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PubMed1999

New alpha-substituted succinate-based hydroxamic acids as TNFalpha convertase inhibitors.

Tumor necrosis factor alpha convertase (TACE), the enzyme responsible for the processing of pro-TNFalpha to TNFalpha, has been reported to be a metalloproteinase closely related to matrix metalloproteinases (MMPs). Current inhibitors of TACE such as succinate-based hydroxamic acids exemplified by Marimastat (TACE IC(50): 3.8 nM; blood IC(50): 7 microM) and BB1101 (TACE IC(50): 0.2 nM; blood IC(50): 2.3 microM) suffer from modest potency in blood and poor in vivo properties. The introduction of new bulky alpha-substituents into these succinate-based hydroxamic acids was studied. Substituents such as thioethers, sulfonamides, and ethers showed improved potency against TACE when compared with Marimastat. Although this improvement did not translate into better blood potency for thioether or ether substituents, the sulfonamide series exhibited improved potency both against TACE and in blood when compared with Marimastat. Optimization of this sulfonamide series has culminated in the identification of heterocyclic bicyclic sulfonamides such as 3t (TACE IC(50): 0.57 nM; blood IC(50): 0.28 microM).

ADAM Proteins↗
PubMed1995

SAM prevents impairment of glucose-stimulated insulin secretion caused by hexose deprivation or starvation.

Succinic acid monomethyl ester (SAM) was recently proposed as an insulinotropic tool in non-insulin-dependent diabetes mellitus. Three models were now used to investigate whether SAM protects the B-cell against the impairment of glucose-stimulated insulin release caused by either glucose deprivation or starvation. In the first model, preincubation of the islets for 180 min at low glucose concentration in the presence of SAM prevented the decrease in the secretory response to D-glucose otherwise observed during a subsequent incubation. In the second model, an impaired secretory response to D-glucose was observed after 3-day culture at low (2.8 or 5.6 mM) as distinct from high (11.1 mM) hexose concentration and the presence of SAM in the culture medium again protected against this anomaly. In the third model, the infusion of SAM for 3 days to starved rats restored the secretory potential of isolated islets to a level comparable to that otherwise found in fed rats. Thus, during glucose deprivation or starvation, SAM is indeed able to maintain B-cell responsiveness to D-glucose.

Animals↗
PubMed2003

Dendritic molecular capsules for hydrophobic compounds.

Reichardt's dye, a highly solvatochromic dye, was encapsulated within poly (glycerol succinic acid) ([Gn]-PGLSA-OH) dendrimers to investigate the interior environment of these dendritic macromolecules. The absorption maximum for the encapsulated Reichardt's dye in water was indicative of a relatively high dielectric constant present within the dye/dendrimer complex. (1)H NMR of the encapsulated complex showed the presence of aromatic protons from Reichardt's dye along with the aliphatic protons of the dendrimer. Additionally, there were substantial changes in T(1) and T(2) times of the encapsulated dye when compared with the free dye, and (1)H NOESY spectra for the complex showed a significant number of intermolecular NOE cross-peaks. These data reveal the close through-space proximity of the dye to the dendrimer and the restricted motion of the encapsulated dye. To demonstrate the potential use of these macromolecules as drug delivery vehicles, the poorly water-soluble anticancer drug 10-hydroxycamptothecin (10HCPT) was encapsulated within a carboxylated PGLSA dendrimer ([G4]-PGLSA-COONa). Cytotoxicity assays with human breast cancer cells showed a significant reduction of cell viability, demonstrating that 10HCPT retains activity upon encapsulation.

Benzene Derivatives↗
PubMed2004

Thermodynamic and structural characterization of amino acid-linked dialkyl lipids.

Using differential scanning calorimetry (DSC), X-ray diffraction (XRD) and Fourier transform infrared spectroscopy (FTIR), we determined some thermodynamic and structural parameters for a series of amino acid-linked dialkyl lipids containing a glutamic acid-succinate headgroup and di-alkyl chains: C12, C14, C16 and C18 in CHES buffer, pH 10. Upon heating, DSC shows that the C12, C14 and annealed C16 lipids undergo a single transition which XRD shows is from a lamellar, chain ordered subgel phase to a fluid phase. This single transition splits into two transitions for C18, and FTIR shows that the upper main transition is predominantly the melting of the hydrocarbon chains whereas the lower transition involves changes in the headgroup ordering as well as changes in the lateral packing of the chains. For short incubation times at low temperature, the C16 lipid appears to behave like the C18 lipid, but appropriate annealing at low temperatures indicates that its true equilibrium behavior is like the shorter chain lipids. XRD shows that the C12 lipid readily converts into a highly ordered subgel phase upon cooling and suggests a model with untilted, interdigitated chains and an area of 77.2A(2)/4 chains, with a distorted orthorhombic unit subcell, a=9.0A, b=4.3A and beta=92.7 degrees . As the chain length n increases, subgel formation is slowed, but untilted, interdigitated chains prevail.

Amino Acids↗
PubMed2004

Regulation of L-alanine dehydrogenase in Rhizobium leguminosarum bv. viciae and its role in pea nodules.

Alanine dehydrogenase (AldA) is the principal enzyme with which pea bacteroids synthesize alanine de novo. In free-living culture, AldA activity is induced by carboxylic acids (succinate, malate, and pyruvate), although the best inducer is alanine. Measurement of the intracellular concentration of alanine showed that AldA contributes to net alanine synthesis in laboratory cultures. Divergently transcribed from aldA is an AsnC type regulator, aldR. Mutation of aldR prevents induction of AldA activity. Plasmid-borne gusA fusions showed that aldR is required for transcription of both aldA and aldR; hence, AldR is autoregulatory. However, plasmid fusions containing the aldA-aldR intergenic region could apparently titrate out AldR, sometimes resulting in a complete loss of AldA enzyme activity. Therefore, integrated aldR::gusA and aldA::gusA fusions, as well as Northern blotting, were used to confirm the induction of aldA activity. Both aldA and aldR were expressed in the II/III interzone and zone III of pea nodules. Overexpression of aldA in bacteroids did not alter the ability of pea plants to fix nitrogen, as measured by acetylene reduction, but caused a large reduction in the size and dry weight of plants. This suggests that overexpression of aldA impairs the ability of bacteroids to donate fixed nitrogen that the plant can productively assimilate. We propose that the role of AldA may be to balance the alanine level for optimal functioning of bacteroid metabolism rather than to synthesize alanine as the sole product of N(2) reduction.

Alanine↗
PubMedDate not supplied

Lack of carcinogenicity of daminozide, alone or in combination with its contaminant 1,1-dimethylhydrazine, in a medium-term bioassay.

The carcinogenicity of daminozide (succinic acid-2,2-dimethylhydrazide; Alar), a plant growth regulator used primarily in apple orchards, has been the subject of recent investigations by several national and international organizations because of contradictory study results. The aim of the present study was to assess the carcinogenicity of daminozide alone and in combination with 1,1-dimethylhydrazine (UDMH), its major contaminant, in a novel medium-term bioassay in Fischer 344 rats, the DEN-PH model. Rats were given diethylnitrosamine (DEN) at 200 mg/kg body weight intraperitoneally and then 2 weeks later were given daminozide at 20,000 ppm or daminozide plus UDMH at 75, 150, or 300 ppm in the diet for 6 weeks and were then killed; all rats underwent a partial (two-thirds) hepatectomy (PH) at week 3. Hepatocarcinogenic potential was assessed by comparing the number and area of preneoplastic foci positive for the glutathione S-transferase placental form (GST-P+) in the liver of treated rats, with those in controls given DEN alone. Daminozide, UDMH, and the combination were not carcinogenic in this model. This novel medium-term bioassay for carcinogenicity is considered to be practical for the rapid evaluation of both agrochemical formulations and contaminants found in agrochemicals and other compounds.

Adjuvants, Immunologic↗
PubMed1993

Comparative effects of monomethylsuccinate and glucose on insulin secretion from perifused rat islets.

In the absence of any other exogenously added fuel, monomethylsuccinate, the methyl ester of succinic acid, at 10-20 mM stimulates insulin release in a biphasic pattern. In quantitative terms, first-phase release evoked by 20 mM MMSucc was comparable to that observed with 20 mM glucose but second-phase release was only 20% of the glucose-induced response. Secretion to both MMSucc and glucose was virtually abolished by the calcium channel antagonist nitrendipine (0.5 microM). In islets that had phosphoinositide pools labeled with [3H]inositol for 2 h, subsequent stimulation with 20 mM MMSucc results in dramatic and sustained increases in [3H]inositol efflux rates. Inositol phosphate levels are also increased. In contrast to secretion, the increase in phosphoinositide hydrolysis caused by MMSucc was largely resistant to nitrendipine, whereas significant reductions in glucose-induced phosphoinositide hydrolysis were observed in the presence of the calcium channel antagonist. MMSucc (2.75-10 mM) substitutes for glucose in that MMSucc supported the insulinotropic effects of the sulfonylurea tolbutamide (200 microM) and the gut hormone cholecystokinin (200 nM). A prior 15-min exposure to 20 mM MMSucc also sensitized islets to the stimulatory effects of 7.5 mM glucose. Finally, a 2-h exposure to 20 mM MMSucc desensitized the islet, in terms of both phosphoinositide hydrolysis and insulin secretion, to a subsequent exposure to 10 mM glucose. Thus, appropriate concentrations of MMSucc can cause qualitatively many of the effects induced by glucose.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗
PubMed2005

[Effects of emoxipine, reamberine and mexidol on neuropathic symptoms and a systolic function of the left ventricular myocardium in patients with diabetes mellitus and diabetic foot syndrome].

AIM: To compare efficacy of 3-oxypiridine and succinic acid derivatives (emoxipine, reamberine and mexidol) in distal neuropathy (DN) and left ventricular myocardium systolic function (LVMSF) in diabetic patients with diabetic foot syndrome (DFS). MATERIAL AND METHODS: We studied 120 patients with diabetes mellitus type 1 and 2 (DM1 and DM2). The patients had neuropathic and neuroischemic forms of DFS (stage 0-1 by Wagner, 1990). The patients were randomized into 4 equal groups matched by gender and number of patients with DM1 and DM2. Group 1 received basic therapy plus intravenous placebo (daily 200 ml drops of the polarizing mixture). Group 2 received additional 150 mg emoxipine. Group 3 was given daily intravenous drop infusions of 400 ml reamberin. Group 4 received once daily 300 mg mexidol. The infusion therapy in all the groups lasted for 14 days. Quantitation of neuropathic symptomatic count (NSC), neuropathic dysfunction count (NDC) and echocardiographic examination of LVMSF were made and venous blood samples were obtained before the treatment and after 2 weeks of therapy. RESULTS: Emoxipin, reamberin and mexidol therapy alleviated DM symptoms. In contrast to placebo, the drugs lessened the scores by NSC and NDC. By NSC, the lowest total score was observed after treatment with reamberin. LVMSF changed most significantly in patients on emoxipin, less significantly in those on reamberin and insignificantly on mexidol. The above positive effect did not depend on metabolic compensation of DM. CONCLUSION: The addition of emoxipin, reamberin and mexidol to the scheme of DM patients with DFS relieves symptoms of DM. Moreover, reduction of DM symptoms due to emoxipin and reamberin is associated with better LVMSF.

Aged↗
PubMedDate not supplied

[Lymphocyte succinate dehydrogenase and acid phosphatase activity in infants on artificial feeding with a varying protein content in the diet].

The activity of succinate dehydrogenase and acid phosphatase in blood lymphocytes was studied in healthy children of the first half year of life kept on formula feeding with the adapted milk mixtures "Malyutka" and "Malysh". The content of protein in the children's diet varied over the range of 2-2.5; 3-3.5 and 4-4.5 g/kg. The activity of succinate dehydrogenase has been shown to be related to the protein content in the diet. The results obtained point to the possibility of assessing this activity as an additional method for determination of the optimum protein content in formula feeding.

Acid Phosphatase↗
PubMed1993

Phenytoin-lipid conjugates as potential prodrugs of phenytoin.

Phenytoin-1-triglycerides and phenytoin-2-triglycerides were synthesized as potential prodrugs of phenytoin by covalent binding of 3-hydroxymethylphenytoin by succinic acid to the positions 1 and 2 of diglycerides, respectively. The corresponding 1- and 2-monoglycerides were prepared. In addition, replacement of glycerol by 3-hydroxy-2-hydroxymethylpropionic acid furnished lipids that allowed direct coupling of 3-hydroxymethylphenytoin. The lipid conjugates proved to be substrates for pancreatic lipase in vitro.

Animals↗
PubMed1995

Synthesis and in vitro degradation of testosterone-lipid conjugates.

Testosterone-lipid conjugates were obtained by covalent binding of the drug to 1,3-dipalmitoylglycerol via succinic acid to 4-(1,3-dipalmitoyl-2-glyceryl)butyric acid and to 3-palmitoyloxy-2-palmitoyloxmethylpropionic acid. In contrast to the corresponding bis-deacyl derivatives, the lipids were not significantly hydrolyzed in aqueous buffers and in plasma. Incubation with pancreatic lipase yielded primarily the bis-deacyl compounds, which are comparable to monoglycerides, and subsequently slowly liberated testosterone. It is concluded that the lipid conjugates are substrates for pancreatic lipase. However, the drug was released very slowly due to steric hindrance.

Animals↗
PubMed2005

Culture of Escherichia coli under dissolved oxygen gradients simulated in a two-compartment scale-down system: metabolic response and production of recombinant protein.

A significant problem of large-scale cultures, but scarcely studied for recombinant E. coli, is the presence of gradients in dissolved oxygen tension (DOT). In this study, the effect of DOT gradients on the metabolic response of E. coli and production of recombinant pre-proinsulin, accumulated as inclusion bodies, was determined. DOT gradients were simulated in a two-compartment scale-down system consisting of two interconnected stirred-tank bioreactors, one maintained at anoxic conditions and the other at a DOT of at least 6%. Cells were continuously circulated between both vessels to simulate circulation times (tc) of 20, 50, 90, and 180 sec. A complete kinetic and stoichiometric characterization was performed in the scale-down system as well as in control cultures maintained at constant DOT in the range of 0-20%. The performance of E. coli cultured under oscillating DOT was significantly affected, even at a tc of 20 sec corresponding to transient exposures of only 13.3 sec to anaerobic conditions. Specific growth rate decreased linearly with tc to a maximum reduction of 30% at the highest tc tested. The negative effect of DOT gradients was even more pronounced for the overall biomass yield on glucose and the maximum concentration and yield of pre-proinsulin. In these cases, the losses were 9%, 27%, and 20%, respectively, at tc of 20 sec and 65%, 94%, and 87%, respectively, at tc of 180 sec. Acetic, lactic, formic, and succinic acids accumulated during oscillatory DOT cultures, indicating that deviation of carbon flow to anaerobic metabolism was responsible for the observed losses. The results of this study indicate that even very short exposures to anaerobic conditions, typical of large-scale operations, can substantially reduce recombinant protein productivity. The information presented here is useful for establishing improved rational scale-up strategies and understanding the behavior of recombinant E. coli exposed to DOT gradients.

Biotechnology↗
PubMed2006

Preparation of a nanowire-structured polyaniline composite and gas sensitivity studies.

To obtain organic nanowire sensors with high sensitivity and rapid response times, based on the inducement effect of surfactants during in situ polymerization, nanostructured polyaniline composites are obtained by using a chemical oxidation method by adding a small amount of surfactant. A casting method is employed on interdigitated carbon electrodes. The gas sensitivity to a series of chemical vapors is examined at room temperature. The results indicate that polyaniline with regular nanowire structure is obtained when succinic acid is added. The gas sensitivity and response rates of a film with nanowire structure are much better than those of conventional polyaniline films produced by means of organic solution spin coating methods. The film described in this work shows good selectivity to trimethylamine and other related gases and, the reaction being reversible with the use of high-purity nitrogen.

Aniline Compounds↗
PubMed2007

Grafting amine-terminated branched architectures from poly(L-lactide) film surfaces for improved cell attachment.

Poly(L-lactide) (PLL) has been used as a bioabsorbable material in the medical and pharmaceutical fields. The unmodified hydrophobic PLL surface generally has low cell affinity; thus, modification of PLL film surface properties is necessary to improve its use as a biomaterial. Our surface modification method involved the use of photografting and typical wet chemistry to create branched architectures containing amine functionalities on the periphery of the grafted layers. Amine (-NH2) groups were first introduced on the PLL film surface by photoinduced grafting of 4,4'-diaminobenzophenone and the grafted branched architectures were created by subsequent reactions with succinic acid and tris(2-aminoethyl) amine. The resulting film surface was analyzed using contact angle goniometry and X-ray photoelectron spectroscopy. MC3T3 fibroblasts were cultured on unmodified PLL film and PLL films grafted with the branched structures and the films were subsequently analyzed by optical microscopy. The contact angle goniometry results showed an initial decrease and subsequent plateau in the water contact angles for the PLL films with each successive generation of the branched architectures. The X-ray photoelectron spectroscopy data provided insight into the structure of the grafted layer and revealed an increase in the nitrogen content with each generation. Optical micrographs showed enhanced cell attachment and viability on the surface-modified PLL films.

Amines↗
PubMed1994

Rapid fluorometric assay for mitochondrial proton adenosine triphosphatase activity for assessment of viability of liver graft tissue.

We developed an improved determination method of mitochondrial proton adenosine triphosphatase (ATPase) activity in the liver. The activity was measured fluorometrically with a 3,3'-dipropylthiodicarbocyanine iodide (diS-C3(5)), which is excited at 625 nm and emits fluorescence at 670 nm. This dye transmits the electric potential across the inner mitochondrial membrane. The fluorescence intensity of diS-C3(5) with mitochondria (100 microliters, 4-16 mg/ml protein) in a 2 ml potassium buffer (pH 7.4) was regarded as a standard electric potential. After confirming the activity of the mitochondrial electron transport chain by succinic acid (9 mumol), we inhibited the chain by antimycin A (1.25 micrograms). Fluorescence intensity decreased by adenosine 5'-triphosphate (ATP) (2 mumol) and oligomycin (25 micrograms) inhibited this depression. The value of mitochondrial proton ATPase activity was calculated as a percentage of the fluorescence intensity change by ATP per the standard electric potential. The activity of mitochondrial proton ATPase in the normal fresh rat livers was 50.3 +/- 2.2%. Good correlation (r2 = 0.807) between two methods for mitochondrial proton ATPase activity, our newly developed method and a conventional colorimetric method, was obtained in the rat livers with various conditions. This method has advantages that the proton ATPase activity can be measured in intact mitochondria, and all procedures can be completed within 40 min. It is suitable for the determination of mitochondrial viability of liver graft in the hepatic resections and transplantations.

Adenosine Triphosphate↗
PubMed1975

Multienzymic nature of pyruvate kinase during development of Hymenolepis diminuta (Cestoda).

H. diminuta at different stages of development contained as many as five pyruvate kinase isozymes. Four of these were unusually sensitive to allosteric activation by fructose-1,6-P2. One isozyme which occurred only in adults or near-adults was insensitive but had a relatively low Km. All were inhibited by ATP and Ca2+, none by alanine, and the pH optimum was unaffected by fructose-1,6-P2. The five isozymes were present in gravid or reproductively active proglottids. Two of them occurred after eight days growth in the rat intestine, and three after four days. These three were also present in the immature, anterior proglottids of adult parasites. Hexacanth larvae from gravid proglottids, as well as cysticercoids developing from these larvae in Tenebrio molitor, possessed only two isozymes. It was inferred from information on tissue concentrations of ADP, ATP, phosphoenolypyruvate (PEP) and on K0.5S and Km that competition between pyruvate kinase and PEP carboxykinase is probably controlled by fructose-1,6-P2 concentrations. Since H. diminuta is an obligatory fermenter in which gluconeogenesis is minimal, the probable function of its L-type pyruvate kinases is to control the specific composition of lactic, acetic and succinic acid mixtures that are excreted at different stages of development.

Adenosine Diphosphate↗
PubMed1999

Inflammatory processes in a murine model of intra-abdominal abscess formation.

Abscess formation has been viewed as a host defense strategy to contain the spread of infection. However, abscesses are also serious and life-threatening manifestations of persisting microbial infection. The initiation of abscess formation, both clinically and experimentally, involves the release of bacteria and an abscess-potentiating agent (e.g., fecal fiber or an analog) into a sterile site, with host defense mechanisms being unable to eliminate the infecting organisms. Abscess formation is aided by a combination of factors that share a common feature: impairment of phagocytic killing and hence clearance of microorganisms. These include bacterial virulence factors (e.g., capsule formation, succinic acid production); complement activation by the abscess potentiating agent; fibrin deposition; and microbial sequestration within abscess neutrophils. Recruitment of cells into the peritoneal cavity follows mast cell activation in the pathogenesis of infection: histamine and tumor necrosis factor alpha can be detected in the peritoneal cavity within minutes of challenge with an abscess-inducing mixture. However, the role of mast cells in host defense is made less clear by the finding of diminished abscess formation (but no mortality or increased morbidity) in mast-cell-depleted mice. This may indicate that mast cell products have a role in not only the initiation of an inflammatory response but also the promotion of fibrin deposition and abscess formation.

Abdominal Abscess↗
PubMed1979

Collaborative study of a GLC method for vitamin E.

The official GLC method of the Association of Official Analytical Chemists (AOAC) for determining vitamin E was modified and collaboratively studied for the National Formulary (NF). The internal standard hexadecyl hexadecanoate (cetyl palmitate) was substituted for the dotriacontane used in the AOAC method, and some other minor changes were made. Eleven samples, representing all types of NF formulations and NF bulk materials, were analyzed by 11 laboratories. The coefficients of variation of the reproducibility and repeatability were 4.5 and 2.4%, respectively, for all laboratories and samples. The values were 3.4 and 1.6%, respectively, when the one laboratory statistically determined to be an outlier was excluded. The coefficients of variation of reproducibility and repeatability for alpha-tocopheryl acid succinate were 2.1 and 1.5%, respectively. All of these values lie within the 5% limit required by the NF.

Analysis of Variance↗