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Effects of Bacillus subtilis iturin A on HepG2 cells in vitro and vivo.

ABSTRACT: Iturin A with cyclic peptide and fatty acid chain isolated from Bacillus subtilis fermentation shows a variety of biological activities. Among them, the anticancer activity attracted much attention. However, the molecular mechanism of its inhibitory effect on hepatocellular carcinoma was still unclear. Thus its effect on hepatocellular carcinoma was tested in this research. It was found that iturin A could enter HepG2 cells immediately and cause reactive oxygen species burst, disrupt cell cycle and induce apoptosis, paraptosis and autophagy in vitro. The iturin A without fatty acid chain showed no antitumor activity. Amphiphilic is critical to the activity of iturin A. The anticancer activity of iturin A to hepatocellular carcinoma was also verified in mice models carrying xenograft tumors constructed by HepG2 cells. At a dosage of 3 mg/kg/day, iturin A significantly inhibited the further increase of the tumor weight by 58.55%, and reduced the expression of Ki67 in tumor. In the tumor treated with iturin A, lymphocyte infiltration was found, and the expressions of TGF-β1and PD-L1 were decreased, which indicated that the tumor immune microenvironment was improved. Besides, iturin A showed no significant harm on the health of mice except slight disturbance of liver function. These results suggested that iturin A had significant antitumor effect in vitro and vivo, and provide a basis for the application of iturin A as anticancer agent.

SUBMITTER: Zhao H

PROVIDER: S-EPMC8110684 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Horizontal transfer of iturin A operon, itu, to Bacillus subtilis 168 and conversion into an iturin A producer.

Project description:Iturin A and its derivatives are lipopeptide antibiotics produced by Bacillus subtilis and several closely related bacteria. Three iturin group operons (i.e., iturin A, mycosubtilin, and bacillomycin D) of those antibiotic-producing strains have been cloned and sequenced thus far, strongly implying the horizontal transfer of these operons. To examine the nature of such horizontal transfer in terms of antibiotic production, a 42-kb region of the B. subtilis RB14 genome, which contains a complete 38-kb iturin A operon, was transferred via competent cell transformation to the genome of a non-iturin A producer, B. subtilis 168, using a method based on double-crossover homologous recombination with two short landing pad sequences (LPSs) in the genome. The recombinant was positively selected by confirming the elimination of the cI repressor gene, which was localized between the two LPSs and substituted by the transferred segment. The iturin A operon-transferred strain 168 was then converted into an iturin A producer by the introduction of an sfp gene, which encodes 4'-phosphopantetheinyl transferase and is mutated in strain 168. By inserting the pleiotropic regulator degQ, the productivity of iturin A increased sevenfold and was restored to about half that of the donor strain RB14, without the transfer of additional genes, such as regulatory or self-resistance genes.

| S-EPMC1280175 | biostudies-literature

Continuous enhancement of iturin A production by Bacillus subtilis with a stepwise two-stage glucose feeding strategy.

Project description:BackgroundThe lipopeptide antibiotic iturin A is an attractive biopesticide with the potential to replace chemical-based pesticides for controlling plant pathogens. However, its industrial fermentation has not been realized due to the high production costs and low product concentrations. This study aims to enhance iturin A production by performing a novel fermentation process with effective glucose feeding control using rapeseed meal as a low-cost nitrogen source.ResultsWe demonstrated that continuous and significant enhancement of iturin A production could be achieved by a novel two-stage glucose-feeding strategy with a stepwise decrease in feeding rate. Using this strategy, the ratio of spores to total cells could be maintained at a desirable/stable level of 0.80-0.86, and the reducing sugar concentration could be controlled at a low level of 2-3 g/L so that optimal substrate balance could be maintained throughout the feeding phase. As a result, the maximum iturin A concentration reached 1.12 g/L, which was two-fold higher than that of batch culture.ConclusionsThis is the first report which uses control of the glucose supply to improve iturin A production by fed-batch fermentation and identifies some important factors necessary to realize industrial iturin A production. This approach may also enhance the production of other useful secondary metabolites by Bacillus subtilis.

| S-EPMC4460961 | biostudies-literature

Direct bio-utilization of untreated rapeseed meal for effective iturin A production by Bacillus subtilis in submerged fermentation.

Project description:The feasibility of using untreated rapeseed meal as a nitrogen source for iturin A production by Bacillus subtilis 3-10 in submerged fermentation was first evaluated by comparison with two different commercial nitrogen sources of peptone and ammonium nitrate. A significant promoting effect of rapeseed meal on iturin A production was observed and the maximum iturin A concentration of 0.60 g/L was reached at 70 h, which was 20% and 8.0 fold higher than that produced from peptone and ammonium nitrate media, respectively. It was shown that rapeseed meal had a positive induction effect on protease secretion, contributing to the release of soluble protein from low water solubility solid rapeseed meal for an effective supply of available nitrogen during fermentation. Moreover, compared to raw rapeseed meal, the remaining residue following fermentation could be used as a more suitable supplementary protein source for animal feed because of the great decrease of major anti-nutritional components including sinapine, glucosinolate and its degradation products of isothiocyanate and oxazolidine thione. The results obtained from this study demonstrate the potential of direct utilization of low cost rapeseed meal as a nitrogen source for commercial production of iturin A and other secondary metabolites by Bacillus subtilis.

| S-EPMC4215929 | biostudies-literature

Optimization of iturin A production from <i>Bacillus subtilis</i> ZK-H2 in submerge fermentation by response surface methodology.

Project description:In this research, single-factor and response surface experiments were conducted in the fed-batch fermentation process to improve the yield of iturin A. The effect of adding various concentrations of precursor amino acids l-asparagine (Asn), l-aspartic acid (Asp), l-glutamic acid (Glu), l-glutamine (Gln), l-Serine (Ser) and l-proline (Pro) at different adding times (3 and 12 h) on iturin A production and cell growth was studied. The respective addition of amino acids (Asp 0.28 g/L; Asn 0.36 g/L; Glu 0.20, 0.28 and 0.360 g/L; Gln 0.20, 0.28 and 0.36 g/L; Pro 0.12, 0.20, 0.28 and 0.36 g/L) at 3 h was shown to improve cell growth but did not affect the yield of iturin A. Meanwhile, the individual addition of the same amino acids at 12 h improved cell growth and increased the yield of iturin A. Excellent correlation was obtained between the predicted and measured values, suggesting that the regression model was accurate and reliable; highly significant (P < 0.0001), and the determination coefficient (R2 = 0.975). When 0.0752 g/L Asn; 0.1992 g/L Gln and 0.1464 g/L Pro were added at 12 h, the yield of iturin A reached 0.85 g/L, which is 32.81%-fold higher than that of the initial process. Therefore, this study obtained optimal parameters for iturin A production by the experimental method, and process validation gave high iturin A yields (0.85 g/L) during a 60 h fermentation. These findings could guide an up-scaling of the fermentation process.Electronic supplementary materialThe online version of this article (10.1007/s13205-020-02540-7) contains supplementary material, which is available to authorized users.

| S-EPMC7788149 | biostudies-literature

Bacillus subtilis WalR (YycF) ChIP-chip Bacillus subtilis; Bacillus subtilis subsp. subtilis str. 168

Project description:Identification of the specific WalR (YycF) binding regions on the B. subtilis chromosome during exponential and phosphate starvation growth phases. The data serves to extend the WalRK regulon in Bacillus subtilis and its role in cell wall metabolism, as well as implying a role in several other cellular processes.

2015-01-26 | GSE65272 | GEO

Bacteriostatic effects of high-intensity ultrasonic treatment on Bacillus subtilis vegetative cells.

Project description:The bacteriostatic effects of high-intensity ultrasonic treatment (HIU) on Bacillus subtilis vegetative cells were evaluated, and the related mechanisms were explored using quantitative proteomics. The bacteriostatic effect of HIU on B. subtilis was proportional to the ultrasound treatment time and power, and the number of cultivable B. subtilis cells was decreased by approximately one log (at 270 W for 15 min) or half log (at 90 W for 25 min or 360 W for 5 min). Scanning electron microscopy images and gel electrophoresis results showed that HIU caused the destruction of the cell structure and intracellular protein leakage. In addition, HIU treatment at 270 W for 15 min resulted in the greatest decrease (84.22%) in intracellular adenosine triphosphate (ATP) content. The quantitative proteomic analysis showed that B. subtilis resisted the stress of HIU treatment by regulating the key proteins in physiological activities related to membrane transport (ATP-binding cassette [ABC] transporter), signal transduction (the two-component system), and energy metabolism (the tricarboxylic acid [TCA] cycle). HIU-induced physical damage, stress, and metabolic disorders were the main causes of the bacteriostatic effects on B. subtilis. These findings provide a foundation for the subsequent optimization and potential applications of HIU inactivation of B. subtilis.

| S-EPMC8665408 | biostudies-literature

Organization and characterization of genetic regions in Bacillus subtilis subsp. krictiensis ATCC55079 associated with the biosynthesis of iturin and surfactin compounds.

Project description:Bacillus subtilis subsp. krictiensis ATCC55079 produces the cyclic lipopeptide antibiotics iturin A-F as well as several surfactins. Here, we analyzed and characterized the biosynthetic genes associated with iturin and surfactin production in this strain. We aligned the sequences of each iturin and surfactin synthetase ORF obtained from a genomic library screen and next generation sequencing. The resulting 37,249-bp and 37,645-bp sequences associated with iturin and surfactin production, respectively, contained several ORFs that are predicted to encode proteins involved in iturin and surfactin biosynthesis. These ORFs showed higher sequence homologies with the respective iturin and surfactin synthetase genes of B. methylotrophicus CAU B946 than with those of B. subtilis RB14 and B. subtilis ATCC6633. Moreover, comparative analysis of the secondary metabolites produced by the wild-type and surfactin-less mutant (with a spectinomycin resistance cassette inserted into the srfAB gene within the putative surfactin gene region) strains demonstrated that the mutant strain showed significantly higher antifungal activity against Fusarium oxysporum than the wild-type strain. In addition, the wild-type strain-specific surfactin high performance liquid chromatography (HPLC) peaks were not observed in the surfactin-less mutant strain. In contrast, the iturin A peak detected by HPLC and liquid chromatography-mass spectrometry (LC/MS) in the surfactin-less mutant strain was 30% greater than that in the wild-type strain. These results suggested that the gene cluster we identified is involved in surfactin biosynthesis, and the biosynthetic pathways for iturin and surfactin in Bacillus strains producing both iturin and surfactin may utilize a common pathway.

| S-EPMC5739386 | biostudies-literature

RNA polymerase trafficking in Bacillus subtilis cells.

Project description:To obtain insight into the in vivo dynamics of RNA polymerase (RNAP) on the Bacillus subtilis genome, we analyzed the distribution of the σ(A) and β' subunits of RNAP and the NusA elongation factor on the genome in exponentially growing cells using chromatin affinity precipitation coupled with gene chip mapping (ChAP-chip). In contrast to Escherichia coli RNAP, which often accumulates at the promoter-proximal region, B. subtilis RΝΑP is evenly distributed from the promoter to the coding sequences. This finding suggests that, in general, B. subtilis RNAP recruited to the promoter promptly translocates away from the promoter to form the elongation complex and proceeds without intragenic transcription attenuation. We detected RNAP accumulation in the promoter-proximal regions of some genes, most of which can be identified as transcription attenuation systems in the leader region. Our findings suggest that the differences in RNAP behavior between E. coli and B. subtilis during initiation and elongation steps might result in distinct strategies for postinitiation control of transcription. The E. coli mechanism involves trapping at the promoter and promoter-proximal pausing of RNAP in addition to transcription attenuation, whereas transcription attenuation in leader sequences is mainly employed in B. subtilis.

| S-EPMC2953687 | biostudies-literature

In Vivo Behavior of the Tandem Glycine Riboswitch in Bacillus subtilis.

Project description:In many bacterial species, the glycine riboswitch is composed of two homologous ligand-binding domains (aptamers) that each bind glycine and act together to regulate the expression of glycine metabolic and transport genes. While the structure and molecular dynamics of the tandem glycine riboswitch have been the subject of numerous in vitro studies, the in vivo behavior of the riboswitch remains largely uncharacterized. To examine the proposed models of tandem glycine riboswitch function in a biologically relevant context, we characterized the regulatory activity of mutations to the riboswitch structure in Bacillus subtilis using ?-galactosidase assays. To assess the impact disruptions to riboswitch function have on cell fitness, we introduced these mutations into the native locus of the tandem glycine riboswitch within the B. subtilis genome. Our results indicate that glycine does not need to bind both aptamers for regulation in vivo and mutations perturbing riboswitch tertiary structure have the most severe effect on riboswitch function and gene expression. We also find that in B. subtilis, the glycine riboswitch-regulated gcvT operon is important for glycine detoxification.IMPORTANCE The glycine riboswitch is a unique cis-acting mRNA element that contains two tandem homologous glycine-binding domains that act on a single expression platform to regulate gene expression in response to glycine. While many in vitro experiments have characterized the tandem architecture of the glycine riboswitch, little work has investigated the behavior of this riboswitch in vivo In this study, we analyzed the proposed models of tandem glycine riboswitch regulation in the context of its native locus within the Bacillus subtilis genome and examined how disruptions to glycine riboswitch function impact organismal fitness. Our work offers new insights into riboswitch function in vivo and reinforces the potential of riboswitches as novel antimicrobial targets.

| S-EPMC5666159 | biostudies-literature

Bacillus subtilis RNase Y activity in vivo analysed by tiling microarrays.

Project description:RNase Y is a key endoribonuclease affecting global mRNA stability in Bacillus subtilis. Its characterization provided the first evidence that endonucleolytic cleavage plays a major role in the mRNA metabolism of this organism. RNase Y shares important functional features with the RNA decay initiating RNase E from Escherichia coli, notably a similar cleavage specificity and a preference for 5' monophosphorylated substrates. We used high-resolution tiling arrays to analyze the effect of RNase Y depletion on RNA abundance covering the entire genome. The data confirm that this endoribonuclease plays a key role in initiating the decay of a large number of mRNAs as well as non coding RNAs. The downstream cleavage products are likely to be degraded by the 5' exonucleolytic activity of RNases J1/J2 as we show for a specific case. Comparison of the data with that of two other recent studies revealed very significant differences. About two thirds of the mRNAs upregulated following RNase Y depletion were different when compared to either one of these studies and only about 10% were in common in all three studies. This highlights that experimental conditions and data analysis play an important role in identifying RNase Y substrates by global transcriptional profiling. Our data confirmed already known RNase Y substrates and due to the precision and reproducibility of the profiles allow an exceptionally detailed view of the turnover of hundreds of new RNA substrates.

| S-EPMC3542257 | biostudies-literature

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