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PubMed1979

Effect of antihistamines on anaphylactoid oedema in rats using a modified plethysmometer for measuring foot volume.

This study reports the quantitative effect of the H1--and H2--receptor antagonists on dextran-induced anaphylactoid oedema in rats. The findings indicate that mepyramine, promethazine and chlorpromazine which are H1--receptor antagonists significantly inhibited this anaphylactoid oedema. While on the other hand burimamide an H2--receptor antagonist at doses below 500 micrograms/kg inhibit dextran-induced oedema but at higher doses enhances oedema formation in the test rats. E.D50 values obtained for mepyramine, chlorpromazine and promethazine are 5.01 mg/kg, 0.36 mg/kg, 1.78 mg/kg respectively. The dual effects of burimamide on dextran-induced oedema merits further investigation and confirmation with the aid of other H1--and/or H2--receptor systems. A modification of the plethysmometric method of Buttle et. al. (1957) is also described.

Anaphylaxis↗
PubMed1976

Modified 5'-nucleotides resistant to 5'-nucleotidase: isolation of 3-(3-amino-3-carboxypropyl) uridine 5'-phosphate and N2, N2-dimethylguanosine 5'-phosphate from snake venom hydrolysates of transfer RNA.

A procedure for the quantitative measurement of the O2'-methylnucleoside constitutents of RNA has recently been developed in this laboratory (Gray, M.W. Can. J. Biochem. 53, 735-746 (1975)). This assay method is based on the resistance of O2'-methylnucleoside 5'-phosphates (pNm) (generated by phosphodiesterase hydrolysis of RNA) to subsequent dephosphorylation by venom 5'-nucleotidase (EC 3.1.3.5). In the present investigation, two base-modified 5'-nucleotides, each displaying an unusual resistance to 5'-nucleotidase, have been identified. These compounds have been characterized by a variety of techniques as N2, N2-dimethylguanosine 5'-phosphate (pm2/2G) and 3-(3-amino-3-carboxypropyl)uridine 5'-phosphate (p4abu3U). Because of their resistance to 5'-nucleotidase, pm2/2G and p4abu3U are isolated along with the pNm in the mononucleotide fraction of venom hydrolysates of transfer RNA. Under hydrolysis conditions, the stability of p4abu3U is comparable to that of a pNm, allowing quantitative assay of the nucleotide. The proportion (mean +/- SD) of p4abu3U in venom hydrolysates of wheat embryo and Escherichia coli tRNA has been determined to be 0.35 +/- 0.03 (n=5) and 0.14 +/- 0.02 (n=4) mol%, respectively. The absence of p4abu3U in venom hydrolysates of yeast tRNA implies the absence of the corresponding nucleoside in yeast tRNA, in agreement with existing data. The variable recovery of pm2/2G from venom hydrolysates of wheat embryo and yeast tRNA indicates that under hydrolysis conditions, this base-modified nucleotide is only partially resistent to 5'-nucleotidase. The complete absence of pm2/2G in venom hydrolysates of E. coli tRNA is consistent with the known absence of N2, N2-dimethylguanosine in this RNA. These observations demonstrate that resistance to 5'-nucleotidase is a necessary but not sufficient criterion for concluding that a 5'-nucleotide is O2'-methylated. When applied to wheat embryo ribosomal RNA, the analytical methods described in this report failed to reveal any compound having the distinctive charge properties of p4abu3U. It therefore appears that 1-methyl-3-(3-amino-3-carboxypropyl)pseudouridine, recently characterized as a constituent of the 18 S rRNA of Chinese hamster cells (Saponara, A.G. & Enger, M.D. Biochim. Biophys. Acta 349, 61-77 (1974)), may not be present in wheat embryo ribosomal RNA.

Guanine Nucleotides↗
PubMed1977

Regulatory effects of purine nucleotide analogs with liver glutamate dehydrogenase.

A total of 26 different purine nucleotides with specific modifications in the base moiety and/or in the polyphosphate chain as well as various combinations of nucleotides were tested as allosteric effectors of beef liver glutamate dehydrogenase (L-glutamate : NAD(P)+ oxidoreductase (deaminating), EC 1.4.1.3). The capacity of these nucleotide analogs to activate or to inhibit the glutamate dehydrogenase activity is expressed quantitatively and scaled between the extreme effects of ADP and GTP, respectively. The significance of distinct structural elements for the enzyme-effector interaction is discussed. While the inhibitory GTP site is less specific, accepting many natural and most modified nucleoside triphosphates as inhibitors, the activating ADP site shows a much higher specificity for nucleotides as activators.

Allosteric Regulation↗
PubMed1977

pD2-, pA2- and pD2'-values of a series of compounds in a histaminic and a cholinergic system.

(1) Affinity and intrinsic activity values of 75 compounds for a histaminergic and a cholinergic system are presented. The quantitative correlations between the affinity values of 35 compounds and some physicochemical constants (Van der Waals volume, lipophilicity, number of hydrogen atoms on the protonated amine) are discussed. (2) Absence of systematic differences between pD2 and pA2 of partial agonists supports the assumption that these values are equivalent expressions of the same affinity. (3) The "mimetic moiety" in a number of the antihistaminic test compounds hardly contributes to their affinity. The affinity mainly depends on an interaction tendency with additional receptor areas. (4) The correlation between pA2 and pD2' of the whole series of compounds in the histaminergic system is artificial. The method only allows determination of both values if their ratio lies between certain limits. (5) The correlation between pA2 and pD2' for 16 closely related compounds in the guinea pig ileum and for nearly all compounds in the rat intestine has to be explained by an influence of the structural differences on drug transference and/or the less specific binding forces. (6) The metactoid receptors in the two systems are different structures. (7) Possible molecular modifications to maximize the separation of antihistaminic form cholinergic affinity are suggested.

Animals↗
PubMed2026

Dictamnine alleviates oxidative stress in rheumatoid arthritis via modulation of the NR1D1-Keap1/Nrf2/ARE axis.

Rheumatoid arthritis (RA) is a persistent systemic disorder of autoimmune origin, with its core pathological manifestation being inflammation of the synovial tissue. The excessive growth of fibroblast-like synoviocytes (FLS) represents a critical pathological mechanism in RA, actively driving the advancement of the condition. Dictamnus dasycarpus Turcz. (D. dasycarpus) exhibits prominent anti-inflammatory effects and shows favorable therapeutic efficacy against RA. Dictamnine (Dic) is a major active component of D. dasycarpus, however, its therapeutic effectiveness and underlying mechanisms in RA have yet to be fully elucidated. This study investigated the effect of Dic on synovial hyperplasia in RA and elucidated the underlying mechanisms. Using a TNF-α-induced human fibroblast-like synoviocyte (HFLS-RA) model and a collagen-induced arthritis (CIA) mouse model, Dic was found to effectively inhibit synovial cell proliferation and pathological hyperplasia. Proteomics analysis was employed to clarify its potential mechanism in ameliorating the disease, and the findings were further validated through hematoxylin and eosin (H&E) staining, immunofluorescence (IF), ROS detection, JC-1 staining, cellular thermal shift assay (CETSA), drug affinity responsive target stability (DARTS) analysis, quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting (WB). The results suggested that the anti-RA activity of Dic is associated with its interaction with the nuclear receptor NR1D1. Moreover, the NR1D1 antagonist SR8278 reversed Dic's effects on Nrf2 and cytoprotection, confirming that Dic functions through NR1D1. This activation consequently influences the Keap1/Nrf2/ARE cascade, leading to decreased intracellular reactive oxygen species (ROS) accumulation and an improvement in compromised mitochondrial membrane potential. siRNA knockdown experiments further confirmed that NR1D1 is a target of Dic and regulates the downstream Keap1/Nrf2/HO-1 signaling pathway, through which Dic ameliorates RA both in vitro and in vivo by upregulating NR1D1 expression to activate the Keap1/Nrf2/ARE antioxidant pathway, thereby mitigating oxidative stress, inhibiting synovial cell proliferation, and ultimately alleviating pathological synovial hyperplasia.

Arthritis, Rheumatoid↗
PubMed2026

Mapping the covalent cysteine interactome of Ebselen reveals high-sensitivity target engagement and redox proteome remodeling.

Ebselen is a covalent organoselenium compound with broad pharmacological activity, yet its cellular cysteine targets and downstream proteomic consequences remain incompletely defined. Here, we integrated competitive gel-based activity-based protein profiling, reactivity-dependent tandem orthogonal proteolysis-activity-based protein profiling, and TMT-based quantitative proteomics to map Ebselen-induced cysteine engagement and proteome remodeling in living cancer cells. Ebselen exhibited dose-dependent cytotoxicity and markedly perturbed intracellular thiol-redox balance, as reflected by glutathione depletion and altered reactive oxygen species-associated fluorescence readouts. Competitive gel-based profiling confirmed concentration-dependent engagement of protein cysteine residues in live cells. Quantitative rdTOP-ABPP further identified hundreds of dose-responsive cysteine sites in HeLa and HepG2 cells and revealed a preference for cysteine microenvironments enriched with basic residues. Cross-cell-line comparison highlighted CDK5 Cys53, SMU1 Cys298, and RPSA2 Cys163 as conserved covalent nodes, among which CDK5 Cys53 showed high sensitivity to Ebselen treatment, a finding validated by competitive labeling and MS-based site assignment. Global TMT proteomics revealed extensive remodeling of redox-related and cell-survival-associated pathways, including compensatory upregulation of selenoproteins such as TXNRD1 and GPX family members. Together, these results define a chemical proteomic atlas of Ebselen-cysteine interactions and provide a framework for understanding and optimizing covalent organoselenium therapeutics.

Humans↗
PubMed1976

Isolation of brain endopeptidases: influence of size and sequence of substrates structurally related to bradykinin.

Two thiol-activated endopeptidases with pH optima near pH 7.5 were isolated from the supernatant fraction of rabbit brain homogenates by DEAE-cellulose chromatography, gel filtration and isoelectrofocusing. Peptide bond hydrolysis was measured quantitatively by ion-exchange chromatography with an amino acid analyzer. Brain kininase A hydrolyzes the Phe5-Ser6 peptide bond in bradykinin (Bk), Arg1-Pro2-Pro3-Gly4-Phe5-Ser6-Pro7-Phe8-Arg9. It is isoelectric near pH 5.2 and has a molecular weight of approximately 71 000. The enzyme also hydrolyzes the Phe-Ser peptide bond in Lys-Bk, Met-Lys-Bk, des-Arg1-Bk, Lys9-Bk, Pro-Gly-Phe-Ser-Pro-Phe-Arg, and Gly-Pro-Phe-Ser-Pro-Phe-Arg, but does not hydrolyze (0.1%) this bond in des-Phe8-Arg9-Bk. Brain kininase B hydrolyzes the Pro7-Phe8 peptide bond in Bk. It is isoelectric at pH 4.9 and has a molecular weight of approximately 68 000. Brain kininase B also hydrolyzes the Pro-Phe bond in Lys-Bk, Met-Lys-Bk, Lys9-Bk, Ser-Pro-Phe-Arg, and Phe-Ser-Pro-Arg. Pretreatment of denatured kininogen with brain kininase A or B did not reduce the amount of trypsin-releasable Bk from this precursor protein, indicating that the Bk sequence, when part of a large protein, is not a substrate for either enzyme. However, kininase A and B hydrolyze the octadecapeptide Gly-Leu-Met-Lys-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg-Ser-Val-Gin-Val. The data show that a large part of the C-terminal portion of bradykinin is important for the brain kininase A activity and, for both enzymes, the size of the peptide and presumably the residues adjacent to the scissle bond are important in determining the rate of peptide bond hydrolysis by these endopeptidases.

Amino Acid Sequence↗
PubMed1975

The antibody-enzyme analogy. Characterization of antibodies to phosphopyridoxyltyrosine derivatives.

Stable analogs of the crucial Schiff base intermediate of enzymatic and nonenzymatic pyridoxal phosphate catalysis have been used as haptens for induction of specific antibodies. N-(5-phosphopyridoxyl)-3'-amino-L-tyrosine and its conformationally distinct cyclized derivative resemble the Schiff base formed upon mixing tyrosine with pyridoxal phosphate. These compounds were covalently coupled to a protein carrier via the 3'-amino group so as to confer a prescribed orientation, with the coenzyme region farthest removed from the carrier. A third antigen, with the phosphopyridoxyl group alone as the hapten, was prepared by linkage of pyridoxal phosphate directly to free amino groups on the carrier protein. Antibodies elicited for each determinant were purified by means of appropriate affinity columns. Antibody heterogeneity was observed in that different species could be separated from a given serum by sequential elution from the affinity columns with 1 M sodium phosphate buffers of pH 7.6, 5.2, 2.6 and 1.5. In assays of quantitative precipitation, inhibition of precipitation, equilibrium dialysis, and fluorescence quenching, antibodies to the phosphopyridoxyltyrosine haptens showed specificity for the phosphorylated form of the coenzyme and binding activity for both the coenzyme and tyrosine portions of the hapten. Antibodies to the phosphopyridoxyl groups alone did not display a similar reactivity toward the tyrosine portion of the complex haptens. The cyclic and noncyclic conformations of the hapten were serologically distinct, as antibody to each reacted preferentially with the homologous form.

Animals↗
PubMed1976

Clonidine and related analogues. Quantitative correlations.

Twenty-two structural derivatives of clonidine [2-(2,6-dichlorophenylimino)imidazolidine] have been synthesized and their main physicochemical parameters (log P, deltaRM, pKa) determined. Quantitative correlations between the peripheral alpha-mimetic action (pithed rats) and physicochemical parameters pointed out the critical role of the steric effect in the ortho positions. On the other hand, attempted quantitative correlations between physicochemical parameters and central hypotensive activity were unsuccessful. These results are discussed in the light of the postulated mechanism of action of clonidine.

Adrenergic alpha-Agonists↗
PubMed1978

New observations concerning the chloroacetaldehyde reaction with some tRNA constituents. Stable intermediates, kinetics and selectivity of the reaction.

The stable intermediates formed in the reaction of cytosine, cytidine and adenosine with chloracetaldehyde were isolated. The -CH2CH/OH/- bridge between the exo and endo nitrogen atoms of the parent base was found in these compounds by means of PMR spectroscopy. Their acid-induced dehydration resulted in formation of appropriate ethenoderivatives. The rate constants of the intermediate formation and its dehydration were found to be 38x10(-4) and 47x10(-4) /min-1/ for adenosine, and 33x10(-4) and 10x10(-4) /min-1/ for cytidine. The PH range of 4.5--5.0 was found to be optimum for both adenosine and cytidine reactions. The quantitative modification of these two nucleosides in the presence of guanosine may be achieved with high selectivity only at a low pH of 3.0--4.0 N6-methyladenosine and N4-methylcytidine react quantitatively with chloroacetaldehyde and the reaction rate is higher than in the case of the parent nucleosides. The structure of the reaction products was assigned on the basis of PMR spectroscopy.

Acetaldehyde↗
PubMed1977

Spontaneous deamidation of a protein antibiotic, neocarzinostatin, at weakly acidic pH. Conversion to a homologous inactive preneocarzinostatin due to change of asparagine 83 to aspartic acid 83 accompanied by conformational and biological alterations.

The amide content of neocarzinostatin (NCS), an antitumor protein, has been determined by analysing asparagine and glutamine in the Pronase-aminopeptidase M digests of tetra-S-carboxymethyl-NCS and carboxyl-modified NCS (modified with a water-soluble carbodiimide and [14C]glycine methyl ester). Preneocarzinostatin (PRE) was separated and purified from a crude NCS preparation by CM-cellulose column chromatography. PRE was found to contain one mole less asparagine than NCS, and asparagine was deamidated to aspartic acid in PRE. A time-dependent conversion of NCS to PRE at pH 3.2 at 4 degrees or in 0.1 M acetic acid at 26 degrees was studied in two ways; first, by quantitative determination of NCS and PRE by CM-cellulose column chromatography and second, by following the release of free NH3 during dialysis in an air-tight container. Within experimental error, PRE was indistinguishable from NCS in amino acid content after acid hydrolysis, as well as in apparent molecular weight as determined by SDS-disc gel electrophoresis (10% acrylamide), and N- and C-terminal amino acid residues. Both NCS and PRE shared a common antigenicity as determined by Ouchterlony's agar diffusion method. Only a slight difference between the two in electrophoresis on a cellulose acetate membrane and on a peptide map of the tryptic digest was demonstrated. PRE, however, was completely devoid of biological activity. In addition to the chromatographic difference, a conformational difference was observed by CD spectroscopy, namely, an apparently looser structure of PRE was indicated by the shallowness of the trough in the 240-265 nm region. This interpretation was supported by the finding that digestions by Pronase were more extensive with PRE than with NCS. These results indicate an important role of the single asparagine residue (Asn 83) of NCS in the biological activity, which is evidently governed by the conformation.

Amino Acids↗
PubMed1977

Intramolecularly-quenched fluorescent peptides as fluorogenic substrates ofleucine aminopeptidase and inhibitors of clostridial aminopeptidase.

Fluorogenic oligopeptide derivatives of the type Lys(ABz)-ONBzl, where ABz iso-aminobenzoyl (anthraniloyl), X stands for Ala Phe, or Ala-Ala, and ONBzlis p-nitrobenzyloxy, were synthesized and shown to be hydrolyzed by leucine aminopeptidase. The hydrolysis is accompanied by an increase in fluorescence due to disruptionof the intramolecular quenching of the fluorescent anthraniloyl moiety by the nitrobenzyester group. The spectral characteristics of the compounds are not consistent withan energy transfer mechanism according to Förster, therefore the quenching isassumed to be caused by a direct encouter between the quenching and the fluorecentgroups. The change in fluorescence that accompanies the enzymic hydrolysis ofthe first peptide bound was used for quantitative measurement of the activity ofthe activity of leucine aminopeptidase and for the determination of some of itskinetic parameters. A bacterial aminopeptidase from Clostrdium histolyticumthat is very similar to leucine aminopeptidase in its substrate specificity inits substrate specificity did not hydrolyze the above peptidederivatives. Thehydrolysis of leucine p-nitroanilide by this enzyme was found to be inhibitedby the three peptides and the corresponding inhibition constants were determined.

Aminopeptidases↗
PubMed1975

Characterization of bleomycin action on DNA.

Cleavage of SV40 DNA by bleomycin was assayed quantitatively in vitro in the presence of various ppolynucleotides. SV40 DNA was protected from bleomycin- duced cleavage by native or denatured DNA of other origins, oly dG-C.poly dG-C, poly dA-T.poly dA-T and poly dA-T (denatured) but not by tRNA of E. coli, apurinic acid, poly dA, poly dT and various deoxyribooligonucleotides. Various bleomycins and their derivatives and various fragments of bleomycin were tested for possible activity in cleaving SV40 DNA and from the results some structure-activity relationships for the action of bleomycin to act on DNA were outlined. Actinomycin D stimulated bleomycin action while ethidium bromide inhibited it.

Animals↗
PubMed1975

Use of 5-deazaFAD to study hydrogen transfer in the D-amino acid oxidase reaction.

The apoprotein of hog kidney D-amino acid oxidase was reconstituted with 5-deazaflavin adenine dinucleotide (5-deazaFAD) to yield a protein which contains 1.5 mol of 5-deazaFAD/mol of enzyme. The deazaFAD-containing enzyme forms complexes with benzoate, 2-amino benzoate, and 4-aminobenzoate which are both qualitatively and quantitatively similar to those observed with native enzyme. The complex with 2-aminobenzoate exhibits a new long wavelength absorption band characteristic of a flavin charge-transfer complex. The reconstituted enzyme exhibits no activity when assayed by D-alanine oxidation. However, the bound chromophore can be reduced by alanine, phenylalanine, proline, methionine, and valine, but not by glutamate or aspartate, indicating the deazaFAD enzyme retains the substrate specificity of the native enzyme. Reduction of the enzyme by D-alanine exhibits a 1.6-fold deuterium isotope effect. Reoxidation of the reduced enzyme occurred in the presence of pyruvate plus ammonia, but not with pyruvate alone or ammonia alone. beta-Phenylpyruvate and alpha-ketobutyrate, but not alpha-ketoglutarate could replace pyruvate. Reduced enzyme isolated following reaction with [alpha-3H]alanine was found to contain 0.5 mol of tritium/mol of deazaFADH2. After denaturation of the tritium-labeled enzyme, the radioactivity was identified as deazaFADH2. Reaction of the reduced tritium-labeled enzyme with pyruvate plus ammonia prior to denaturation yields [alpha-3H]alanine and unlabeled deazaFAD. These results suggest that reduction and reoxidation of enzyme-bound deazaFAD involves the stereo-specific transfer of alpha-hydrogen from substrate to deazaFAD.

Aminobenzoates↗
PubMed1979

Nonlinear dependence of biological activity on hydrophobic character: the bilinear model.

In homologous series of compounds biological activity is linearly dependent on hydrophobic character until a cut-off point is reached where this linear relationship changes to a nonlinear relationship: biological activity increases with increase of hydrophobic character, reaches a maximum and then decreases with further increase of hydrophobic character. Drug transport in biological systems is determined by the rate constants of transfer of the drug through aqueous and organic compartments. In simple in vitro systems the rate constant k1 of transport of a drug from an aqueous phase into an organic phase and the rate constant k2 of the reverse process can be described as functions of the partition coefficient P: log k1 = log P - log (beta P + 1) + c and log k2 = - log (beta P + 1) + c. Observed and calculated k1 and k2 values are used to simulate drug transport in different multicompartment systems. Based on the McFarland probability model a new model for the quantitative description of the dependence of biological activity on hydrophobic character, called bilinear model, log 1/C = a log P - b log (beta P + 1) + C, has been derived recently: unsymmetrical curves with linear ascending and descending sides and a parabolic part within the range of optimal lipophilicity result from this model. The bilinear model is applied to experimental data of drug absorption, drug distribution and drug activity in biological systems. A comparison of the parabolic model and the bilinear model shows that in nearly all cases a better fit of the data results from the bilinear model.

Acids↗