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Microbiology Spectrum Oct 2021Asthma is a multifactorial disorder, and microbial dysbiosis enhances lung inflammation and asthma-related symptoms. Probiotics have shown anti-inflammatory effects and... (Randomized Controlled Trial)
Randomized Controlled Trial
Asthma is a multifactorial disorder, and microbial dysbiosis enhances lung inflammation and asthma-related symptoms. Probiotics have shown anti-inflammatory effects and could regulate the gut-lung axis. Thus, a 3-month randomized, double-blind, and placebo-controlled human trial was performed to investigate the adjunctive efficacy of probiotics in managing asthma. Fifty-five asthmatic patients were randomly assigned to a probiotic group ( = 29; received Bifidobacterium lactis Probio-M8 powder and Symbicort Turbuhaler) and a placebo group ( = 26; received placebo and Symbicort Turbuhaler), and all 55 subjects provided details of their clinical history and demographic data. However, only 31 patients donated a complete set of fecal and blood samples at all three time points for further analysis. Compared with those of the placebo group, co-administering Probio-M8 with Symbicort Turbuhaler significantly decreased the fractional exhaled nitric oxide level at day 30 (= 0.049) and improved the asthma control test score at the end of the intervention (= 0.023). More importantly, the level of alveolar nitric oxide concentration decreased significantly among the probiotic receivers at day 30 (= 0.038), and the symptom relief effect was even more obvious at day 90 (= 0.001). Probiotic co-administration increased the resilience of the gut microbiome, which was reflected by only minor fluctuations in the gut microbiome diversity (> 0.05, probiotic receivers; < 0.05, placebo receivers). Additionally, the probiotic receivers showed significantly changes in some species-level genome bins (SGBs), namely, increases in potentially beneficial species Bifidobacterium animalis, Bifidobacterium longum, and sp. CAG and decreases in Parabacteroides distasonis and (< 0.05). Compared with that of the placebo group, the gut metabolic potential of probiotic receivers exhibited increased levels of predicted microbial bioactive metabolites (linoleoyl ethanolamide, adrenergic acid, erythronic acid) and serum metabolites (5-dodecenoic acid, tryptophan, sphingomyelin) during/after intervention. Collectively, our results suggested that co-administering Probio-M8 synergized with conventional therapy to alleviate diseases associated with the gut-lung axis, like asthma, possibly via activating multiple anti-inflammatory pathways. The human gut microbiota has a potential effect on the pathogenesis of asthma and is closely related to the disease phenotype. Our trial has demonstrated that co-administering Probio-M8 synergized with conventional therapy to alleviate asthma symptoms. The findings of the present study provide new insights into the pathogenesis and treatment of asthma, mechanisms of novel therapeutic strategies, and application of probiotics-based therapy.
Topics: Adolescent; Adult; Aged; Anti-Asthmatic Agents; Anti-Inflammatory Agents; Asthma; Bifidobacterium animalis; Budesonide, Formoterol Fumarate Drug Combination; Double-Blind Method; Dysbiosis; Female; Gastrointestinal Microbiome; Humans; Lung; Male; Middle Aged; Nitric Oxide; Placebos; Probiotics; Young Adult
PubMed: 34612663
DOI: 10.1128/Spectrum.00859-21 -
Applied and Environmental Microbiology Feb 2022It has been demonstrated that quorum sensing (QS) is widely employed by bacterial cells to coordinately regulate various group behaviors. Diffusible signal factor... (Review)
Review
It has been demonstrated that quorum sensing (QS) is widely employed by bacterial cells to coordinately regulate various group behaviors. Diffusible signal factor (DSF)-type signals have emerged as a growing family of conserved cell-cell communication signals. In addition to the DSF signal initially identified in Xanthomonas campestris pv. campestris, iffusible ignal actor (BDSF) (-2-dodecenoic acid) has been recognized as a conserved DSF-type signal with specific characteristics in both signal perception and transduction from DSF signals. Here, we review the history and current progress of the research on this type of signal, especially focusing on its biosynthesis, signaling pathways, and biological functions. We also discuss and explore the huge potential of targeting this kind of QS system as a new therapeutic strategy to control bacterial infections and diseases.
Topics: Bacterial Proteins; Burkholderia; Burkholderia cenocepacia; Fatty Acids, Monounsaturated; Gene Expression Regulation, Bacterial; Quorum Sensing; Suppressor Factors, Immunologic
PubMed: 34985987
DOI: 10.1128/aem.02342-21 -
Nutrition & Metabolism Jun 2023Non-alcoholic steatohepatitis (NASH) is a major contributor to liver cirrhosis and hepatocellular carcinoma. There remains no effective pharmacological therapy. The...
BACKGROUND
Non-alcoholic steatohepatitis (NASH) is a major contributor to liver cirrhosis and hepatocellular carcinoma. There remains no effective pharmacological therapy. The hepatic lipid metabolism and fatty acid β-oxidation are regulated by Perilipin5 (Plin5). However, it is yet unknown how Plin5 affects NASH and the molecular process.
METHODS
High-fat, high-cholesterol and high-fructose (HFHC) diets were used to mimic the progression of NASH in wild type (WT) mice and Plin5 knockout (Plin5 KO) mice. The degree of ferroptosis was measured by detecting the expression of key genes of ferroptosis and the level of lipid peroxide. The degree of NASH was judged by observing the morphology of the liver, detecting the expression of inflammation and fibrosis related genes of liver damage. Plin5 was overexpressed in the liver of mice by tail vein injection of adenovirus, and the process of NASH was simulated by methionine choline deficiency (MCD) diet. The occurrence of ferroptosis and NASH was detected by the same detection method. Targeted lipidomics sequencing was used to detect the difference in free fatty acid expression in the WT Plin5 KO group. Finally, it was verified in cell experiments to further study the effect of free fatty acids on ferroptosis of hepatocytes.
RESULTS
In various NASH models, hepatic Plin5 was dramatically reduced. Plin5 knockout (KO) worsened NASH-associated characteristics in mice given a high-fat/high-cholesterol (HFHC) diet, such as lipid accumulation, inflammation and hepatic fibrosis. It has been shown that ferroptosis is involved in NASH progression. We revealed that Plin5 KO in mice aggravated the degree of ferroptosis in NASH models. Conversely, overexpression of Plin5 significantly alleviated ferroptosis and further ameliorated progression of MCD-induced NASH. Analysis of livers obtained from HFHC diet-fed mice by targeted lipidomics revealed that 11-Dodecenoic acid was significantly decreased in Plin5 KO mice. Addition of 11-Dodecenoia acid to Plin5 knockdown hepatocytes effectively prevented ferroptosis.
CONCLUSION
Our study demonstrates that Plin5 protects against NASH progression by increasing 11-Dodecenoic acid level and further inhibiting ferroptosis, suggesting that Plin5 has therapeutic potential as a target for the management of NASH.
PubMed: 37349836
DOI: 10.1186/s12986-023-00751-2 -
Applied and Environmental Microbiology Apr 2019Quorum sensing (QS) signals are widely used by bacterial pathogens to control biological functions and virulence in response to changes in cell population densities....
Quorum sensing (QS) signals are widely used by bacterial pathogens to control biological functions and virulence in response to changes in cell population densities. employs a molecular mechanism in which the -2-dodecenoic acid (named iffusible ignal actor [BDSF]) QS system regulates -acyl homoserine lactone (AHL) signal production and virulence by modulating intracellular levels of cyclic diguanosine monophosphate (c-di-GMP). Thus, inhibition of BDSF signaling may offer a non-antibiotic-based therapeutic strategy against BDSF-regulated bacterial infections. In this study, we report the synthesis of small-molecule mimics of the BDSF signal and evaluate their ability to inhibit BDSF QS signaling in A novel structural analogue of BDSF, 14-Me-C (-14-methylpentadec-2-enoic acid), was observed to inhibit BDSF production and impair BDSF-regulated phenotypes in , including motility, biofilm formation, and virulence, while it did not inhibit the growth rate of this pathogen. 14-Me-C also reduced AHL signal production. Genetic and biochemical analyses showed that 14-Me-C inhibited the production of the BDSF and AHL signals by decreasing the expression of their synthase-encoding genes. Notably, 14-Me-C attenuated BDSF-regulated phenotypes in various species. These findings suggest that 14-Me-C could potentially be developed as a new therapeutic agent against pathogenic species by interfering with their QS signaling. is an important opportunistic pathogen which can cause life-threatening infections in susceptible individuals, particularly in cystic fibrosis and immunocompromised patients. It usually employs two types of quorum sensing (QS) systems, including the -2-dodecenoic acid (BDSF) system and -acyl homoserine lactone (AHL) system, to regulate virulence. In this study, we have designed and identified an unsaturated fatty acid compound (-14-methylpentadec-2-enoic acid [14-Me-C]) that is capable of interfering with QS signaling and virulence. We demonstrate that 14-Me-C reduced BDSF and AHL signal production in It also impaired QS-regulated phenotypes in various species. These results suggest that 14-Me-C could interfere with QS signaling in many species and might be developed as a new antibacterial agent.
Topics: Acyl-Butyrolactones; Bacterial Proteins; Biofilms; Burkholderia Infections; Burkholderia cenocepacia; Cyclic GMP; Fatty Acids, Monounsaturated; Gene Expression Regulation, Bacterial; Microbial Sensitivity Tests; Phenotype; Quorum Sensing; Signal Transduction; Virulence
PubMed: 30770405
DOI: 10.1128/AEM.00105-19 -
Proceedings of the National Academy of... Dec 2017Quorum sensing (QS) signals are used by bacteria to regulate biological functions in response to cell population densities. Cyclic diguanosine monophosphate (c-di-GMP)...
Quorum sensing (QS) signals are used by bacteria to regulate biological functions in response to cell population densities. Cyclic diguanosine monophosphate (c-di-GMP) regulates cell functions in response to diverse environmental chemical and physical signals that bacteria perceive. In , the QS signal receptor RpfR degrades intracellular c-di-GMP when it senses the QS signal -2-dodecenoic acid, also called diffusible signal factor (BDSF), as a proxy for high cell density. However, it was unclear how this resulted in control of BDSF-regulated phenotypes. Here, we found that RpfR forms a complex with a regulator named GtrR (BCAL1536) to enhance its binding to target gene promoters under circumstances where the BDSF signal binds to RpfR to stimulate its c-di-GMP phosphodiesterase activity. In the absence of BDSF, c-di-GMP binds to the RpfR-GtrR complex and inhibits its ability to control gene expression. Mutations in and had overlapping effects on both the transcriptome and BDSF-regulated phenotypes, including motility, biofilm formation, and virulence. These results show that RpfR is a QS signal receptor that also functions as a c-di-GMP sensor. This protein thus allows to integrate information about its physical and chemical surroundings as well as its population density to control diverse biological functions including virulence. This type of QS system appears to be widely distributed in beta and gamma proteobacteria.
Topics: Animals; Bacterial Load; Bacterial Proteins; Biofilms; Burkholderia Infections; Burkholderia cenocepacia; Cyclic GMP; Fatty Acids, Monounsaturated; Gene Expression Regulation, Bacterial; Mice; Mutation; Phenotype; Quorum Sensing; Signal Transduction; Virulence
PubMed: 29158389
DOI: 10.1073/pnas.1709048114 -
Redox Biology Jan 20134-Hydroxy-2-nonenal (HNE) is one of the most studied products of phospholipid peroxidation, owing to its reactivity and cytotoxicity. It can be formed by several... (Review)
Review
4-Hydroxy-2-nonenal (HNE) is one of the most studied products of phospholipid peroxidation, owing to its reactivity and cytotoxicity. It can be formed by several radical-dependent oxidative routes involving the formation of hydroperoxides, alkoxyl radicals, epoxides, and fatty acyl cross-linking reactions. Cleavage of the oxidized fatty acyl chain results in formation of HNE from the methyl end, and 9-oxo-nonanoic acid from the carboxylate or esterified end of the chain, although many other products are also possible. HNE can be metabolized in tissues by a variety of pathways, leading to detoxification and excretion. HNE-adducts to proteins have been detected in inflammatory situations such as atherosclerotic lesions using polyclonal and monoclonal antibodies, which have also been applied in ELISAs and western blotting. However, in order to identify the proteins modified and the exact sites and nature of the modifications, mass spectrometry approaches are required. Combinations of enrichment strategies with targetted mass spectrometry routines such as neutral loss scanning are now facilitating detection of HNE-modified proteins in complex biological samples. This is important for characterizing the interactions of HNE with redox sensitive cell signalling proteins and understanding how it may modulate their activities either physiologically or in disease.
Topics: Aldehydes; Lipid Peroxidation
PubMed: 24024147
DOI: 10.1016/j.redox.2013.01.007 -
Biomedical and Environmental Sciences :... Nov 2018To evaluate the efficacy of cis-2-dodecenoic acid (BDSF) in the treatment and prevention of vaginal candidiasis in vivo.
OBJECTIVE
To evaluate the efficacy of cis-2-dodecenoic acid (BDSF) in the treatment and prevention of vaginal candidiasis in vivo.
METHODS
The activities of different concentrations of BDSF against the virulence factors of Candida albicans (C. albicans) were determined in vitro. An experimental mouse model of Candida vaginitis was treated with 250 μmol/L BDSF. Treatment efficiency was evaluated in accordance with vaginal fungal burden and inflammation symptoms.
RESULTS
In vitro experiments indicated that BDSF attenuated the adhesion and damage of C. albicans to epithelial cells by decreasing phospholipase secretion and blocking filament formation. Treatment with 30 μmol/L BDSF reduced the adhesion and damage of C. albicans to epithelial cells by 36.9% and 42.3%, respectively. Treatment with 200 μmol/L BDSF completely inhibited phospholipase activity. In vivo mouse experiments demonstrated that BDSF could effectively eliminate vaginal infection and relieve inflammatory symptoms. Four days of treatment with 250 μmol/L BDSF reduced vaginal fungal loads by 6-fold and depressed inflammation. Moreover, BDSF treatment decreased the expression levels of the inflammatory chemokine-associated genes MCP-1 and IGFBP3 by 2.5- and 2-fold, respectively.
CONCLUSION
BDSF is a novel alternative drug that can efficiently control vaginal candidiasis by inhibiting the virulence factors of C. albicans.
Topics: Animals; Candida albicans; Candidiasis, Vulvovaginal; Chemokine CCL2; Disease Models, Animal; Fatty Acids, Monounsaturated; Female; Fungal Proteins; Humans; Insulin-Like Growth Factor Binding Protein 3; Mice; Virulence; Virulence Factors
PubMed: 30558702
DOI: 10.3967/bes2018.109 -
International Journal of Molecular... Jul 2022The genome of the neotropical fruit bat was recently sequenced, revealing an unexpected gene encoding a plant-like protein, CYP74C44, which shares ca. 90% sequence...
The genome of the neotropical fruit bat was recently sequenced, revealing an unexpected gene encoding a plant-like protein, CYP74C44, which shares ca. 90% sequence identity with the putative CYP74C of . The preparation and properties of the recombinant CYP74C44 are described in the present work. The CYP74C44 enzyme was found to be active against the 13- and 9-hydroperoxides of linoleic and α-linolenic acids (13-HPOD, 13-HPOT, 9-HPOD, and 9-HPOT, respectively), as well as the 15-hydroperoxide of eicosapentaenoic acid (15-HPEPE). All substrates studied were specifically transformed into chain cleavage products that are typical for hydroperoxide lyases (HPLs). The HPL chain cleavage reaction was validated by the identification of NaBH-reduced products (Me/TMS) of 15-HPEPE and 13- and 9-hydroperoxides as (all-)-14-hydroxy-5,8,11-tetradecatrienoic, (9)-12-hydroxy-9-dodecenoic, and 9-hydroxynonanoic acids (Me/TMS), respectively. Thus, CYP74C44 possessed the HPL activity that is typical for the CYP74C subfamily proteins.
Topics: Aldehyde-Lyases; Animals; Chiroptera; Cytochrome P-450 Enzyme System; Hydrogen Peroxide; Plant Proteins; Substrate Specificity
PubMed: 35887355
DOI: 10.3390/ijms23148009 -
Microorganisms Jan 2020-2-dodecenoic acid (i.e., Diffusible Signal Factor, BDSF), a signaling molecule produced by but not by , can prevent hyphal formation. The mechanism by which BDSF...
-2-dodecenoic acid (i.e., Diffusible Signal Factor, BDSF), a signaling molecule produced by but not by , can prevent hyphal formation. The mechanism by which BDSF controls the morphological switch of is still unknown. To address this issue, we used the cDNA microarray method to investigate the differential expression of genes in in the presence and absence of BDSF. The microarray result indicated that 305 genes were significantly different in the expression level. This included the downregulation of 75 genes and the upregulation of 230 genes. Based on the microarray data, a mutant library was screened to search for genes, once mutated, conferred insensitivity to BDSF. The results showed that the repressors (Ubi4 and Sfl1 proteins) and the activator (Sfl2 protein) of filamentous growth are involved in the BDSF regulation of hyphal morphogenesis. Ubi4, an ubiquitin polypeptide that participates in ubiquitin-mediated protein turnover, is the protein required for the degradation of Sfl2. Sfl1 and Sfl2 proteins antagonistically control morphogenesis. In the hyphal induction condition, the amount of Ubi4 and Sfl1 protein increased rapidly with the exogenous addition of BDSF. As a result, the protein level of the activator of filamentous growth, Sfl2, decreased correspondingly, thereby facilitating the cells to remain in the yeast form.
PubMed: 31947778
DOI: 10.3390/microorganisms8010075 -
Microbiology Spectrum Aug 2022Burkholderia cenocepacia is a human opportunistic pathogen that mostly employs two types of quorum-sensing (QS) systems to regulate its various biological functions and...
Burkholderia cenocepacia is a human opportunistic pathogen that mostly employs two types of quorum-sensing (QS) systems to regulate its various biological functions and pathogenicity: the -2-dodecenoic acid (BDSF) system and the -acyl homoserine lactone (AHL) system. In this study, we reported that oridonin, which was screened from a collection of natural products, disrupted important B. cenocepacia phenotypes, including motility, biofilm formation, protease production, and virulence. Genetic and biochemical analyses showed that oridonin inhibited the production of BDSF and AHL signals by decreasing the expression of their synthase-encoding genes. Furthermore, we revealed that oridonin directly binds to the regulator RqpR of the two-component system RqpSR that dominates the above-mentioned QS systems to inhibit the expression of the BDSF and AHL signal synthase-encoding genes. Oridonin also binds to the transcriptional regulator CepR of the AHL system to inhibit its binding to the promoter of . These findings suggest that oridonin could potentially be developed as a new QS inhibitor against pathogenic B. cenocepacia. Burkholderia cenocepacia is an important human opportunistic pathogen that can cause life-threatening infections in susceptible individuals. It employs quorum-sensing (QS) systems to regulate biological functions and virulence. In this study, we have identified a lead compound, oridonin, that is capable of interfering with B. cenocepacia QS signaling and physiology. We demonstrate that oridonin suppressed -2-dodecenoic acid (BDSF) and -acyl homoserine lactone (AHL) signal production and attenuated virulence in B. cenocepacia. Oridonin also impaired QS-regulated phenotypes in various Burkholderia species. These results suggest that oridonin could interfere with QS signaling in many Burkholderia species and might be developed as a new antibacterial agent.
Topics: Acyl-Butyrolactones; Bacterial Proteins; Burkholderia cenocepacia; Diterpenes, Kaurane; Gene Expression Regulation, Bacterial; Humans; Quorum Sensing; Virulence
PubMed: 35856676
DOI: 10.1128/spectrum.01787-22