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PubMed2001

Indole can act as an extracellular signal in Escherichia coli.

Previous work has shown that lacZ fusions to the cysK, astD, tnaB, and gabT genes in Escherichia coli are activated by self-produced extracellular signals. Using a combination of ethyl acetate extraction, reversed-phase C(18) chromatography, and thin-layer chromatography, we have purified an extracellular activating signal from E. coli supernatants. Mass spectrometry revealed a molecule with an m/z peak of 117, consistent with indole. Nuclear magnetic resonance analysis of the purified E. coli factor and synthetic indole revealed identical profiles. Using synthetic indole, a dose-dependent activation was observed with lacZ fusions to the gabT, astD, and tnaB genes. However, cysK::lacZ and several control fusions were not significantly activated by indole. Conditioned medium prepared from a tnaA (tryptophanase) mutant, deficient in indole production, supported 26 to 41% lower activation of the gabT and astD fusions. The residual level of activation may be due to a second activating signal. Activation of the tnaB::lacZ fusion was reduced by greater than 70% in conditioned medium from a tnaA mutant.

Amino Acid Transport Systems↗
PubMed1982

Spot indole test: evaluation of four reagents.

Kovacs indole reagent, p-dimethylaminobenzaldehyde, Ehrlich indole reagent and p-dimethylaminocinnamaldehyde were used as spot indole reagents to test 359 strains of gram-negative rods growing on 5% sheep blood agar, Trypticase soy agar (BBL Microbiology Systems), and MacConkey agar. The p-dimethylaminocinnamaldehyde reagent was the most sensitive of those tested and provided results that were easiest to interpret. The p-dimethylaminocinnamaldehyde reagent was able to detect providencia alcalifaciens indole production because of the red-violet color unique to that organism. All reagents tested were accurate in detecting indole produced by members of the Enterobacteriaceae family, with the exception of P. alcalifaciens.

Bacteriological Techniques↗
PubMed1982

Identification of Proteus penneri sp. nov., formerly known as Proteus vulgaris indole negative or as Proteus vulgaris biogroup 1.

The name Proteus penneri sp. nov. is proposed for a group of organisms previously called Proteus vulgaris indole negative or P. vulgaris biogroup 1. All of these strains were salicin negative, esculin negative, and chloramphenicol resistant (zone size, less than 14 mm). DNA relatedness studies indicated that when DNA from P. penneri strain 1808-73 was labeled and tested against unlabeled DNA from 13 other P penneri strains, a highly related group was formed (88 to 99% relatedness at 60 degrees C and 67 to 99% relatedness at 75 degrees C). Strain 1808-73 (ATCC 33519) is proposed as the type strain of P. penneri. In this study, two distinct groups of indole-positive P. vulgaris strains were also apparent. The first group (defined as P. vulgaris biogroup 2) was indole positive, salicin positive, and esculin positive, and the second group (defined as P. vulgaris biogroup 3) was indole positive, salicin negative, and esculin negative. The current type strain of P. vulgaris (ATCC 13315) belongs to biogroup 3. The DNA from P. penneri strains was not highly related to labeled DNA from the type strain of P. vulgaris (14 to 30% relatedness at 75 degrees C) or from P. vulgaris strain PR 1 (ATCC 29905), which belongs to biogroup 2 (27 to 33% relatedness at 75 degrees C). Strains of biogroup 2 were sensitive to chloramphenicol (zone size, greater than 19mm), and 10 of these strains formed a highly related group by DNA hybridization when DNA from PR 1 was labeled (64 to 100% relatedness at 60 degrees C and 70 to 100% relatedness at 75 degrees C), but they were not highly relatedness to the type strain of P. vulgaris (51 to 68% relatedness at 60 degrees C and 14 to 44% relatedness at 75 degrees C). Further DNA relatedness studies are needed on strains of biogroup 3 before a definitive taxonomic proposal can be made for these two indole-positive biogroups.

Anti-Bacterial Agents↗
PubMed1975

Motility-indole-lysine medium for presumptive identification of enteric pathogens of Enterobacteriaceae.

Detection of lysine decarboxylase activity is a useful supplement to reactions on triple sugar-iron (TSI) and urea agars in the initial examination of suspected pathogenic isolates from fecal cultures. Owing to the added value of motility and indole production in the differentiation of enteric pathogens, we prepared and evaluated a motility-indole-lysine (MIL) medium. The following 890 organisms were tested: 264 Shigella, 2 Edwardsiella, 182 Salmonella enteritidis, 235 S. typhi, 3 Arizona, 32 Yersinia enterocolitica, and 172 other members of the family Enterobacteriaceae. With few exceptions the MIL medium gave the same results as the standard motility, indole, and lysine decarboxylase (Moeller) test media. All discrepancies were with the indole reaction, which was weak in 2 of 67 strains of Escherichia coli and falsely negative in 6 of 32 strains of Y. enterocolitica. When both TSI agar and lysine-iron agar (LIA) slants are used in the evaluation isolates from fecal cultures, detection of H2S is duplicated. Both LIA and MIL medium detect lysine decarboxylase and deaminase activity equally well. Because of its ability to detect motility and indole production, the MIL medium is more useful than LIA when used with TSI agar. The combination of TSI agar, MIL medium, and urea agar enables reliable initial recognition of enteric pathogens of the Enterobacteriaceae.

Carboxy-Lyases↗
PubMed1980

Indole toxicity in cattle.

Indole and 3-methylindole (3MI) are ruminal metabolites of L-tryptophan (TRP) and have similar physical and chemical properties. 3-Methylindole causes acute bovine pulmonary emphysema (ABPE). The effects of indole when administered orally to cows were determined. Four mature Holstein cows were given increasing doses of 0.05, 0.1 and 0.2 g indole per kg body-weight orally at two-week intervals. The animals were killed one week after the last dose. Plasma indole concentrations peaked three house after administration at 4.5, 8.8 and 19.8 microgram per ml after the 0.05, 0.1 and 0.2 doses, respectively. Detectable concentrations of indole (more than 0.02 microgram per ml) persisted in the plasma from three to 25 hours after dosing. Packed cell volume was decreased (P less than 0.01) at 48 and 72 hours after the 0.2 g per kg dose and at 72 hours after the 0.1 g per kg dose. Plasma haemoglobin was increased (P less than 0.05) at 48 hours after the 0.2 and 0.1 g per kg doses. By 72 hours after the 0.2 g per kg dose, all cows had mild diarrhoea and haemolysis and two of the cows had haemoglobinuria. At necropsy, microscopic lesions of haemoglobinuric nephrosis were seen in all four cows. No lesions of ABPE were found in any of the animals.

Animals↗
PubMed1980

Antibiotic resistance of indole-positive Klebsiella pneumoniae.

Resistance patterns to antibiotics differed markedly between indole-positive and indole-negative Klebsiella pneumoniae strains. Multiple-drug-resistant strains were almost exclusively indole-negative. Ampicillin and kanamycin resistances in the indolepositive strains tested were not transmissible, whereas many of those resistances in the indole-negative strains were transmissible, together with other drug resistances to an Escherichia coli recipient. The substrate profile of the beta-lactamase from the indole-positive strains was fairly different from that of the beta-lactamase mediated by the ampicillin resistance plasmid.

Ampicillin↗
PubMed1999

Synthesis and biological activity of N-(aminoiminomethyl)-1H-indole carboxamide derivatives as Na+/H+ exchanger inhibitors.

A series of N-(aminoiminomethyl)-1H-indole carboxamide derivatives were synthesized and their inhibitory potencies against the Na+/H+ exchanger were measured. Variation of the carbonylguanidine group at the 2- to 7-position of the indole ring system showed that a substitution at the 2-position improved the Na+/H+ exchanger inhibitory activity the most in vitro. This led to the synthesis and evaluation of an extensive series of N-(aminoiminomethyl)-1H-indole-2-carboxamide derivatives. Derivatives having an alkyl or substituted alkyl group at the 1-position of the indole ring system showed higher levels of in vitro activities. N-(aminoiminomethyl)- 1-(2-phenylethyl)-1H-indole-2-carboxamide (49) had the strongest activity.

Animals↗
PubMed1995

[Chemical studies of indole alkaloids].

Up to now, more than two thousands indole alkaloids having structural variety have been found from the three families of Gentianales: Loganiaceae, Apocynaceae, and Rubiaceae plants. These compounds generally possess characteristic biological activities and many of them are utilized for the medicinal purpose and for the lead-compounds to develop new synthetic drugs. The author of this review has been investigated the alkaloidal constituents of the above mentioned plants native to Japan and overseas countries. Especially, a cooperative work with Thai researchers concerning the plants in Thailand was developed. On the basis of biogenetic consideration of the structures of monoterpenoid indole alkaloids, chemical bond cleavage between the C3-N4 linkage in the C/D ring of indole alkaloids was discovered. It was speculated that, either in biogenesis, the flexibility of the ring-opening compounds having ten membered ring enabled the construction of indole alkaloids having highly strained polycyclic structures. Along with this conception, the syntheses of structurally complex indole alkaloids utilizing a biomimetic procedure have been investigated. In this review, recent results on the chemical synthesis of many skeletally varied Gelsemium alkaloids (Loganiaceae plant) are mainly described.

Alkaloids↗
PubMed2005

Recent developments in the medicinal chemistry of cannabimimetic indoles, pyrroles and indenes.

During the development of new nonsteroidal anti-inflammatory agents, it was discovered that 1-aminoalkyl-3-aroylindoles have affinity for the cannabinoid brain (CB(1)) receptor. This has led to the development of over 100 cannabimimetic aminoalkylindoles, and the development of SAR for these compounds. Later work demonstrated that the aminoalkyl moiety was not necessary, and could be replaced by a four- to six-membered alkyl chain without loss of affinity. Investigation of these indoles led to the discovery of a CB(2) selective ligand, 3-(1-naphthoyl)-N-propylindole. Subsequent work has provided several additional CB(2) selective indoles. On the basis of a proposed pharmacophore for the cannabimimetic indoles, a series of pyrroles and indenes were developed, some of which are potent cannabinoids. SAR for several series of pyrroles have been developed. Two groups have described cannabimimetic indenes, which have been employed as rigid models for the receptor interactions of cannabimimetic indoles with the CB(1) receptor. There is some evidence that the indoles bind to a somewhat different site on the receptor than traditional cannabinoids, and interact with the receptor primarily by aromatic stacking.

Animals↗
PubMed2001

Dietary indoles and isothiocyanates that are generated from cruciferous vegetables can both stimulate apoptosis and confer protection against DNA damage in human colon cell lines.

The natural indoles 3,3'-diindolylmethane (DIM), ascorbigen (ASG), indole-3-carbinol (I3C), and indolo[3,2-b]carbazole (ICZ), as well as the natural isothiocyanates sulforaphane (SUL), benzyl isothiocyanate (BITC) and phenethyl isothiocyanate (PEITC), all possess cancer chemopreventive properties. It is now shown that DIM, ICZ, SUL, and BITC can each stimulate apoptosis in human colon adenocarcinoma LS-174 and Caco-2 cells. Treatment of LS-174 cells with nontoxic doses of DIM, ASG, I3C, or ICZ affected an increase of up to 21-fold in cytochrome P450 1A1 (CYP1A1). None of these indoles caused an elevation in either aldo-keto reductase 1C1 (AKR1C1) or the gamma-glutamylcysteine synthetase heavy subunit (GCS(h)), but DIM, I3C, and ICZ produced a very modest increase in NAD(P)H:quinone oxidoreductase 1 (NQO1). By contrast, nontoxic doses of SUL, BITC, or PEITC failed to induce expression of CYP1A1 in LS-174 cells, but caused an increase of between 11- and 17-fold in the protein levels of AKR1C1, NQO1, and GCS(h). Treatment of the colon cell line with ICZ or SUL caused increases in the levels of mRNA for CYP1A1, AKR1C1, and NQO1 that were consistent with the enzyme data. Exposure of Caco-2 cells to media containing indoles or isothiocyanates gave similar results to those obtained using LS-174 cells. Evidence is presented that the ability of indoles and isothiocyanates to stimulate either xenobiotic response element- or antioxidant response element-driven gene expression accounts for the two groups of phytochemicals inducing different gene batteries. Pretreatment of LS-174 cells for 24 h with ICZ and SUL before exposure for 24 h to benzo(a)pyrene (BaP) reduced to <20% the number of single-strand DNA breaks produced by the carcinogen. Neither ICZ alone nor SUL alone were able to confer the same degree of protection against DNA damage produced by BaP as they achieved in combination. Similar results were obtained with H(2)O(2) as the genotoxic agent. Together, these phytochemicals may prevent colon tumorigenesis by both stimulating apoptosis and enhancing intracellular defenses against genotoxic agents.

20-Hydroxysteroid Dehydrogenases↗
PubMed1989

Structure-activity relationships of 1H-indole-7-carboxamides as a novel series of selective alpha 1-adrenoceptor agonists.

The present isolated tissue study was designed to quantitate the alpha-adrenoceptor agonist activity of AY- 30,191 (5-(1-hydroxy-2-amino-ethyl)-1H-indole-7-carboxamide) and a series of related compounds. AY-30,191 induced contractions in the rabbit aorta, which were blocked by prazosin. In the rat vas deferens, while clonidine inhibited the electrically induced twitch response, AY-30,191 caused a prazosin-sensitive augmentation. In the dog saphenous vein, rauwolscine was less effective than the combination of rauwolscine and prazosin in inhibiting the contractions induced by AY-30,191. Pretreatment of the dog saphenous vein with phenoxybenzamine reduced the response to AY-30,191. The addition of rauwolscine to phenoxybenzamine-treated tissues had no effect on the contractions to AY-30,191 remaining after phenoxybenzamine treatment. These results suggest that AY-30,191 is a selective alpha 1-adrenoceptor agonist. Optimal alpha 1-adrenoceptor agonist activity in the 1H-indole-7-carboxamide series was seen in compounds in which a) the indole ring and the ethylamine side chain were intact; b) the indole nitrogen was unsubstituted; and c) the carboxamide was present at the 7-position in the indole ring. Removal of the carboxamide decreased alpha 1-adrenoceptor activity and, more importantly, resulted in a loss of alpha 1-adrenoceptor selectivity. Replacement of the carboxamide in the 7 position with methanesulfonamide resulted in a decrease in activity but a retention of alpha 1-adrenoceptor selectivity, whereas the dimethylamino analog was nonselective and the phosphoramidic acid diethylester analog was inactive.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Agonists↗
PubMed1980

[Regulation of alpha and beta/gamma-thrombin activity by heparin and indole].

Indole was shown to stimulate TAME hydrolysis by alpha-thrombin with KA=7,7 mM, alpha=0,55, beta=1,5 and that by beta/gamma-thrombin with KA=9,5 mM, alpha=0,47 and beta=2,08. Indole promotes both the formation and transformation of the enzyme-substrate complex. No effect of substrate activation was observed in the presence of indole, which suggests the identity of the binding sites of indole and the added TAME molecule. Heparin was shown to form an equimolar stoicheometric complex with both alpha- and beta/gamma-thrombin, which results in 40% inhibition of the TAME-esterase, clotting and prothrombinolytic activities of alpha-thrombin and 25% and 40% inhibition of the TAME-esterase and prothrombinolytic activity of beta/gamma-thrombin, respectively. The fact that alpha- and beta/gamma-thrombin partially retain their catalytic properties even at a 5-fold molar excess of the inhibitor indicates that heparin binds to the thrombin molecule at a site other than the active center. Heparin does not prevent the effect of substrate activation at high TAME concentrations. This finding suggests that the localization of binding sites of heparin and the added TAME molecule (and, therefore, indole) in the thrombin molecule is different.

Animals↗
PubMed1996

Enzymology of indole alkaloid biosynthesis in Catharanthus roseus.

Indole alkaloids in Catharanthus roseus have been in focus because of their medicinal value. These alkaloids consist of an indole moiety provided by tryptamine and a terpenoid portion provided by the secologanin. The most important catharanthus alkaloids are vinblastine (VLB), vincristine (VCR) and ajmalicine. VLB and VCR are clinically useful anticancer agents whereas ajmalicine is used for the treatment of circulatory diseases. VCR and VLB are the most expensive because of their low abundance in the plant, and are formed by the coupling of monomeric indole alkaloids vindoline and catharanthine, catalysed by peroxidases. The pathway that lead to monomeric indole alkaloids involves more than 20 enzymes of which 16 enzymes have been isolated and characterized biochemically, and only three at the molecular level. The present state of knowledge on enzymes and genes involved in indole alkaloid biosynthesis and various aspects of their regulation has been discussed.

Alkaloids↗
PubMed1994

Molecular cloning and sequence analysis of an Azospirillum brasilense indole-3-pyruvate decarboxylase gene.

Azospirillum brasilense isolated from the rhizosphere of different plants has the ability to excrete indole-3-acetic acid (IAA) into the culture media. Cosmid p0.2, isolated from an A. brasilense Sp245 genome library in pLAFR1, complements the Tn5-induced mutant SpM7918 of A. brasilense Sp6 which excretes reduced amounts of IAA. Restriction mapping and gene expression studies identified a BglII-EcoRI 4.3 kb fragment of p0.2 sufficient for the restoration of high levels of IAA production in mutant SpM7918. Tn5 mutagenesis localized the gene responsible on a 1.8 kb SmaI fragment. Nucleotide sequence analysis revealed that this fragment contains one complete open reading frame. The predicted protein sequence shows extensive homology with the indole-3-pyruvate decarboxylase of Enterobacter cloacae and the pyruvate decarboxylases of Saccharomyces cerevisiae and Zymomonas mobilis. The A. brasilense mutant Sp245a, constructed by homogenotization of a Tn5 insertion derivative of the 1.8 kb SmaI fragment, also displayed reduced IAA production. Introduction of the cloned wild-type gene into Rhizobium meliloti 1021 resulted in increased IAA production. Cell-free extracts prepared from R. meliloti and A. brasilense transconjugants harboring this gene could convert indole-3-pyruvic acid to indole-3-acetaldehyde and tryptophol. These results clearly demonstrate that IAA production in A. brasilense is mediated by indole-3-pyruvate decarboxylase.

Amino Acid Sequence↗
PubMed1997

Active and indolent chronic lymphocytic leukaemia--immune and hormonal peculiarities.

A group of 138 B cell chronic lymphocytic leukaemia (B-CLL) patients, 83 with active disease and 53 having the indolent form of the disease, were evaluated. The aim of the study was to clarify whether indolent and active B-CLL differ in their immune and hormonal characteristics. Peripheral blood lymphocyte proliferation in response to phytohaemagglutinin, concanavalin A, recombinant interleukin-2, dextran sulphate, Pisum sativatum agglutinin and wheat germ agglutinin was investigated. Serum immunoglobulin and beta 2 microglobulin levels were determined. Adrenocorticotropic hormone (ACTH), cortisol, follicle-stimulating hormone luteinizing hormone, 17 beta-oestradiol, testosterone, triiodothyronine, thyroxine, thyroglobulin and thyrotropic hormone levels were determined by radioimmunoassay. Active and indolent CLL presented differences in immunological characteristics, as demonstrated by the more severe suppression of T lymphocyte function, reduced IgA level and considerably higher serum beta 2-microglobulin values in active disease. Immune disturbances were accompanied by hormonal imbalance, depending on disease status: lower ACTH, cortisol and triiodothyronine levels were established to occur in active CLL compared to indolent disease. Male patients demonstrated striking changes in sex hormones, which were more evident in active disease. The findings point to the complexity of immuno-hormonal disturbances in CLL with differences in the active and indolent state of the disease.

Adult↗
PubMed1999

Indole glucosinolate and auxin biosynthesis in Arabidopsis thaliana (L.) Heynh. glucosinolate mutants and the development of clubroot disease.

Mutants and wild type plants of Arabidopsis thaliana were analysed for differences in glucosinolate accumulation patterns, indole-3-acetic acid (IAA) biosynthesis and phenotype. A previously identified series of mutants, termed TU, with altered glucosinolate patterns was used in this study. Only the line TU8 was affected in shoot phenotype (shorter stems, altered branching pattern). Synthesis of IAA and metabolism were not much affected in the TU8 mutant during seedling development, although the content of free IAA peaked earlier in TU8 during plant development than in the wild type. Indole glucosinolates and IAA may, however, be involved in the development of clubroot disease caused by the obligate biotrophic fungus Plasmodiophora brassicae since the TU3 line had a lower infection rate than the wild type, and lines TU3 and TU8 showed decreased symptom development. The decline in clubroot formation was accompanied by a reduced number of fungal structures within the root cortex and slower development of the fungus. Indole glucosinolates were lower in infected roots of TU3 and TU8 than in control roots of these lines, whereas in wild-type plants the differences were not as prominent. Free IAA and indole-3-acetonitrile (IAN) were increased in infected roots of the wild type and mutants with normal clubroot symptoms, whereas they were reduced in infected roots of mutants TU3 and TU8. These results indicate a role for indole glucosinolates and IAN/IAA in relation to symptom development in clubroot disease.

Arabidopsis↗
PubMed2000

Physiological evidence for differently regulated tryptophan-dependent pathways for indole-3-acetic acid synthesis in Azospirillum brasilense.

Disruption of ipdC, a gene involved in indole-3-acetic acid (IAA) production by the indole pyruvate pathway in Azospirillum brasilense Sp7, resulted in a mutant strain that was not impaired in IAA production with lactate or pyruvate as the carbon source. A tryptophan auxotroph that is unable to convert indole to tryptophan produced IAA if tryptophan was present but did not synthesise IAA from indole. Similar results were obtained for a mutant strain with additional mutations in the genes ipdC and trpD. This suggests the existence of an alternative Trp-dependent route for IAA synthesis. On gluconate as a carbon source, IAA production by the ipdC mutant was inhibited, suggesting that the alternative route is regulated by catabolite repression. Using permeabilised cells we observed the enzymatic conversion of tryptamine and indole-3-acetonitrile to IAA, both in the wild-type and in the ipdC mutant. IAA production from tryptamine was strongly decreased when gluconate was the carbon source.

Artificial Gene Fusion↗
PubMed1995

Anti-calmodulin potency of indol alkaloids in in vitro systems.

We have demonstrated that bis-indol Vinca alkaloids of anti-mitotic activities (vinblastine, vincristine, and navelbine) bind to calmodulin in a Ca(2+)-dependent manner. We designed direct binding tests (fluorescence energy transfer and circular dichroism measurements) to quantify the interactions of bis-indol derivatives with calmodulin. The dissociation constants of calmodulin-navelbine and calmodulin-vinblastine complexes with 1:1 stoichiometry are 0.5 microM and 3 microM, respectively. These values indicate that the binding affinities of these Vinca alkaloids to calmodulin and tubulin are comparable. Immunological, enzyme kinetic and fluorescence anisotropy measurements showed that bis-indol alkaloids inhibit the interactions of calmodulin with target proteins. The results of indirect enzyme-linked immunosorbent assay showed that bis-indol alkaloids effectively antagonize with anti-calmodulin antibody for calmodulin binding (IC50 = 90 microM, 400 microM, and 430 microM for navelbine, vincristine and vinblastine, respectively). According to the fluorescence anisotropy and enzyme kinetic measurements, vinblastine, vincristine and vinblastine, similarly to trifluoperazine, the classic calmodulin antagonist, compete with target enzyme [phosphofructokinase (ATP: D-fructose 6-phosphate 1-phosphotransferase, EC 2.7.1.11)] for an inhibitory effect either on immunocomplex formation or on calmodulin-enzyme interaction. Navelbine appeared in our tests as the most potent drug in inhibiting the association of calmodulin to target proteins in comparison to other bis-indol derivatives. Since navelbine and vinblastine possess identical vindoline moiety, although they differ in the catharantine part, the difference in anti-calmodulin potencies is suggested to reside predominantly on this portion of the molecules. These findings might establish the pharmacological importance of these activities in the specificity and toxicity of the drugs.

Animals↗