Indole and 3-indolylacetonitrile inhibit spore maturation in Paenibacillus alvei

<p>Abstract</p> <p>Background</p> <p>Bacteria use diverse signaling molecules to ensure the survival of the species in environmental niches. A variety of both Gram-positive and Gram-negative bacteria produce large quantities of indole that functions as an intercellular signal controlling diverse aspects of bacterial physiology.</p> <p>Results</p> <p>In this study, we sought a novel role of indole in a Gram-positive bacteria <it>Paenibacillus alvei </it>that can produce extracellular indole at a concentration of up to 300 μM in the stationary phase in Luria-Bertani medium. Unlike previous studies, our data show that the production of indole in <it>P. alvei </it>is strictly controlled by catabolite repression since the addition of glucose and glycerol completely turns off the indole production. The addition of exogenous indole markedly inhibits the heat resistance of <it>P. alvei </it>without affecting cell growth. Observation of cell morphology with electron microscopy shows that indole inhibits the development of spore coats and cortex in <it>P. alvei</it>. As a result of the immature spore formation of <it>P. alvei</it>, indole also decreases <it>P. alvei </it>survival when exposed to antibiotics, low pH, and ethanol. Additionally, indole derivatives also influence the heat resistance; for example, a plant auxin, 3-indolylacetonitrile dramatically (2900-fold) decreased the heat resistance of <it>P. alvei</it>, while another auxin 3-indoleacetic acid had a less significant influence on the heat resistance of <it>P. alvei</it>.</p> <p>Conclusions</p> <p>Together, our results demonstrate that indole and plant auxin 3-indolylacetonitrile inhibit spore maturation of <it>P. alvei </it>and that 3-indolylacetonitrile presents an opportunity for the control of heat and antimicrobial resistant spores of Gram-positive bacteria.</p

Suppression of Fluconazole Resistant Candida albicans Biofilm Formation and Filamentation by Methylindole Derivatives

Candida albicans is an opportunistic fungal pathogen and most prevalent species among clinical outbreaks. It causes a range of infections, including from mild mucosal infections to serious life-threatening candidemia and disseminated candidiasis. Multiple virulence factors account for the pathogenic nature of C. albicans, and its morphological transition from budding yeast to hyphal form and subsequent biofilm formation is regarded as the most important reason for the severity of Candida infections. To address the demanding need for novel antifungals, we investigated the anti-biofilm activities of various methylindoles against C. albicans using a crystal violet assay, and the metabolic activity was assessed by using a 2,3-bis (2-methoxy-4-nitro-5-sulfo-phenyl)-2H-tetrazolium-5-carboxanilide reduction assay. Changes in biofilm morphologies and thicknesses were determined by confocal laser scanning microscopy and scanning electron microscopy, respectively. Of the 21 methylindoles tested, 1-methylindole-2-carboxylic acid (1MI2CA) at 0.1 mM (17.5 μg ml-1) and 5-methylindole-2-carboxylic acid (5MI2CA) at 0.1 mM effectively inhibited biofilm formation by C. albicans DAY185 and ATCC10231 strains. Moreover, 1MI2CA and 5MI2CA both effectively inhibited hyphal formation, and thus, improved C. albicans infected nematode survival without inducing acute toxic effects. Furthermore, our in silico molecular modeling findings were in-line with in vitro observations. This study provides information useful for the development of novel strategies targeting candidiasis and biofilm-related infections

Antibiofilm and Antivirulence Activities of 6-Gingerol and 6-Shogaol Against Candida albicans Due to Hyphal Inhibition

Candida albicans is an opportunistic pathogen and responsible for candidiasis. C. albicans readily forms biofilms on various biotic and abiotic surfaces, and these biofilms can cause local and systemic infections. C. albicans biofilms are more resistant than its free yeast to antifungal agents and less affected by host immune responses. Transition of yeast cells to hyphal cells is required for biofilm formation and is believed to be a crucial virulence factor. In this study, six components of ginger were investigated for antibiofilm and antivirulence activities against a fluconazole-resistant C. albicans strain. It was found 6-gingerol, 8-gingerol, and 6-shogaol effectively inhibited biofilm formation. In particular, 6-shogaol at 10 μg/ml significantly reduced C. albicans biofilm formation but had no effect on planktonic cell growth. Also, 6-gingerol and 6-shogaol inhibited hyphal growth in embedded colonies and free-living planktonic cells, and prevented cell aggregation. Furthermore, 6-gingerol and 6-shogaol reduced C. albicans virulence in a nematode infection model without causing toxicity at the tested concentrations. Transcriptomic analysis using RNA-seq and qRT-PCR showed 6-gingerol and 6-shogaol induced several transporters (CDR1, CDR2, and RTA3), but repressed the expressions of several hypha/biofilm related genes (ECE1 and HWP1), which supported observed phenotypic changes. These results highlight the antibiofilm and antivirulence activities of the ginger components, 6-gingerol and 6-shogaol, against a drug resistant C. albicans strain

The pNNx Heart Rate Variability Statistics: An Application to Neuroautonomic Dysfunction of Clozapine-Treated Subjects

Objective The percentage Of Successive normal cardiac interbeat intervals greater than 50 msec (pNN50) is a widely used heart rate variability measure, which is useful in identifying the neuroautonomic dysfunction of psychiatric disorders. However, pNN50 is only one member of a larger family of pNNx statistics, where x is greater than 0 msec. The potential application of the general pNNx statistics has not yet been explored in the psychiatric field. The authors examined the pNNx statistics in clozapine-treated subjects and normal controls to evaluate the usefulness of the general pNNx statistics. Methods Sixty-one schizophrenic patients treated with clozapine and fifty-nine normal controls were evaluated. probability values for the differences between the groups at each pNN value (range: pNN1-pNN100) were calculated using data obtained from a 30-minute electrocardiogram. Results The conventional pNN50 and pNNx values with x<50 msec were all significantly lower in the patient group (p<0.05). The distinction between the two groups was more prominent at pNN values less than 50 msec than that observed at pNN50. The maximum separation between groups occurred at pNN5 (68.2 +/- 19.1 vs 22.5 +/- 20.5, p<10(-22)). Conclusion The pNNx with x<50 msec provided more robust discrimination between the groups than the conventional pNN50, suggesting the importance of analyzing very small variations of interbeat interval in discriminating normal and pathological heart rate patterns. The results also Suggest that the general pNNx statistics may be applied and useful in evaluating the neuroautonomic dysfunction in patients treated with clozapine, complementing the traditionally Computed pNN50 value. Psychiatry Invest 2009;6:294-298This study was supported in part by the Brain Korea 21 project for Medicine, Dentistry, and Pharmacy (Seoul National University) and by Grant No. 04-2006-0540 from Seoul National University Hospital.Duschek S, 2009, HYPERTENS RES, V32, P938, DOI 10.1038/hr.2009.115Lollgen D, 2009, MUSCLE NERVE, V39, P536, DOI 10.1002/mus.21242Siepmann M, 2008, APPL PSYCHOPHYS BIOF, V33, P195, DOI 10.1007/s10484-008-9064-zBar KB, 2008, J CLIN PSYCHOPHARM, V28, P694, DOI 10.1097/JCP.0b013e31818a6d25Bar KJ, 2008, PSYCHIAT RES, V157, P255, DOI 10.1016/j.psychres.2007.04.021Bar KJ, 2007, CLIN NEUROPHYSIOL, V118, P2009, DOI 10.1016/j.clinph.2007.06.012Bar KJ, 2007, SCHIZOPHR RES, V95, P115, DOI 10.1016/j.schres.2007.05.034Kim JH, 2006, EUR NEUROPSYCHOPHARM, V16, P459, DOI 10.1016/j.euroneuro.2005.11.003Mujica-Parodi LR, 2005, NEUROPSYCHOBIOLOGY, V51, P10, DOI 10.1159/000082850KIM W, 2005, J KOREAN NEUROPSYCHI, V44, P176Tank J, 2004, HYPERTENSION, V43, P1035, DOI 10.1161/01.HYP.0000125729.90521.94Kim JH, 2004, PROG NEURO-PSYCHOPH, V28, P371, DOI 10.1016/j.pnpbp.2003.11.007Mueck-Weymann M, 2004, CLIN AUTON RES, V14, P15, DOI 10.1007/s10286-004-0123-0Yeragani VK, 2003, PSYCHIAT RES, V121, P185, DOI 10.1016/S0165-1781(03)00235-XAgelink MW, 2003, PHARMACOPSYCHIATRY, V36, P166Mietus JE, 2002, HEART, V88, P378Yeragani VK, 2002, BIOL PSYCHIAT, V52, P418Eschweiler GW, 2002, PHARMACOPSYCHIATRY, V35, P96Goldberger AL, 2002, P NATL ACAD SCI USA, V99, P2466, DOI 10.1073/pnas.012579499Ansakorpi H, 2002, J NEUROL NEUROSUR PS, V72, P26MALASPINA D, 2002, CNS SPECTRUMS, V7, P53Mueck-Weymann M, 2002, DEPRESS ANXIETY, V16, P93, DOI 10.1002/da.10037Cohen H, 2001, BRIT J PSYCHIAT, V179, P167Haapaniemi TH, 2001, J NEUROL NEUROSUR PS, V70, P305Cohen H, 2001, CLIN NEUROPHARMACOL, V24, P106Agelink MW, 2001, J CLIN PSYCHOPHARM, V21, P8Toichi M, 1999, INT J PSYCHOPHYSIOL, V31, P147Malaspina D, 1997, BIOL PSYCHIAT, V41, P612Korpelainen JT, 1996, STROKE, V27, P2059HALL RCW, 1995, PSYCHOSOMATICS, V36, P267RECHLIN T, 1994, BIOL PSYCHIAT, V35, P888*AM PSYCH ASS, 1994, DIAGN STAT MAN MENT, P273HUIKURI HV, 1990, AM J CARDIOL, V65, P391BIGGER JT, 1988, AM J CARDIOL, V61, P208KAY SR, 1987, SCHIZOPHRENIA BULL, V13, P261EWING DJ, 1984, BRIT HEART J, V52, P396GUY W, 1976, ECDEU ASSESSMENT PSY

No Association between PAWR Gene Polymorphisms and Tardive Dyskinesia in Schizophrenia Patients

Tardive dyskinesia (TD) is a hyperkinetic movement disorder associated with the prolonged use of antipsychotic drugs. Since prostate apoptosis response 4 (Par-4) is a key ligand of the dopamine D2 receptor, the Par-4 gene (PAWR) is a good candidate gene to study in the context of TD susceptibility. We examined the association between PAWR gene polymorphisms and TD. Three single nucleotide polymorphisms of PAWR were selected for the analysis: rs7979987, rs4842318, and rs17005769. Two hundred and eighty unrelated Korean schizophrenic patients participated in this study (105 TD and 175 non-TD patients). Genotype/allele-wise and haplotype-wise analyses were performed. There were no significant differences in genotype and allele frequencies between the two groups. Haplotype analysis also did not reveal a difference between the two groups. Within the limitations imposed by the size of the clinical sample, these findings suggest that PAWR gene variants do not significantly contribute to an increased risk of TD

No Association of Functional Polymorphisms in Methlylenetetrahydrofolate Reductase and the Risk and Minor Physical Anomalies of Schizophrenia in Korean Population

Methylenetetrahydrofolate reductase (MTHFR), a critical enzyme in folate metabolism, plays an important role in DNA methylation. It has been suggested that abnormal DNA methylation contributes to the pathogenesis of schizophrenia and congenital anomalies. The previous findings regarding the genetic relationship between MTHFR and schizophrenia are controversial. This study investigated the association of the two functional polymorphisms of MTHFR, C677T and A1298C, with the risk for schizophrenia. Furthermore, we conducted an updated meta-analysis on the two polymorphisms. In addition, we investigated the relationship between the polymorphisms and minor physical anomaly (MPA), which may represent neurodevelopmental aberrations in 201 schizophrenia patients and 350 normal control subjects. There was no significant association between either of the two polymorphisms and the risk of schizophrenia (chi-square = 0.001, df = 1, P = 0.971 for C677T; chi-square = 1.319, df = 1, P = 0.251 for A1298C). However, in meta-analysis, the C677T polymorphism showed a significant association in the combined and Asian populations (OR = 1.13, P = 0.005; OR = 1.21, P = 0.011, respectively) but not in the Korean and Caucasian populations alone. Neither polymorphism was associated with MPAs measured by the Waldrop scale (chi-square = 2.513, df = 2, P = 0.285). In conclusion, the present findings suggest that in the Korean population, the MTHFR polymorphisms are unlikely to be associated with the risk for schizophrenia and neurodevelopmental abnormalities related to schizophrenia

Pathway-based expression profiling of benign prostatic hyperplasia and prostate cancer delineates an immunophilin molecule associated with cancer progression

Aberrant restoration of AR activity is linked with prostate tumor growth, therapeutic failures and development of castrate-resistant prostate cancer. Understanding the processes leading to ARreactivation should provide the foundation for novel avenues of drug discovery. A differential gene expression study was conducted using biopsies from CaP and BPH patients to identify the components putatively responsible for reinstating AR activity in CaP. From the set of genes upregulated in CaP, FKBP52, an AR co-chaperone, was selected for further analysis. Expression of FKBP52 was positively correlated with that of c-Myc. The functional cross-talk between c-Myc and FKBP52 was established using c-Myc specific-siRNA to LNCaP cells that resulted in reduction of FKBP52. A non-canonical E-box sequence housing a putative c-Myc binding site was detected on the FKBP4 promoter using in silico search. LNCaP cells transfected with the FKBP52 promoter cloned in pGL3 basic showed increased luciferase activity which declined considerably when the promoter-construct was co-transfected with c-Myc specific-siRNA. ChIP-PCR confirmed the binding of c-Myc with the conserved E-box located in the FKBP52 promoter. c-Myc downregulation concomitantly affected expression of FGF8. Since expression of FGF8 is controlled by AR, our study unveiled a novel functional axis between c-Myc, AR and FGF8 operating through FKBP52

Identification of New Genetic Risk Variants for Type 2 Diabetes

Although more than 20 genetic susceptibility loci have been reported for type 2 diabetes (T2D), most reported variants have small to moderate effects and account for only a small proportion of the heritability of T2D, suggesting that the majority of inter-person genetic variation in this disease remains to be determined. We conducted a multistage, genome-wide association study (GWAS) within the Asian Consortium of Diabetes to search for T2D susceptibility markers. From 590,887 SNPs genotyped in 1,019 T2D cases and 1,710 controls selected from Chinese women in Shanghai, we selected the top 2,100 SNPs that were not in linkage disequilibrium (r2<0.2) with known T2D loci for in silico replication in three T2D GWAS conducted among European Americans, Koreans, and Singapore Chinese. The 5 most promising SNPs were genotyped in an independent set of 1,645 cases and 1,649 controls from Shanghai, and 4 of them were further genotyped in 1,487 cases and 3,316 controls from 2 additional Chinese studies. Consistent associations across all studies were found for rs1359790 (13q31.1), rs10906115 (10p13), and rs1436955 (15q22.2) with P-values (per allele OR, 95%CI) of 6.49×10−9 (1.15, 1.10–1.20), 1.45×10−8 (1.13, 1.08–1.18), and 7.14×10−7 (1.13, 1.08–1.19), respectively, in combined analyses of 9,794 cases and 14,615 controls. Our study provides strong evidence for a novel T2D susceptibility locus at 13q31.1 and the presence of new independent risk variants near regions (10p13 and 15q22.2) reported by previous GWAS