appears that this glucose-formaldehyde product resists rumen fermentation but does not become metabolically available to sheep as indicated by large quantities of product excreted in urine and feces.

Abomasum↗
PubMed1997

Thrombin-mediated activation of factor XI results in a thrombin-activatable fibrinolysis inhibitor-dependent inhibition of fibrinolysis.

Recently, it has been shown that Factor XI can be activated by thrombin, and that Factor XIa significantly contributes to the generation of thrombin via the intrinsic pathway after the clot has been formed. This additional thrombin, generated inside the clot, was found to protect the clot from fibrinolysis. A plausible mechanism for this inhibitory effect of thrombin involves TAFI (thrombin-activatable fibrinolysis inhibitor, procarboxypeptidase B) which, upon activation, may inhibit fibrinolysis by removing carboxy-terminal lysines from fibrin. We studied the role of Factor XI and TAFI in fibrinolysis using a clot lysis assay. The lysis time was decreased twofold when TAFI was absent, when TAFI activation was inhibited by anti-TAFI antibodies, or when activated TAFI was inhibited by the competitive inhibitor (2-guanidinoethylmercapto)succinic acid. Inhibition of either TAFI activation or Factor XIa exhibited equivalent profibrinolytic effects. In the absence of TAFI, no additional effect of anti-Factor XI was observed on the rate of clot lysis. We conclude that the mechanism of Factor XI-dependent inhibition of fibrinolysis is through the generation of thrombin via the intrinsic pathway, and is dependent upon TAFI. This pathway may play a role in determining the fate of in vivo formed clots.

Antibodies, Monoclonal↗
PubMed2003

Degradation of alkanes and highly chlorinated benzenes, and production of biosurfactants, by a psychrophilic Rhodococcus sp. and genetic characterization of its chlorobenzene dioxygenase.

Rhodococcus sp. strain MS11 was isolated from a mixed culture. It displays a diverse range of metabolic capabilities. During growth on 1,2,4-trichlorobenzene, 1,2,4,5-tetrachlorobenzene (1,2,4,5-TeCB) and 3-chlorobenzoate stoichiometric amounts of chloride were released. It also utilized all three isomeric dichlorobenzenes and 1,2,3-trichlorobenzene as the sole carbon and energy source. Furthermore, the bacterium grew well on a great number of n-alkanes ranging from n-heptane to n-triacontane and on the branched alkane 2,6,10,14-tetramethylpentadecane (pristane) and slowly on n-hexane and n-pentatriacontane. It was able to grow at temperatures from 5 to 30 degrees C, with optimal growth at 20 degrees C, and could tolerate 6 % NaCl in mineral salts medium. Genes encoding the initial chlorobenzene dioxygenase were detected by using a primer pair that was designed against the alpha-subunit (TecA1) of the chlorobenzene dioxygenase of Ralstonia (formerly Burkholderia) sp. strain PS12. The amino acid sequence of the amplified part of the alpha-subunit of the chlorobenzene dioxygenase of Rhodococcus sp. strain MS11 showed >99 % identity to the alpha-subunit of the chlorobenzene dioxygenase from Ralstonia sp. strain PS12 and the parts of both alpha-subunits responsible for substrate specificity were identical. The subsequent enzymes dihydrodiol dehydrogenase and chlorocatechol 1,2-dioxygenase were induced in cells grown on 1,2,4,5-TeCB. During cultivation on medium-chain-length n-alkanes ranging from n-decane to n-heptadecane, including 1-hexadecene, and on the branched alkane pristane, strain MS11 produced biosurfactants lowering the surface tension of the cultures from 72 to </=29 mN m(-1). Glycolipids were extracted from the supernatant of a culture grown on n-hexadecane and characterized by (1)H- and (13)C-NMR-spectroscopy and mass spectrometry. The two major components consisted of alpha,alpha-trehalose esterified at C-2 or C-4 with a succinic acid and at C-2' with a decanoic acid. They differed from one another in that one 2,3,4,2'-trehalosetetraester, found in higher concentration, was esterified at C-2, C-3 or C-4 with one octanoic and one decanoic acid and the other one, of lower concentration, with two octanoic acids. The results demonstrate that Rhodococcus sp. strain MS11 may be well suited for bioremediation of soils and sediments contaminated for a long time with di-, tri- and tetrachlorobenzenes as well as alkanes.

Alkanes↗
PubMed2006

Synthesis of 2'-paclitaxel methyl 2-glucopyranosyl succinate for specific targeted delivery to cancer cells.

A novel glucose-conjugated paclitaxel 5 was synthesized using succinic acid as linker between 2'-paclitaxel and methyl 2'-glucopyranose. 5 has not only improved the pharmaceutical properties of paclitaxel, such as solubility and stability, but also enhanced the specific target delivery to MCF-7 cells without the cytotoxicity against normal cells. Therefore, the glucose conjugation may be potentially used in the targeted delivery of other drugs into cells via glucose transporters (GLUTs) for cancer therapy.

Antineoplastic Agents, Phytogenic↗
PubMed2001

Carbon sources affect metabolic capacities of Bacillus species for the production of industrial enzymes: theoretical analyses for serine and neutral proteases and alpha-amylase.

The metabolic fluxes through the central carbon pathways were calculated for the genus Bacillus separately for the enzymes serine alkaline protease (SAP), neutral protease (NP) and alpha-amylase (AMY) on five carbon sources that have different reduction degrees (gamma), to determine the theoretical ultimate limits of the production capacities of Bacillus species and to predict the selective substrate for the media design. Glucose (gamma=4.0), acetate (gamma=4.0), and the TCA cycle organic-acids succinate (gamma=3.5), malate (gamma=3.0), and citrate (gamma=3.0) were selected for the theoretical analyses and comparisons. A detailed mass flux balance-based general stoichiometric model based on the proposed metabolic reaction network starting with the alternative five carbon sources for the synthesis of each enzyme in Bacillus licheniformis that simulates the behaviour of the metabolic pathways with 107 metabolites and 150 reaction fluxes is developed. Highest and lowest specific cell growth rates (&mgr;) were calculated as 1.142 and 0.766h(-1), respectively, when glucose that has the highest degree of reduction and citrate that has the lowest degree of reduction were used as the carbon sources. Highest and lowest SAP, NP and AMY synthesis rates were also obtained, respectively, when glucose and citrate were used. Metabolic capacity analyses showed that the maximum SAP, NP, and AMY synthesis rates were, respectively, 0.0483, 0.0215 and 0.0191mmolg(-1)DWh(-1) when glucose uptake rate was 10mmolg(-1)DWh(-1) and specific growth rate was zero. The amino acid compositions and the molecular weights of the enzyme influence the production yield and selectivity. For SAP and NP oxaloacetate and pyruvate, for AMY oxaloacetate appear to be the critical main branch points. Consequently, for SAP and NP syntheses the fluxes towards the alanine group and aspartate group, and for AMY synthesis the flux towards the aspartate group amino acids need to be high. The results encourage the discussion of the potential strategies for improving productions of SAP, NP and AMY.

Journal Article↗
PubMed1997

[Chronic renal failure and guanidino compounds].

Guanidino compounds are known as uremic toxins which increase in the blood of patients with renal failure. Guanidino succinic acid (GSA) and methyl guanidine (MG) have been intensively studied since they are toxic and are candidate markers which reflect the pathological stage of nephritis. GSA correlates well with blood urea nitrogen and therefore indicates the reduction of renal function. MG does not appear in the early stage of renal failure and abruptly increases at the stage of serious uremia. MG is produced by the oxidation of creatinine (CTN) with active oxygen. The MG/CTN ratio in the serum therefore reflects the degree of the generation of active oxygen. Accordingly, active oxygen scavengers may be useful for the treatment of uremia.

Animals↗
PubMed2001

Effect of phensuccinal on pancreatic beta-cells in rats with neonatally induced streptozotocin diabetes mellitus.

The effect of phensuccinal, a low-toxic succinic acid derivative, on the function of pancreatic beta-cells in the evolution of absolute insulin insufficiency was studied in rats with neonatally induced streptozotocin diabetes mellitus. Phensuccinal (25 mg/kg body weight) prevented disorders in the secretory response of beta-cells to glucose load at all stages of the study (2, 5, and 14 days after diabetes induction). This effect was realized via stimulation of the regenerative processes in the insulin-producing system of the pancreas and activation of the antioxidant system in diabetic animals.

Animals↗
PubMed1980

Extrusion of metabolites from baker's yeast during glucose-induced acidification.

Extrusion of metabolites (glycerol, lactic, malic, and succinic acid) during the medium acidification caused by resting baker's yeast supplied with 200 mM glucose was studied under aerobic and anaerobic conditions and in the absence and presence of 14 mM KCl. The maximum levels of glycerol and of the sum of acids (about 13 and 8 mM, respectively) were attained anaerobically; aerobiosis reduced the levels by 40-50% and the presence of K+ ions by another 10-20%. The time courses of glucose consumption and medium acidification were similar aerobically and anaerobically. The glucose consumption curves exhibited a short plateau about 2 min after glucose addition, caused probably by a rapid osmotic equilibration of glucose across the cell mambrane. Metabolite extrusion indicates that at high glucose concentrations the alcohol dehydrogenase reaction is supplemented by other reactions aiding in the maintenance of a balanced NAD+/NADH ratio in the cells.

Anaerobiosis↗
PubMed1969

Some factors affecting fermentation capacity and net growth of rumen microorganisms.

The fermentation rate of rumen microorganisms obtained from a sheep fed on hay was determined at different hours after feeding. The highest rate of fermentation was obtained immediately after feeding whereas the lowest rate was always before feeding. The effect of adding glucose, sucrose, and starch alone or in combination with urea, sodium citrate, or succinic acid on the maximal fermentation rate was studied. In no case was the maximal fermentation rate greater than that obtained in the presence of concentrate and straw. An investigation on the effect of C/N ratios, dilution, and substrate concentration on the net growth of rumen microorganisms was undertaken. The highest net growth value was obtained with a C/N ratio of 16.5 to 17.5, which is the ratio found for the ration fed to the animal. It was possible to increase net growth approximately threefold by using the proper dilution and fivefold by using the proper feed concentration.

Animal Feed↗
PubMed1967

Transient repression of the lac operon.

Severe transient repression of constitutive or induced beta-galactosidase synthesis occurs upon the addition of glucose to cells of Escherichia coli growing on glycerol, succinic acid, or lactic acid. Only mutants particularily well adapted to growth on glucose exhibit this phenomenon when transferred to a glucose-containing medium. No change in ribonucleic acid (RNA) metabolism was observed during transient repression. We could show that transient repression is pleiotropic, affecting all products of the lac operon. It occurs in a mutant insensitive to catabolite repression. It is established much more rapidly than catabolite repression, and is elicited by glucose analogues that are phosphorylated but not further catabolized by the cell. Thus, transient repression is not a consequence of the exclusion of inducer from the cell, does not require catabolism of the added compound, and does not involve a gross change in RNA metabolism. We conclude that transient repression is distinct from catabolite repression.

Carbon Isotopes↗
PubMed2006

Effects of cadmium amendments on low-molecular-weight organic acid exudates in rhizosphere soils of tobacco and sunflower.

To recognize physiological response of plants to cadmium (Cd) toxicity in rhizosphere of plants, the pot experiments were employed to investigate how low-molecular-weight organic acids (LMWOAs) were exudated from tobacco and sunflower roots of Cd-amended soils. The aims of this study were to assess the effect of LMWOAs on uptake of Cd by tobacco and sunflower under pot experiments, thus comparing the ability of tobacco and sunflower for phytoremediation. Surface soils (0-20 cm) were collected from Taichung Experiment Station (TC) (silty loam). Cadmium chloride (CdCl(2)) was amended into TC soil, giving Cd concentrations of 1, 5, 10 mg kg(-1) soil. Soils with different concentrations of Cd were put into 12 cm (i.d.) pots for incubation, and then 2-week-old tobacco and sunflower seedlings were transplanted into the pots. Tobacco and sunflower were grown in greenhouse for 50 days, respectively. The rhizosphere and bulk soils, and fresh plant tissues were collected after harvest. The Cd concentrations in the plant and transfer factor values in the sunflower were higher than that in the tobacco. No LMWOAs were detected by gas chromatograph in bulk soils, and low amounts of LMWOAs were found in uncontaminated rhizosphere soils. Acetic, lactic, glycolic, malic, maleic, and succinic acids were found in the tobacco and sunflower rhizosphere soils. Concentrations of LMWOAs increased with increasing amendment of Cd concentrations in tobacco and sunflower rhizosphere soils. Correlation coefficient (r) of concentrations of Cd amendment versus LMWOAs exudates of tobacco and sunflower were 0.85 and 0.98, respectively. These results suggest that the different levels of LMWOAs present in the rhizosphere soil play an important role in the solubilization of Cd that bound with soil particle into soil solution and then uptake by plants.

Biomass↗