Integrative Molecular Phenotyping
INTEGRATIVE MOLECULAR
PHENOTYPING
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY

PubMed

In vivo evaluation of the effect of sickle cell hemoglobin S, C and therapeutic transfusion on erythrocyte metabolism and cardiorenal dysfunction

Mon, 27/03/2023 - 12:00
Am J Hematol. 2023 Mar 27. doi: 10.1002/ajh.26923. Online ahead of print.ABSTRACTDespite a wealth of exploratory plasma metabolomics studies in sickle cell disease (SCD), no study to date has evaluate a large and well phenotyped cohort to compare the primary erythrocyte metabolome of hemoglobin SS, SC and transfused AA red blood cells (RBCs) in vivo. The current study evaluates the RBC metabolome of 587 subjects with sickle cell sickle cell disease (SCD) from the WALK-PHaSST clinical cohort. The set includes hemoglobin SS, hemoglobin SC SCD patients, with variable levels of HbA related to RBC transfusion events. Here we explore the modulating effects of genotype, age, sex, severity of hemolysis, and transfusion therapy on sickle RBC metabolism. Results show that RBCs from patients with Hb SS genotypes - compared to AA RBCs from recent transfusion events or SC RBCs - are characterized by significant alterations of RBC acylcarnitines, pyruvate, sphingosine 1-phosphate, creatinine, kynurenine and urate metabolism. Surprisingly, the RBC metabolism of SC RBCs is dramatically different from SS, with all glycolytic intermediates significantly elevated in SS RBCs, with the exception of pyruvate. This result suggests a metabolic blockade at the ATP-generating phosphoenolpyruvate to pyruvate step of glycolysis, which is catalyzed by redox-sensitive pyruvate kinase. Metabolomics, clinical and hematological data were collated in a novel online portal. In conclusion, we identified metabolic signatures of HbS RBCs that correlate with the degree of steady state hemolytic anemia, cardiovascular and renal dysfunction and mortality. This article is protected by copyright. All rights reserved.PMID:36971592 | DOI:10.1002/ajh.26923

Defatted hempseed meal altered metabolic profile of fermented yogurt and enhanced the ability to alleviate constipation in rats

Mon, 27/03/2023 - 12:00
J Sci Food Agric. 2023 Mar 27. doi: 10.1002/jsfa.12575. Online ahead of print.ABSTRACTBACKGROUND: Hempseeds (Cannabis sativa L.) are rich in easily digestible proteins, fats, polyunsaturated fatty acids, and insoluble fiber, which are of highly nutritional value. Probiotics have been found to relieve constipation, which solved a health problem that constantly troubles most people. Therefore, the changes in the metabolites of fermented yogurt with or without 10% defatted hempseed meal (10% SHY or 0% SHY) were studied and their laxative effects were performed through animal experiment.RESULTS: Amino acids and peptides, terpene glycosides, carbohydrates, lineolic acids, and fatty acids were found to be the major contributors to the discrimination of metabolic profile between 0% SHY and 10% SHY. The differentially accumulated metabolites may lead to the discrepancy on yogurts' functionality. Animal experiments showed that 10% SHY treatment prevented constipation by increasing fecal number, fecal water content and small intestinal transit rate, and reducing inflammatory injury in loperamide-induced constipation rats. Further analysis of the gut microbiota revealed that 10% SHY gavage increased the relative abundances of the genera Lactobacillus, Allobaculum, Turicibacter, Oscillibacter, Ruminococcus, and Phascolarctobacterium in the constipated rats, whereas decreased that of Akkermansia, Clostridium_XlVa, Bacteroides, Staphylococcus, and Clostridium_lV. The combination of defatted hempseed meal and probiotics was found to be effective in relieving constipation, probably due to the enriched amino acids and peptides, such as Thr-Leu and lysinoalanine through correlation analysis.CONCLUSION: Our findings indicated that defatted hempseed meal in yogurt altered the metabolic profile and effectively alleviated constipation in rats, which is a promising therapeutic candidate for constipation. This article is protected by copyright. All rights reserved.PMID:36971462 | DOI:10.1002/jsfa.12575

Multi-Omics Analysis Provides Crucial Insights into the Drought Adaptation of <em>Glycyrrhiza uralensis</em> Fisch

Mon, 27/03/2023 - 12:00
J Agric Food Chem. 2023 Mar 27. doi: 10.1021/acs.jafc.2c07163. Online ahead of print.ABSTRACTDrought adaptation of plants is closely related to resistance and tolerance to drought stress as well as the ability to recover after the elimination of the stress. Glycyrrhiza uralensis Fisch is a commonly applied herb whose growth and development are greatly affected by drought. Here, we provide the first comprehensive analysis of the transcriptomic, epigenetic, and metabolic responses of G. uralensis to drought stress and rewatering. The hyper-/hypomethylation of genes may lead to up-/downregulated gene expression, and epigenetic changes can be regarded as an important regulatory mechanism of G. uralensis under drought stress and rewatering. Moreover, integrated transcriptome and metabolome analysis revealed that genes and metabolites involved in pathways of antioxidation, osmoregulation, phenylpropanoid biosynthesis, and flavonoid biosynthesis may regulate the drought adaptation of G. uralensis. This work provides crucial insights into the drought adaptation of G. uralensis and offers epigenetic resources for cultivating G. uralensis with high drought adaptation.PMID:36971245 | DOI:10.1021/acs.jafc.2c07163

Phospholipase A2 (PLA2) injured lymphatic endothelial cells leading to progression of secondary lymphoedema

Mon, 27/03/2023 - 12:00
Biotechnol Genet Eng Rev. 2023 Mar 27:1-24. doi: 10.1080/02648725.2023.2195082. Online ahead of print.ABSTRACTSecondary lymphoedema is one of the common complications after lymph node dissection for gynecologic malignancies and breast cancer. In this study, the relationship between PLA2 and postoperative lymphoedema in cancer at the molecular level has been explored through transcriptomics and metabolomic assays. Transcriptome sequencing technology, as well as metabolomic assays, were utilized to explore the expression of PLA2 in lymphoedema patients, and search for potential pathways in the pathogenesis and exacerbation mechanism of lymphoedema. The effect of sPLA2 on human lymphatic endothelial cells was investigated by culturing human lymphatic endothelial cells. Secretory phospholipases A2 (sPLA2) showed high expression levels in lymphoedema tissues, however, cytoplasmic phospholipases A2 (cPLA2), showed low expression in lymphoedema, as demonstrated by RT-qPCR. By culturing human lymphatic vascular endothelial cells, the study found that sPLA2 causes HLEC vacuolization and has an inhibitory effect on HLEC proliferation and migration. By detecting sPLA2 in the serum of lymphoedema patients and analyzing clinical data, it was found that sPLA2 was positively correlated with the severity of lymphoedema. Secretory Phospholipase A2 (sPLA2) is highly expressed in lymphoedema tissue, damages lymphatic vessel endothelial cells, is strongly associated with disease severity, and can be used as a potential predictor of disease severity.Abbreviations: PLA2: Phospholipase A2; DEGs: differentially expressed genes; DMP: differential metabolic production.PMID:36971244 | DOI:10.1080/02648725.2023.2195082

Phytochemical Analysis and Anti-<em>Ascaris suum</em> Activity of Different <em>Zanthoxylum</em> Species <em>In Vitro</em> and <em>In Vivo</em>

Mon, 27/03/2023 - 12:00
J Agric Food Chem. 2023 Mar 27. doi: 10.1021/acs.jafc.2c08949. Online ahead of print.ABSTRACTZanthoxylum plants (ZPs), including multiple Chinese prickly ash species, are dual-purpose functional foods favored by the general population around the world in foods, cosmetics, and traditional medicines and have antipruritic, insecticidal, and fungicidal bioactivities. For the first time, the anti-roundworm bioactivity of ZPs and the active ingredients were compared and investigated. Through nontarget metabolomics following targeted quantitative analysis, qinbunamides, sanshools, sanshooel, asarinin, and sesamin were found to be the main different components of Zanthoxylum species. Coincidentally, the 12 chemical components were also the dominant anti-roundworm ingredients of ZP extracts. The extracts of three species of Chinese prickly ash (1 mg/mL) decreased the hatchability of roundworm eggs significantly, and the ChuanJiao seed killed roundworms (insecticidal rate 100%) and alleviated the symptoms of pneumonia in mice. Furthermore, retention time-accurate mass-tandem mass spectrometry-ion ratio (RT-AM-MS/MS-IR) were modeled by assaying 108 authentic compounds of ZP extracts, and 20 metabolites were confidently identified in biological samples from ZP extract-treated mice by analyzing the m/z values and the empirical substructures. This study provides a good reference for the proper application of ZPs.PMID:36971186 | DOI:10.1021/acs.jafc.2c08949

ATM inhibition enhances the efficacy of radiation across distinct molecular subgroups of pediatric high-grade glioma

Mon, 27/03/2023 - 12:00
Neuro Oncol. 2023 Mar 27:noad064. doi: 10.1093/neuonc/noad064. Online ahead of print.ABSTRACTBACKGROUND: Pediatric high-grade glioma (pHGG) is largely incurable and accounts for most brain tumor-related deaths in children. Radiation is a standard therapy, yet the benefit from this treatment modality is transient, and most children succumb to disease within 2 years. Recent large-scale genomic studies suggest that pHGG have alterations in DNA damage response (DDR) pathways that induce resistance to DNA damaging agents. The aim of this study was to evaluate the therapeutic potential and molecular consequences of combining radiation with selective DDR inhibition in pHGG.METHODS: We conducted an unbiased screen in pHGG cells that combined radiation with clinical candidates targeting the DDR and identified the ATM inhibitor AZD1390. Subsequently, we profiled AZD1390 + radiation in an extensive panel of early passage pHGG cell lines, mechanistically characterized response to the combination in vitro in sensitive and resistant cells and evaluated the combination in vivo using TP53 wild-type and TP53 mutant orthotopic xenografts.RESULTS: AZD1390 significantly potentiated radiation across molecular subgroups of pHGG by increasing mutagenic non-homologous end joining and augmenting genomic instability. In contrast to previous reports, ATM inhibition significantly improved the efficacy of radiation in both TP53 wild-type and TP53 mutant isogenic cell lines and distinct orthotopic xenograft models. Furthermore, we identified a novel mechanism of resistance to AZD1390 + radiation that was marked by an attenuated ATM pathway response which dampened sensitivity to ATM inhibition and induced synthetic lethality with ATR inhibition.CONCLUSIONS: Our study supports the clinical evaluation of AZD1390 in combination with radiation in pediatric patients with HGG.PMID:36971093 | DOI:10.1093/neuonc/noad064

Effects of Radiation Exposure and Storage on the Energy Metabolome of Platelets in Whole Blood

Mon, 27/03/2023 - 12:00
Transfusion. 2023 Mar 27. doi: 10.1111/trf.17332. Online ahead of print.ABSTRACTBACKGROUND: Exposure to radiation through battlefield use of nuclear weapons, terrorist attacks or accidents at nuclear power plants is a current concern for the military. Beyond the risk of exposure to personnel is the intentional or accidental irradiation of our blood banking supply system. It is unknown how large doses of ionizing radiation affect storage of blood and blood products, including platelets. The major function of platelets is clot formation which includes aggregation, shape change, vesicle release, and fibrinogen attachment; these tasks require a significant amount of energy. Here we determine if ionizing radiation effects the energy metabolome of platelets in storage.STUDY DESIGN AND METHODS: Fresh whole blood from healthy volunteers was subjected to 0, 25 or 75Gy of X-irradiation, and stored at 4°C. Platelets were isolated from stored WB at 0, 1, 7, 14 and 21 days of storage. Krebs cycle intermediates, nicotinamide adenine dinucleotides, and the tri-, di and mono- phosphorylated versions of adenosine and guanosine were extracted and measured by tandem mass spectroscopy.RESULTS: Irradiation at either 25Gy or 75Gy had no significant effect on the amount of any metabolite measured compared to control (0Gy). However, there was a significant fall over time in storage for most of the metabolites measured.DISCUSSION: These data show that irradiation at high doses has no effect on the concentration of the energy metabolome of platelets derived from whole blood stored in 4°C for up to 21 days and suggests that platelets can maintain their metabolome even after radiation exposure. This article is protected by copyright. All rights reserved.PMID:36971034 | DOI:10.1111/trf.17332

Evaluation of the effectiveness of personalised therapy for the patients with irritable bowel syndrome

Mon, 27/03/2023 - 12:00
Benef Microbes. 2023 Mar 27:1-12. doi: 10.3920/BM2022.0053. Online ahead of print.ABSTRACTIntestinal microbiota correction in the therapy of irritable bowel syndrome (IBS) is an important medical problem. We conducted a laboratory and pilot clinical trial to investigate the effect of autoprobiotic bacteria, indigenous bifidobacteria and enterococci isolated from faeces and grown on artificial media to use as personified food additives in IBS treatment. Convincing evidence of the clinical efficacy of autoprobiotic was demonstrated by the disappearance of dyspeptic symptoms. The microbiome of patients with IBS was compared to a group of healthy volunteers and changes in the microbiome after autoprobiotic use were detected by quantitative polymerase chain reaction and 16S rRNA metagenome analysis. The possibility of reducing opportunistic microorganisms in the treatment of IBS with autoprobiotics has been convincingly proven. The quantitative content of enterococci in the intestinal microbiota was higher in IBS patients than in healthy volunteers and increased after therapy. An increase in the relative abundance of genera Coprococcus, Blautia and a decrease in the relative abundance of Paraprevotella spp. were found at the end of therapy. A metabolome study which was performed by gas chromatography and mass spectrometry demonstrated an increase in the content of oxalic acid, a decrease of dodecanoate, lauric acid, and other metabolome components after taking autoprobiotics. Some of these parameters correlated with the relative abundances of Paraprevotella spp., Enterococcus spp., and Coprococcus spp. representative of the microbiome. Apparently, they reflected the peculiarities of metabolic compensation and changes in the microbiota. Therefore, the use of autoprobiotics for treatment of IBS may lead to a stable positive clinical effect, associated with compensatory changes in the intestinal microbiota, and accompanied by corresponding changes in metabolic processes in the organism.PMID:36970947 | DOI:10.3920/BM2022.0053

The Effects of Amyloid-β on Metabolomic Profiles of Cardiomyocytes and Coronary Endothelial Cells

Mon, 27/03/2023 - 12:00
J Alzheimers Dis. 2023 Mar 23. doi: 10.3233/JAD-221199. Online ahead of print.ABSTRACTBACKGROUND: An increasing number of experimental and clinical studies show a link between Alzheimer's disease and heart diseases such as heart failure, ischemic heart disease, and atrial fibrillation. However, the mechanisms underlying the potential role of amyloid-β (Aβ) in the pathogenesis of cardiac dysfunction in Alzheimer's disease remain unknown. We have recently shown the effects of Aβ 1 - 40 and Aβ 1 - 42 on cell viability and mitochondrial function in cardiomyocytes and coronary artery endothelial cells.OBJECTIVE: In this study, we investigated the effects of Aβ 1 - 40 and Aβ 1 - 42 on the metabolism of cardiomyocytes and coronary artery endothelial cells.METHODS: Gas chromatography-mass spectrometry was used to analyze metabolomic profiles of cardiomyocytes and coronary artery endothelial cells treated with Aβ 1 - 40 and Aβ 1 - 42. In addition, we determined mitochondrial respiration and lipid peroxidation in these cells.RESULTS: We found that the metabolism of different amino acids was affected by Aβ 1 - 42 in each cell type, whereas the fatty acid metabolism is consistently disrupted in both types of cells. Lipid peroxidation was significantly increased, whereas mitochondrial respiration was reduced in both cell types in response to Aβ 1 - 42.CONCLUSION: This study revealed the disruptive effects of Aβ on lipid metabolism and mitochondria function in cardiac cells.PMID:36970904 | DOI:10.3233/JAD-221199

Hypoxia Drives Material-Induced Heterotopic Bone Formation by Enhancing Osteoclastogenesis via M2/Lipid-Loaded Macrophage Axis

Mon, 27/03/2023 - 12:00
Adv Sci (Weinh). 2023 Mar 27:e2207224. doi: 10.1002/advs.202207224. Online ahead of print.ABSTRACTHeterotopic ossification (HO) is a double-edged sword. Pathological HO presents as an undesired clinical complication, whereas controlled heterotopic bone formation by synthetic osteoinductive materials shows promising therapeutic potentials for bone regeneration. However, the mechanism of material-induced heterotopic bone formation remains largely unknown. Early acquired HO being usually accompanied by severe tissue hypoxia prompts the hypothesis that hypoxia caused by the implantation coordinates serial cellular events and ultimately induces heterotopic bone formation in osteoinductive materials. The data presented herein shows a link between hypoxia, macrophage polarization to M2, osteoclastogenesis, and material-induced bone formation. Hypoxia inducible factor-1α (HIF-1α), a crucial mediator of cellular responses to hypoxia, is highly expressed in an osteoinductive calcium phosphate ceramic (CaP) during the early phase of implantation, while pharmacological inhibition of HIF-1α significantly inhibits M2 macrophage, subsequent osteoclast, and material-induced bone formation. Similarly, in vitro, hypoxia enhances M2 macrophage and osteoclast formation. Osteoclast-conditioned medium enhances osteogenic differentiation of mesenchymal stem cells, such enhancement disappears with the presence of HIF-1α inhibitor. Furthermore, metabolomics analysis reveals that hypoxia enhances osteoclastogenesis via the axis of M2/lipid-loaded macrophages. The current findings shed new light on the mechanism of HO and favor the design of more potent osteoinductive materials for bone regeneration.PMID:36970815 | DOI:10.1002/advs.202207224

Survival of <em>Escherichia coli</em> after high-antibiotic stress is dependent on both the pregrown physiological state and incubation conditions

Mon, 27/03/2023 - 12:00
Front Microbiol. 2023 Mar 10;14:1149978. doi: 10.3389/fmicb.2023.1149978. eCollection 2023.ABSTRACTINTRODUCTION: The survival of bacterial cells exposed to antibiotics depends on the mode of action, the antibiotics concentration, and the duration of treatment. However, it also depends on the physiological state of the cells and the environmental conditions. In addition, bacterial cultures contain sub-populations that can survive high antibiotic concentrations, so-called persisters. Research on persisters is challenging due to multiple mechanisms for their formation and low fractions, down to and below one millionth of the total cell population. Here, we present an improved version of the persister assay used to enumerate the amount of persisters in a cell population.METHODS: The persister assay with high antibiotic stress exposure was performed at both growth supporting and non-supporting conditions. Escherichia coli cells were pregrown to various growth stages in shake flasks and bench-top bioreactors. In addition, the physiological state of E. coli before antibiotic treatment was determined by quantitative mass spectrometry-based metabolite profiling.RESULTS: Survival of E. coli strongly depended on whether the persister assay medium supported growth or not. The results were also highly dependent on the type of antibiotic and pregrown physiological state of the cells. Therefore, applying the same conditions is critical for consistent and comparable results. No direct connection was observed between antibiotic efficacy to the metabolic state. This also includes the energetic state (i.e., the intracellular concentration of ATP and the adenylate energy charge), which has earlier been hypothesized to be decisive for persister formation.DISCUSSION: The study provides guides and suggestions for the design of future experimentation in the research fields of persisters and antibiotic tolerance.PMID:36970700 | PMC:PMC10036391 | DOI:10.3389/fmicb.2023.1149978

Alterations in the gut microbiome and metabolome profiles of septic mice treated with Shen FuHuang formula

Mon, 27/03/2023 - 12:00
Front Microbiol. 2023 Mar 8;14:1111962. doi: 10.3389/fmicb.2023.1111962. eCollection 2023.ABSTRACTSepsis has a high mortality rate, and treating sepsis remains a significant challenge worldwide. In former studies, our group found that traditional Chinese medicine, Shen FuHuang formula (SFH), is a promising medicine in treating coronavirus disease 2019 (COVID-19) patients with the septic syndrome. However, the underlying mechanisms remain elusive. In the present study, we first investigated the therapeutic effects of SFH on septic mice. To investigate the mechanisms of SFH-treated sepsis, we identified the gut microbiome profile and exploited untargeted metabolomics analyses. The results demonstrated that SFH significantly enhanced the mice's 7-day survival rate and hindered the release of inflammatory mediators, i.e., TNF-α, IL-6, and IL-1β. 16S rDNA sequencing further deciphered that SFH decreased the proportion of Campylobacterota and Proteobacteria at the phylum level. LEfSe analysis revealed that the treatment of SFH enriched Blautia while decreased Escherichia_Shigella. Furthermore, serum untargeted metabolomics analysis indicated that SFH could regulate the glucagon signaling pathway, PPAR signaling pathway, galactose metabolism, and pyrimidine metabolism. Finally, we found the relative abundance of Bacteroides, Lachnospiraceae_NK4A136_group, Escherichia_Shigella, Blautia, Ruminococcus, and Prevotella were closely related to the enrichment of the metabolic signaling pathways, including L-tryptophan, uracil, glucuronic acid, protocatechuic acid, and gamma-Glutamylcysteine. In conclusion, our study demonstrated that SFH alleviated sepsis by suppressing the inflammatory response and hence reduced mortality. The mechanism of SFH for treating sepsis may be ascribed to the enrichment of beneficial gut flora and modulation in glucagon signaling pathway, PPAR signaling pathway, galactose metabolism, and pyrimidine metabolism. To sum up, these findings provide a new scientific perspective for the clinical application of SFH in treating sepsis.PMID:36970673 | PMC:PMC10030955 | DOI:10.3389/fmicb.2023.1111962

An untargeted exometabolomics approach to characterize dissolved organic matter in groundwater of the Samail Ophiolite

Mon, 27/03/2023 - 12:00
Front Microbiol. 2023 Mar 9;14:1093372. doi: 10.3389/fmicb.2023.1093372. eCollection 2023.ABSTRACTThe process of serpentinization supports life on Earth and gives rise to the habitability of other worlds in our Solar System. While numerous studies have provided clues to the survival strategies of microbial communities in serpentinizing environments on the modern Earth, characterizing microbial activity in such environments remains challenging due to low biomass and extreme conditions. Here, we used an untargeted metabolomics approach to characterize dissolved organic matter in groundwater in the Samail Ophiolite, the largest and best characterized example of actively serpentinizing uplifted ocean crust and mantle. We found that dissolved organic matter composition is strongly correlated with both fluid type and microbial community composition, and that the fluids that were most influenced by serpentinization contained the greatest number of unique compounds, none of which could be identified using the current metabolite databases. Using metabolomics in conjunction with metagenomic data, we detected numerous products and intermediates of microbial metabolic processes and identified potential biosignatures of microbial activity, including pigments, porphyrins, quinones, fatty acids, and metabolites involved in methanogenesis. Metabolomics techniques like the ones used in this study may be used to further our understanding of life in serpentinizing environments, and aid in the identification of biosignatures that can be used to search for life in serpentinizing systems on other worlds.PMID:36970670 | PMC:PMC10033605 | DOI:10.3389/fmicb.2023.1093372

Remodeling of the gut microbiome by <em>Lactobacillus johnsonii</em> alleviates the development of acute myocardial infarction

Mon, 27/03/2023 - 12:00
Front Microbiol. 2023 Mar 8;14:1140498. doi: 10.3389/fmicb.2023.1140498. eCollection 2023.ABSTRACTINTRODUCTION: The gut microbial community, which can be disturbed or repaired by changes in the internal environment, contributes to the development of acute myocardial infarction (AMI). Gut probiotics play a role in microbiome remodeling and nutritional intervention post-AMI. A newly isolated Lactobacillus johnsonii strain EU03 has shown potential as a probiotic. Here, we investigated the cardioprotective function and mechanism of L. johnsonii through gut microbiome remodeling in AMI rats.METHODS: A rat model of left anterior descending coronary artery ligation (LAD)-mediated AMI was assessed with echocardiography, histology, and serum cardiac biomarkers to evaluate the beneficial effects of L. johnsonii. The immunofluorescence analysis was utilized to visualize the intestinal barrier changes. Antibiotic administration model was used for assessing the gut commensals' function in the improvement of cardiac function post-AMI. The underlying beneficial mechanism through L. johnsonii enrichment was further investigated by metagenomics and metabolomics analysis.RESULTS: A 28-day treatment with L. johnsonii protected cardiac function, delayed cardiac pathology, suppressed myocardial injury cytokines, and improved gut barrier integrity. The microbiome composition was reprogrammed by enhancing the abundance of L. johnsonii. Microbiome dysbiosis by antibiotics abrogated the improvement of cardiac function post-AMI by L. johnsonii. L. johnsonii enrichment caused remodeling of gut microbiome by increasing the abundance of Muribaculaceae, Lactobacillus, and decreasing Romboutsia, Clostridia UCG-014, which were correlated with cardiac traits and serum metabolic biomarkers 16,16-dimethyl-PGA2, and Lithocholate 3-O-glucuronide.CONCLUSION: These findings reveal that gut microbiome remodeling by L. johnsonii ameliorates the cardiac function post-AMI and might advance microbiome-targeted nutritional intervention.Graphical Abstract.PMID:36970663 | PMC:PMC10030800 | DOI:10.3389/fmicb.2023.1140498

Optimization of the growth conditions through response surface methodology and metabolomics for maximizing the auxin production by <em>Pantoea agglomerans</em> C1

Mon, 27/03/2023 - 12:00
Front Microbiol. 2023 Mar 8;14:1022248. doi: 10.3389/fmicb.2023.1022248. eCollection 2023.ABSTRACTINTRODUCTION: The fermentative production of auxin/indole 3-acetate (IAA) using selected Pantoea agglomerans strains can be a promising approach to developing novel plant biostimulants for agriculture use.METHODS: By integrating metabolomics and fermentation technologies, this study aimed to define the optimal culture conditions to obtain auxin/IAA-enriched plant postbiotics using P. agglomerans strain C1. Metabolomics analysis allowed us to demonstrate that the production of a selected.RESULTS AND DISCUSSION: Array of compounds with plant growth-promoting- (IAA and hypoxanthine) and biocontrol activity (NS-5, cyclohexanone, homo-L-arginine, methyl hexadecenoic acid, and indole-3-carbinol) can be stimulated by cultivating this strain on minimal saline medium amended with sucrose as a carbon source. We applied a three-level-two-factor central composite design (CCD) based response surface methodology (RSM) to explore the impact of the independent variables (rotation speed and medium liquid-to-flask volume ratio) on the production of IAA and IAA precursors. The ANOVA component of the CCD indicated that all the process-independent variables investigated significantly impacted the auxin/IAA production by P. agglomerans strain C1. The optimum values of variables were a rotation speed of 180 rpm and a medium liquid-to-flask volume ratio of 1:10. Using the CCD-RSM method, we obtained a maximum indole auxin production of 208.3 ± 0.4 mg IAAequ/L, which was a 40% increase compared to the growth conditions used in previous studies. Targeted metabolomics allowed us to demonstrate that the IAA product selectivity and the accumulation of the IAA precursor indole-3-pyruvic acid were significantly affected by the increase in the rotation speed and the aeration efficiency.PMID:36970660 | PMC:PMC10030972 | DOI:10.3389/fmicb.2023.1022248

Investigating the induction of polyphenol biosynthesis in the cultured <em>Cycolocarya paliurus</em> cells and the stimulatory mechanism of co-induction with 5-aminolevulinic acid and salicylic acid

Mon, 27/03/2023 - 12:00
Front Bioeng Biotechnol. 2023 Mar 9;11:1150842. doi: 10.3389/fbioe.2023.1150842. eCollection 2023.ABSTRACTBackground: Plant cell culture technology is a potential way to produce polyphenols, however, this way is still trapped in the dilemma of low content and yield. Elicitation is regarded as one of the most effective ways to improve the output of the secondary metabolites, and therefore has attracted extensive attention. Methods: Five elicitors including 5-aminolevulinic acid (5-ALA), salicylic acid (SA), methyl jasmonate (MeJA), sodium nitroprusside (SNP) and Rhizopus Oryzae Elicitor (ROE) were used to improve the content and yield of polyphenols in the cultured Cyclocarya paliurus (C. paliurus) cells, and a co-induction technology of 5-ALA and SA was developed as a result. Meanwhile, the integrated analysis of transcriptome and metabolome was adopted to interpret the stimulation mechanism of co-induction with 5-ALA and SA. Results: Under the co-induction of 50 μM 5-ALA and SA, the content and yield of total polyphenols of the cultured cells reached 8.0 mg/g and 147.12 mg/L, respectively. The yields of cyanidin-3-O-galactoside, procyanidin B1 and catechin reached 28.83, 4.33 and 2.88 times that of the control group, respectively. It was found that expressions of TFs such as CpERF105, CpMYB10 and CpWRKY28 increased significantly, while CpMYB44 and CpTGA2 decreased. These great changes might further make the expression of CpF3'H (flavonoid 3'-monooxygenase), CpFLS (flavonol synthase), CpLAR (leucoanthocyanidin reductase), CpANS (anthocyanidin synthase) and Cp4CL (4-coumarate coenzyme A ligase) increase while CpANR (anthocyanidin reductase) and CpF3'5'H (flavonoid 3', 5'-hydroxylase) reduce, ultimately enhancing the polyphenols accumulation Conclusion: The co-induction of 5-ALA and SA can significantly promote polyphenol biosynthesis in the cultured C. paliurus cells by regulating the expression of key transcription factors and structural genes associated with polyphenol synthesis, and thus has a promising application.PMID:36970633 | PMC:PMC10034720 | DOI:10.3389/fbioe.2023.1150842

Gene network reveals <em>LASP1, TUBA1C</em>, and <em>S100A6</em> are likely playing regulatory roles in multiple sclerosis

Mon, 27/03/2023 - 12:00
Front Neurol. 2023 Mar 9;14:1090631. doi: 10.3389/fneur.2023.1090631. eCollection 2023.ABSTRACTINTRODUCTION: Multiple sclerosis (MS), a non-contagious and chronic disease of the central nervous system, is an unpredictable and indirectly inherited disease affecting different people in different ways. Using Omics platforms genomics, transcriptomics, proteomics, epigenomics, interactomics, and metabolomics database, it is now possible to construct sound systems biology models to extract full knowledge of the MS and recognize the pathway to uncover the personalized therapeutic tools.METHODS: In this study, we used several Bayesian Networks in order to find the transcriptional gene regulation networks that drive MS disease. We used a set of BN algorithms using the R add-on package bnlearn. The BN results underwent further downstream analysis and were validated using a wide range of Cytoscape algorithms, web based computational tools and qPCR amplification of blood samples from 56 MS patients and 44 healthy controls. The results were semantically integrated to improve understanding of the complex molecular architecture underlying MS, distinguishing distinct metabolic pathways and providing a valuable foundation for the discovery of involved genes and possibly new treatments.RESULTS: Results show that the LASP1, TUBA1C, and S100A6 genes were most likely playing a biological role in MS development. Results from qPCR showed a significant increase (P < 0.05) in LASP1 and S100A6 gene expression levels in MS patients compared to that in controls. However, a significant down regulation of TUBA1C gene was observed in the same comparison.CONCLUSION: This study provides potential diagnostic and therapeutic biomarkers for enhanced understanding of gene regulation underlying MS.PMID:36970516 | PMC:PMC10035600 | DOI:10.3389/fneur.2023.1090631

Qingfei Jiedu Granules fight influenza by regulating inflammation, immunity, metabolism, and gut microbiota

Mon, 27/03/2023 - 12:00
J Tradit Complement Med. 2022 Sep 27;13(2):170-182. doi: 10.1016/j.jtcme.2022.09.001. eCollection 2023 Mar.ABSTRACTBACKGROUND AND AIM: Qingfei Jiedu Granules (QFJD) are a new Traditional Chinese Medicine (TCM) which has been clinically used against coronavirus pneumonia in China. In this study, the therapeutic effect and the underlying mechanisms of QFJD against influenza were investigated.EXPERIMENTAL PROCEDURE: Pneumonia mice were induced by influenza A virus. Survival rate, weight loss, lung index and lung pathology were measured to evaluate the therapeutic effect of QFJD. The expression of inflammatory factors and lymphocytes was used to assess anti-inflammatory and immunomodulatory effect of QFJD. Gut microbiome analysis was performed to decipher the potential effect of QFJD on intestinal microbiota. Metabolomics approach was conducted to explore the overall metabolic regulation of QFJD.RESULT AND CONCLUSION: QFJD shows a significant therapeutic effect on the treatment of influenza and the expression of many pro-inflammatory cytokines were obviously inhibited. QFJD also markedly modulates the level of T and B lymphocytes. The high-dose QFJD has shown similar therapeutic efficiency compared to positive drugs. QFJD profoundly enriched Verrucomicrobia and maintained the balance between Bacteroides and Firmicutes. QFJD associated with 12 signaling pathways in metabolomics study, 9 of which were the same as the model group and were closely related to citrate cycle and amino acid metabolism.To sum up, QFJD is a novel and promising drug against influenza. It can regulate inflammation, immunity, metabolism, and gut microbiota to fight influenza. Verrucomicrobia shows great potential to improve influenza infection and may be an important target.PMID:36970461 | PMC:PMC10037062 | DOI:10.1016/j.jtcme.2022.09.001

Efficacy of Triphala extracts on the changes of obese fecal microbiome and metabolome in the human gut model

Mon, 27/03/2023 - 12:00
J Tradit Complement Med. 2023 Feb 28;13(2):207-217. doi: 10.1016/j.jtcme.2023.02.011. eCollection 2023 Mar.ABSTRACTTriphala is a mixture of tree fruits obtained from Terminalia chebula, Terminalia bellerica, and Phyllanthus emblica. It is one of the Ayurveda medicinal recipes used to treat health diseases such as obesity. The chemical composition analysis of Triphala extracts obtained from an equal portion of three fruits was performed. The contents of total phenolic compounds (62.87 ± 0.21 mg gallic acid equivalent/mL), total flavonoids (0.24 ± 0.01 mg catechin equivalent/mL), hydrolyzable tannins (177.27 ± 10.09 mg gallotannin equivalent/mL), and condensed tannins (0.62 ± 0.11 mg catechin equivalent/mL) were observed in Triphala extracts. The 1 mg/mL of Triphala extracts was applied to batch culture fermentation which contained the feces from voluntarily obese female adults (body mass index of 35.0-40.0 kg/m2) for 24 h. The extraction of DNA and metabolites was each conducted on the samples obtained from batch culture fermentation within and without Triphala extracts treatment. The 16S rRNA gene sequencing and untargeted metabolomic analysis were carried out. There was no statistically significant difference between Triphala extracts and control treatments on the changes in microbial profiles (p-value <0.05). While the metabolomic analysis showed statistically significant differences of 305 up-regulated and 23 down-regulated metabolites in the treatment of Triphala extracts when compared with the control (p-value <0.05 and fold-change ≥2) belonging to 60 pathways. The pathway analysis revealed that Triphala extracts play an important role in the activation of phenylalanine, tyrosine and tryptophan biosynthesis. In this study, phenylalanine and tyrosine were identified metabolites which involve in the regulation of energy metabolism. The treatment of Triphala extracts possesses the induction of phenylalanine, tyrosine and tryptophan biosynthesis in fecal batch culture fermentation of obese adults and therefore it can be suggested as a probable herbal medicinal recipe for obesity treatment.PMID:36970454 | PMC:PMC10037071 | DOI:10.1016/j.jtcme.2023.02.011

Pulmonary arterial hypertension associated with congenital heart disease: An omics study

Mon, 27/03/2023 - 12:00
Front Cardiovasc Med. 2023 Mar 10;10:1037357. doi: 10.3389/fcvm.2023.1037357. eCollection 2023.ABSTRACTPulmonary arterial hypertension associated with congenital heart disease (PAH-CHD) is a severely progressive condition with uncertain physiological course. Hence, it has become increasingly relevant to clarify the specific mechanisms of molecular modification, which is crucial to identify more treatment strategies. With the rapid development of high-throughput sequencing, omics technology gives access to massive experimental data and advanced techniques for systems biology, permitting comprehensive assessment of disease occurrence and progression. In recent years, significant progress has been made in the study of PAH-CHD and omics. To provide a comprehensive description and promote further in-depth investigation of PAH-CHD, this review attempts to summarize the latest developments in genomics, transcriptomics, epigenomics, proteomics, metabolomics, and multi-omics integration.PMID:36970344 | PMC:PMC10036813 | DOI:10.3389/fcvm.2023.1037357

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