PubMed

Target Oncol. 2023 Aug 26. doi: 10.1007/s11523-023-00992-4. Online ahead of print.ABSTRACTBACKGROUND: In patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), salvage chemotherapy regimens (e.g., rituximab, ifosfamide, carboplatin, and etoposide, R-ICE) yield poor outcomes. Carfilzomib, an irreversible proteasome inhibitor, can overcome acquired rituximab-chemotherapy resistance and, when combined with R-ICE, improves outcomes in patients with R/R DLBCL.OBJECTIVE: This analysis aimed to develop a population pharmacokinetic/pharmacodynamic (PK/PD) model for carfilzomib in R/R DLBCL patients.PATIENTS AND METHODS: In a single-center, open-label, prospective phase 1 study, patients received carfilzomib (10, 15, or 20 mg/m2) on days 1, 2, 8, and 9, and standard doses of R-ICE on days 3-6 every 21 days (maximum of three cycles). Carfilzomib plasma concentrations up to 24 h postinfusion were measured by liquid chromatography coupled with tandem mass spectrometry. Proteasome activity (PD biomarker) in peripheral blood mononuclear cells was assessed on days 1-2 with sparse sampling. PK/PD models were developed using NONMEM v7.4.1 interfaced with Finch Studio v1.1.0 and PsN v4.7.0. Model selection was guided by objective function value, goodness-of-fit, and visual predictive checks. Stepwise covariate modeling was used for covariate selection.RESULTS: Twenty-eight patients were enrolled in the PK/PD analysis, from whom 217 PK samples and 127 PD samples were included. Carfilzomib PK was best described by a two-compartment model with linear disposition (typical total clearance of 133 L/h). Proteasome activity was best characterized using a turnover model with irreversible inactivation. All parameters were estimated with good precision. No statistically significant covariates were identified.CONCLUSIONS: A validated population-based PK/PD model of carfilzomib was developed successfully. Further research is needed to identify sources of variability in response to treatment with carfilzomib in combination with R-ICE.CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier number NCT01959698.PMID:37632592 | DOI:10.1007/s11523-023-00992-4

J Ren Nutr. 2023 Aug 21:S1051-2276(22)00213-8. doi: 10.1053/j.jrn.2022.12.004. Online ahead of print.ABSTRACTThere is increasing interest in the therapeutic potential of manipulating the gut microbiome of patients with chronic kidney disease (CKD). This is because there is a substantial deviation from a balanced gut microbiota profile in CKD, with many deleterious downstream effects. Nutritional interventions such as plant-based diets with reduced animal protein intake and the use of probiotics, prebiotics, and synbiotics may alter the microbiome. This article aims to briefly describe what is known about the gut microbiome in patients with CKD, factors contributing to gut dysbiosis, and outline important evidence gaps. Future potential therapies, including restoring the microbiota with food and microbiota-based and metabolomic-based therapies, are also discussed.PMID:37632511 | DOI:10.1053/j.jrn.2022.12.004

J Biomol Struct Dyn. 2023 Aug 26:1-16. doi: 10.1080/07391102.2023.2251067. Online ahead of print.ABSTRACTDanzhi-xiaoyao-San (DZXYS), a Traditional Chinese Medicine, plays an essential role in the clinical treatment of depression, but its mechanisms in humans remain unclear. To investigate its pharmacological effects and mechanisms as an add-on therapy for depression, we conducted a double-blind, placebo-controlled trial with depressed patients receiving selective serotonin reuptake inhibitors (SSRIs). Serum and fecal samples were collected for metabolomic and microbiome analysis using UHPLC-QTRAP-MS/MS and 16S rRNA gene sequencing technologies, respectively. Depression symptoms were assessed using the 24-item Hamilton Depression Scale. We employed network pharmacology, metabolomics, and molecular docking to identify potential targets associated with DZXYS. We also examined the correlation between gut microbes and metabolites to understand how DZXYS affects the microbiota-gut-brain axis. The results showed that DZXYS combined with SSRIs was more effective than SSRIs alone in improving depression. We identified 39 differential metabolites associated with DZXYS treatment and found seven upregulated metabolic pathways. The active ingredients quercetin and luteolin were docked to targets (AVPR2, EGFR, F2, and CDK6) associated with the enriched pathways 'pancreatic cancer' and 'phospholipase D signaling pathway', which included the metabolite lysophosphatidic acid [LPA(0:0/16:0)]. Additionally, we identified 32 differential gut microbiota species related to DZXYS treatment, with Bacteroides coprophilus and Ruminococcus gnavus showing negative correlations with specific metabolites such as L-2-aminobutyric acid and LPA(0:0/16:0). Our findings indicate that DZXYS's antidepressant mechanisms involve multiple targets, pathways, and the regulation of LPA and the microbiota-gut-brain axis. These insights from our systems pharmacology analysis contribute to a better understanding of DZXYS's potential pharmacological mechanisms in depression treatment.Communicated by Ramaswamy H. Sarma.PMID:37632305 | DOI:10.1080/07391102.2023.2251067

Biomed Chromatogr. 2023 Aug 26:e5718. doi: 10.1002/bmc.5718. Online ahead of print.ABSTRACTWe present a GC-MS metabolomics workflow for analyzing metabolites in urine samples infected with schistosomiasis. Schistosomiasis, a neglected tropical disease, affects 85% of the global population, with the majority residing in Sub-Saharan Africa. The workflow utilized in this study involved the utilization of the AMDIS freeware, Metab R for pre-processing, and multivariate statistical classification through partial least squares-discriminant analysis (PLS-DA). This classification aimed to categorize volatile metabolites found in urine samples from humans infected with schistosomiasis. All samples were collected from individuals in Botswana. A solid-phase microextraction-fused silica fiber was used to adsorb volatile metabolites from the urine samples and inserted into the GC-MS injection port for data acquisition. The acquired data were then subjected to AMDIS auto-deconvolution, Metab R pre-processing, and statistical evaluation for metabolite mining. A total of 12 metabolites, including 3-chloropropionic acid and heptadecyl ester with an AMDIS match factor of 96% at an approximated amount of 0.35% and cyclohexylamine with an AMDIS match factor of 100% and approximated amount of 0.39%, were identified. PLS-DA was used for the classification of the metabolites. The method showed good sensitivity and specificity as indicated by the receiver operating characteristic measured by the areas under the curves. Results indicated that metabolomics is a useful tool for mining metabolites because of the variance in metabolite composition of infected and non-infected urine samples.PMID:37632284 | DOI:10.1002/bmc.5718

Pharmaceutics. 2023 Aug 14;15(8):2140. doi: 10.3390/pharmaceutics15082140.ABSTRACTStudies have demonstrated that pigment-epithelium-derived factor (PEDF) is a robust inhibitor of tumour growth and development, implying that this may serve as a promising target for therapeutic intervention. However, the precise impact of PEDF on cancerous cell metabolic pathways remains uncertain despite ongoing research. In this light, this study aimed to employ a metabolomics approach for understanding the metabolic reprogramming events in breast cancer across different glycaemic loads and their response to PEDF. Gas chromatography-quadrupole mass spectrometry (GC/Q-MS) analysis revealed metabolic alterations in ER+ human cell line MCF-7 cells treated with PEDF under varying glycaemic conditions. The identification of significantly altered metabolites was accomplished through MetaboAnalyst (v.5.0) and R packages, which enabled both multivariate and univariate analyses. Out of the 48 metabolites identified, 14 were chosen based on their significant alterations in MCF-7 cells under different glycaemic conditions and PEDF treatment (p < 0.05, VIP > 0.8). Dysregulation in pathways associated with amino acid metabolism, intermediates of the TCA cycle, nucleotide metabolism, and lipid metabolism were detected, and they exhibited different responses to PEDF. Our results suggest that PEDF has a diverse influence on the metabolism of MCF-7 cells in both normo- and hyperglycaemic environments, thereby warranting studies using patient samples to correlate our findings with clinical response in the future.PMID:37631354 | DOI:10.3390/pharmaceutics15082140

Pharmaceutics. 2023 Aug 8;15(8):2101. doi: 10.3390/pharmaceutics15082101.ABSTRACTType 2 diabetes is a metabolic disorder that leads to accelerated skeletal muscle atrophy. In this study, we aimed to evaluate the effect of salbutamol (SLB) on skeletal muscle atrophy in high-fat diet (HFD)/streptozotocin (STZ)-induced diabetic rats. Male Sprague Dawley rats were divided into four groups (n = 6): control, SLB, HFD/STZ, and HFD/STZ + SLB (6 mg/kg orally for four weeks). After the last dose of SLB, rats were assessed for muscle grip strength and muscle coordination (wire-hanging, rotarod, footprint, and actophotometer tests). Body composition was analyzed in live rats. After that, animals were sacrificed, and serum and gastrocnemius (GN) muscles were collected. Endpoints include myofibrillar protein content, muscle oxidative stress and antioxidants, serum pro-inflammatory cytokines (interleukin-1β, interleukin-2, and interleukin-6), serum muscle markers (myostatin, creatine kinase, and testosterone), histopathology, and muscle 1H NMR metabolomics. Findings showed that SLB treatment significantly improved muscle strength and muscle coordination, as well as increased lean muscle mass in diabetic rats. Increased pro-inflammatory cytokines and muscle markers (myostatin, creatine kinase) indicate muscle deterioration in diabetic rats, while SLB intervention restored the same. Also, Feret's diameter and cross-sectional area of GN muscle were increased by SLB treatment, indicating the amelioration in diabetic rat muscle. Results of muscle metabolomics exhibit that SLB treatment resulted in the restoration of perturbed metabolites, including histidine-to-tyrosine, phenylalanine-to-tyrosine, and glutamate-to-glutamine ratios and succinate, sarcosine, and 3-hydroxybutyrate (3HB) in diabetic rats. These metabolites showed a pertinent role in muscle inflammation and oxidative stress in diabetic rats. In conclusion, findings showed that salbutamol could be explored as an intervention in diabetic-associated skeletal muscle atrophy.PMID:37631314 | DOI:10.3390/pharmaceutics15082101

Plants (Basel). 2023 Aug 21;12(16):3009. doi: 10.3390/plants12163009.ABSTRACTOur previous study has demonstrated that the nuclear-origin supplementation of the PSII core subunit D1 protein stimulates growth and increases grain yields in transgenic rice plants by enhancing photosynthetic efficiency. In this study, the underlying mechanisms have been explored regarding how the enhanced photosynthetic capacity affects metabolic activities in the transgenic plants of rice harboring the integrated transgene RbcSPTP-OspsbA cDNA, cloned from rice, under control of the AtHsfA2 promoter and N-terminal fused with the plastid-transit peptide sequence (PTP) cloned from the AtRbcS. Here, a comparative metabolomic analysis was performed using LC-MS in flag leaves of the transgenic rice plants during the grain-filling stage. Critically, the dramatic reduction in the quantities of nucleotides and certain free amino acids was detected, suggesting that the increased photosynthetic assimilation and grain yield in the transgenic plants correlates with the reduced contents of free nucleotides and the amino acids such as glutamine and glutamic acid, which are cellular nitrogen sources. These results suggest that enhanced photosynthesis needs consuming more free nucleotides and nitrogen sources to support the increase in biomass and yields, as exhibited in transgenic rice plants. Unexpectedly, dramatic changes were measured in the contents of flavonoids in the flag leaves, suggesting that a tight and coordinated relationship exists between increasing photosynthetic assimilation and flavonoid biosynthesis. Consistent with the enhanced photosynthetic efficiency, the substantial increase was measured in the content of starch, which is the primary product of the Calvin-Benson cycle, in the transgenic rice plants under field growth conditions.PMID:37631220 | DOI:10.3390/plants12163009

Plants (Basel). 2023 Aug 8;12(16):2897. doi: 10.3390/plants12162897.ABSTRACTRhododendron latoucheae Franch. (R. latoucheae) is a valuable woody plant known for its high ornamental value. While purple flowers are a distinct and attractive variant phenotype of R. latoucheae, the underlying mechanism regulating its flower color is still poorly understood. To investigate the molecular regulatory mechanism responsible for the variation in flower color, we selected plants with white-pink and purple petals as the object and conducted analyses of metabolites, key genes, and transcription factors associated with flower color. A combined metabolome-transcriptome analysis was performed, and the expression of key genes was subsequently verified through qRT-PCR experiments. The results of our study demonstrated a significant enrichment of differential metabolites in the flavonoid metabolic pathway. Changes in anthocyanin content followed the same trend as the observed flower color variations, specifically showing significant correlations with the contents of malvidin-3-O-glucoside, dihydromyricetin, gallocatechin, and peonidin-3-O-glucoside. Furthermore, we identified three key structural genes (F3GT1, LAR, ANR) and four transcription factors (bHLH130, bHLH41, bHLH123, MYB4) that are potentially associated with the biosynthesis of flavonoid compounds, thereby influencing the appearance of purple flower color in R. latoucheae.PMID:37631109 | DOI:10.3390/plants12162897

Pharmaceuticals (Basel). 2023 Aug 1;16(8):1093. doi: 10.3390/ph16081093.ABSTRACTNutrigenomics is the study of the impact of diets or nutrients on gene expression and phenotypes using high-throughput technologies such as transcriptomics, proteomics, metabolomics, etc. The bioactive components of diets and nutrients, as an environmental factor, transmit information through altered gene expression and hence the overall function and traits of the organism. Dietary components and nutrients not only serve as a source of energy but also, through their interactions with genes, regulate gut microbiome composition, the production of metabolites, various biological processes, and finally, health and disease. Antimicrobial resistance in pathogenic and probiotic microorganisms has emerged as a major public health concern due to the presence of antimicrobial resistance genes in various food products. Recent evidence suggests a correlation between the regulation of genes and two-component and other signaling systems that drive antibiotic resistance in response to diets and nutrients. Therefore, diets and nutrients may be alternatively used to overcome antibiotic resistance against novel antibiotics. However, little progress has been made in this direction. In this review, we discuss the possible implementations of nutrigenomics in antibiotic resistance against novel antibiotics.PMID:37631008 | DOI:10.3390/ph16081093

Nutrients. 2023 Aug 21;15(16):3665. doi: 10.3390/nu15163665.ABSTRACTThe POUNDS Lost trial is a 2-year clinical trial testing the effects of dietary interventions on weight loss. This study included 811 adults with overweight or obesity who were randomized to one of four diets that contained either 15% or 25% protein and 20% or 40% fat in a 2 × 2 factorial design. By 2 years, participants on average lost from 2.9 to 3.6 kg in body weight in the four intervention arms, while no significant difference was observed across the intervention arms. In POUNDS Lost, we performed a series of ancillary studies to detect intrinsic factors particular to genomic, epigenomic, and metabolomic markers that may modulate changes in weight and other cardiometabolic traits in response to the weight-loss dietary interventions. Genomic variants identified from genome-wide association studies (GWASs) on obesity, type 2 diabetes, glucose and lipid metabolisms, gut microbiome, and dietary intakes have been found to interact with dietary macronutrients (fat, protein, and carbohydrates) in relation to weight loss and changes of body composition and cardiometabolic traits. In addition, we recently investigated epigenomic modifications, particularly blood DNA methylation and circulating microRNAs (miRNAs). We reported DNA methylation levels at NFATC2IP, CPT1A, TXNIP, and LINC00319 were related to weight loss or changes of glucose, lipids, and blood pressure; we also reported thrifty miRNA expression as a significant epigenomic marker related to changes in insulin sensitivity and adiposity. Our studies have also highlighted the importance of temporal changes in novel metabolomic signatures for gut microbiota, bile acids, and amino acids as predictors for achievement of successful weight loss outcomes. Moreover, our studies indicate that biochemical, behavioral, and psychosocial factors such as physical activity, sleep disturbance, and appetite may also modulate metabolic changes during dietary interventions. This review summarized our major findings in the POUNDS Lost trial, which provided preliminary evidence supporting the development of precision diet interventions for obesity management.PMID:37630855 | DOI:10.3390/nu15163665

Nutrients. 2023 Aug 19;15(16):3642. doi: 10.3390/nu15163642.ABSTRACTPu-erh tea is recognized for its weight loss effects, but its potential association with gut microbiota and metabolites remains unclear. This research explored the alterations in gut flora and metabolite composition upon treatment with a co-fermented Pu-erh tea with an aqueous corn silk extract (CPC) in obese mice by employing integrated 16S ribosomal RNA gene sequencing and untargeted metabolomics processes. For 8 weeks, mice were fed control, high-fat, and high-fat diets which included a 46 mg/mL CPC extract. The CPC extract the alleviated high-fat diet (HFD), it stimulated systemic chronic inflammation, and it reduced the body weight, daily energy consumption, and adipose tissue weight of the mice. It also modified the gut microbiota composition and modulated the Lactobacillus, Bifidobacterium, Allobaculum, Turicibacter, and Rikenella genera. Fecal metabolomics analysis revealed that the CPC extract influenced the caffeine, cysteine, methionine, tryptophan, biotin metabolism pathways, primary bile acid, and steroid biosynthesis. This research revealed that the CPC extract could inhibit HFD-stimulated abnormal weight gain and adipose tissue accumulation in mice, and modulate mice gut microbiota composition and multiple metabolic pathways.PMID:37630832 | DOI:10.3390/nu15163642

Nutrients. 2023 Aug 19;15(16):3640. doi: 10.3390/nu15163640.ABSTRACTThe liver is a key organ that is responsible for the metabolism of proteins, fats, and carbohydrates and the absorption and storage of micronutrients. Unfortunately, the prevalence of chronic liver diseases at various stages of advancement in the world population is significant. Due to the physiological function of the liver, its dysfunction can lead to malnutrition and sarcopenia, and the patient's nutritional status is an important prognostic factor. This review discusses key issues related to the diet therapy of patients with chronic liver diseases, as well as those qualified for liver transplantation and in the postoperative period.PMID:37630830 | DOI:10.3390/nu15163640

Nutrients. 2023 Aug 14;15(16):3576. doi: 10.3390/nu15163576.ABSTRACTFood insecurity affects more than 40 million individuals in the United States and is linked to negative health outcomes due, in part, to poor dietary quality. Despite the emergence of metabolomics as a modality to objectively characterize nutritional biomarkers, it is unclear whether food security is associated with any biomarkers of dietary quality. This scoping review aims to summarize studies that examined associations between nutritional biomarkers and food security, as well as studies that investigated metabolomic differences between people with and without food insecurity. PubMed, Embase, Scopus, and AGRICOLA were searched through August 2022 for studies describing food insecurity and metabolic markers in blood, urine, plasma, hair, or nails. The 78 studies included consisted of targeted assays quantifying lipids, dietary nutrients, heavy metals, and environmental xenobiotics as biochemical features associated with food insecurity. Among those biomarkers which were quantified in at least five studies, none showed a consistent association with food insecurity. Although three biomarkers of dietary quality have been assessed between food-insecure versus food-secure populations, no studies have utilized untargeted metabolomics to characterize patterns of small molecules that distinguish between these two populations. Further studies are needed to characterize the dietary quality profiles of individuals with and without food insecurity.PMID:37630766 | DOI:10.3390/nu15163576

Nutrients. 2023 Aug 10;15(16):3530. doi: 10.3390/nu15163530.ABSTRACTAlcoholic liver disease (ALD) can be induced by excessive alcohol consumption, and has a worldwide age-standardized incidence rate (ASIR) of approximately 5.243%. Inonotus hispidus (Bull.) P. Karst. (IH) is a mushroom with pharmacological effects. In ALD mice, the hepatoprotective effects of IH were investigated. IH strongly ameliorated alcohol-induced pathological changes in the liver, including liver structures and its function-related indices. Intestinal microbiota and serum metabolomics analysis showed that IH altered the associated anti-inflammatory microbiota and metabolites. According to results obtained from Western blot, immunohistochemistry (IHC), and enzyme-linked immunosorbent assay (ELISA), IH downregulated the levels of pro-inflammation factors interleukin (IL)-1β, IL-6 and tumor necrosis factor-α (TNF-α), enhanced the expressions of peroxisome proliferator-activated receptor alpha (PPARα) and 15-hydroxprostaglandin dehydrogenase (15-PGDH), and inhibited the phosphorylated activation of Janus kinase (JAK) 1 and signal transducer and activator of transcription (STAT) 3, confirming the hepatoprotection of IH against alcohol damage via anti-inflammation. This study provides the experimental evidence for the hepatoprotective effects of IH in chronic ALD.PMID:37630721 | DOI:10.3390/nu15163530

Microorganisms. 2023 Aug 16;11(8):2092. doi: 10.3390/microorganisms11082092.ABSTRACTYaks live in the harsh environment of the Qinghai-Tibet Plateau, and the cold climate causes lower growth efficiency. The aim of this experiment was to explore the effects of drinking warm water on the growth performance in yak calves and investigate the underlying physiological mechanisms. A total of 24 Datong yak calves were selected and randomly assigned into the cold water group (group C, water temperature around 0-10 °C without any heating; 58.03 ± 3.111 kg) and the warm water group (group W, water constantly heated at 2 °C; 59.62 ± 2.771 kg). After the 60-day experiment, body weight was measured, and rumen fluid and blood serum samples were collected for analysis. The results show that the body weight and average daily gain of yaks that drank warm water were higher compared to those that drank cold water (p < 0.05). The acetic, propionic, isobutyric, valeric, and isovaleric acid concentrations were higher in group W than in group C (p < 0.05). Additionally, warm water changed the ruminal microbes at different levels. At the phylum level, the relative abundance of Tenericutes, Kiritimatiellaeota, and Elusimicrobiota was higher in group C (p < 0.05). At the genus level, three genera were increased by warm water, including Ruminococcoides and Eubacteriales Family XIII. Incertae Sedis, and 12 genera were decreased, including Ruminococcus (p < 0.05). At the species level, unclassified Prevotellaceae and Ruminococcoides bili were increased by warm water compared to cold water (p < 0.05). According to the metabolomics results, metabolites, including valine, isoleucine, PC (15:0/22:2(13Z,16Z)), and LysoPC (18:0/0:0), were increased in the warm water group compared to the cold water group (p < 0.05), and were enriched in glycerophospholipid and amino acid metabolism pathways. This study analyzed the differences in ruminal microbes and metabolomes of yak calves provided with water at different temperatures and revealed the potential mechanism for better performance promoted by warm drinking water.PMID:37630652 | DOI:10.3390/microorganisms11082092

Microorganisms. 2023 Aug 9;11(8):2045. doi: 10.3390/microorganisms11082045.ABSTRACTPlant-microbe interactions are of rising interest in plant sustainability, biomass production, plant biology, and systems biology. These interactions have been a challenge to detect until recent advancements in mass spectrometry imaging. Plants and microbes interact in four main regions within the plant, the rhizosphere, endosphere, phyllosphere, and spermosphere. This mini review covers the challenges within investigations of plant and microbe interactions. We highlight the importance of sample preparation and comparisons among time-of-flight secondary ion mass spectroscopy (ToF-SIMS), matrix-assisted laser desorption/ionization (MALDI), laser desorption ionization (LDI/LDPI), and desorption electrospray ionization (DESI) techniques used for the analysis of these interactions. Using mass spectral imaging (MSI) to study plants and microbes offers advantages in understanding microbe and host interactions at the molecular level with single-cell and community communication information. More research utilizing MSI has emerged in the past several years. We first introduce the principles of major MSI techniques that have been employed in the research of microorganisms. An overview of proper sample preparation methods is offered as a prerequisite for successful MSI analysis. Traditionally, dried or cryogenically prepared, frozen samples have been used; however, they do not provide a true representation of the bacterial biofilms compared to living cell analysis and chemical imaging. New developments such as microfluidic devices that can be used under a vacuum are highly desirable for the application of MSI techniques, such as ToF-SIMS, because they have a subcellular spatial resolution to map and image plant and microbe interactions, including the potential to elucidate metabolic pathways and cell-to-cell interactions. Promising results due to recent MSI advancements in the past five years are selected and highlighted. The latest developments utilizing machine learning are captured as an important outlook for maximal output using MSI to study microorganisms.PMID:37630605 | DOI:10.3390/microorganisms11082045

Microorganisms. 2023 Jul 30;11(8):1949. doi: 10.3390/microorganisms11081949.ABSTRACTHow bacteria respond at the systems level to both genetic and environmental perturbations imposed at the same time is one fundamental yet open question in biology. Bioengineering or synthetic biology provides an ideal system for studying such responses, as engineered strains always have genetic changes as opposed to wildtypes and are grown in conditions which often change during growth for maximal yield of desired products. So, engineered strains were used to address the outstanding question. Two Bacillus subtilis strains (MT1 and MT2) were created previously for the overproduction of N-acetylglucosamine (GlcNAc), which were grown in an environment with a carbon shift from glucose to glucose and xylose in the same culture system. We had four groups: (1) a wildtype (WT) grown with glucose at t1; (2) a WT with glucose and xylose at t2; (3) a mutant (MT1) grown with glucose at t1; and (4) MT1 with glucose and xylose at t2. By measuring transcriptomes and metabolomes, we found that GlcNAc-producing mutants, particularly MT2, had a higher yield of N-acetylglucosamine than WT but displayed a smaller maximum growth rate than the wildtype, despite MT1 reaching higher carrying capacity. Underlying the observed growth, the engineered pathways leading to N-acetylglucosamine had both higher gene expression and associated metabolite concentrations in MT1 than WT at both t1 and t2; in bioenergetics, there was higher energy supply in terms of ATP and GTP, with the energy state metric higher in MT1 than WT at both timepoints. Additionally, most top key precursor metabolites were equally abundant in MT1 and WT at either timepoints. Besides that, one prominent feature was the high consistency between transcriptomics and metabolomics in revealing the response. First, both metabolomes and transcriptomes revealed the same PCA clusters of the four groups. Second, we found that the important functions enriched both by metabolomes and transcriptomes overlapped, such as amino acid metabolism and ABC transport. Strikingly, these functions overlapped those enriched by the genes showing a high (positive or negative) correlation with metabolites. Furthermore, these functions also overlapped the enriched KEGG pathways identified using weighted gene coexpression network analysis. All these findings suggest that the responses to simultaneous genetic and environmental perturbations are well coordinated at the metabolic and transcriptional levels: they rely heavily on bioenergetics, but core metabolism does not differ much, while amino acid metabolism and ABC transport are important. This serves as a design guide for bioengineering, synthetic biology, and systems biology.PMID:37630509 | DOI:10.3390/microorganisms11081949

Microorganisms. 2023 Jul 28;11(8):1930. doi: 10.3390/microorganisms11081930.ABSTRACTTo discover novel antimalarial and anticancer compounds, we carried out a genome analysis, bioassay, metabolite profiling, and molecular docking of marine sediment actinobacteria strain GMY01. The whole-genome sequence analysis revealed that Streptomyces sp. GMY01 (7.9 Mbp) is most similar to Streptomyces sennicomposti strain RCPT1-4T with an average nucleotide identity (ANI) and ANI based on BLAST+ (ANIb) values of 98.09 and 97.33% (>95%). An in vitro bioassay of the GMY01 bioactive on Plasmodium falciparum FCR3, cervical carcinoma of HeLa cell and lung carcinoma of HTB cells exhibited moderate activity (IC50 value of 46.06; 27.31 and 33.75 µg/mL) with low toxicity on Vero cells as a normal cell (IC50 value of 823.3 µg/mL). Metabolite profiling by LC-MS/MS analysis revealed that the active fraction of GMY01 contained carbohydrate-based compounds, C17H29NO14 (471.15880 Da) as a major compound (97.50%) and mannotriose (C18H32O16; 504.16903 Da, 1.96%) as a minor compound. Molecular docking analysis showed that mannotriose has a binding affinity on glutathione reductase (GR) and glutathione-S-transferase (GST) of P. falciparum and on autophagy proteins (mTORC1 and mTORC2) of cancer cells. Streptomyces sennicomposti GMY01 is a potential bacterium producing carbohydrate-based bioactive compounds with anti-plasmodial and anticancer activities and with low toxicity to normal cells.PMID:37630491 | DOI:10.3390/microorganisms11081930

Molecules. 2023 Aug 18;28(16):6115. doi: 10.3390/molecules28166115.ABSTRACTAstragalus membranaceus (Fisch.) Bge. var. mongholicus (Bge.) P. K. Hsiao (MO) and Astragalus membranaceus (Fisch.) Bug. (ME) are two primary sources of the Astragalus herb, also known as "Huangqi" in China, which is widely applied to treat hypertension, glomerulonephritis, ischemic heart disease, and diabetes mellitus. As two different sources of the Astragalus herb, the chemical profiles of MO and ME may be different. Previous studies showed abundant differences in chemical composition between MO and ME. Therefore, the by-products of MO and ME, such as Astragalus membranaceus (Fisch.) Bge. var. mongholicus (Bge.) P. K. Hsiao flower (MOF) and Astragalus membranaceus (Fisch.) Bug. flower (MEF), may have different phytochemical profiles. In this paper, a metabolomics method combined with ultra-high-performance liquid chromatography and electrospray ionization/quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS/MS) was employed to analyze the components of MOF and MEF. Consequently, the results of principal component analysis (PCA) showed that MOF and MEF could be separated clearly. In total, 31 chemical markers differentiating MOF and MEF were successfully identified, including 22 flavonoids, 8 isoflavones and 1 benzopyran. Among them, the contents of 18 components, including Calycosin, Cyanidin-3-O-glucoside, Quercetin, Rutin, Kaempferol, Formononetin, Isomucronulatol and Prim-O-glucosylcimifugin in MEF, were significantly higher than in MOF. In turn, the contents of another 13 components, covering Biochanin A, Tectoridin, Isomucronulatol-7-O-glucoside, Liquiritin, Rhamnetin, etc., were lower in the MEF group than that in the MOF group. It is worth noting that flavonoids, especially flavonoid glycosides, were the primary active chemical ingredients in MOF and MEF. The 18 ingredients in MEF with a higher level carried out diverse activities, like anti-oxidant, anti-inflammatory, anti-bacterial and anti-tumor activities, which led us to speculate that MEF may have greater pharmacological effects and potential development prospects than MOF. The present results displayed that the contents of ingredients in the two different species of plants were radically different, and there was significant uniqueness to the components of MOF and MEF. Our study not only provides helpful chemical information for further quality assessment and active mechanism research of MOF and MEF but also offers scientific support for the resource utilization of MOF and MEF.PMID:37630367 | DOI:10.3390/molecules28166115

Molecules. 2023 Aug 13;28(16):6039. doi: 10.3390/molecules28166039.ABSTRACTThe stems of Dendrobium chrysotoxum (DC) are commonly used as health-promoting foods due to their excellent biological activities. However, the stems of D. thyrsiflorum (DT) are often used to meet the scarcity of DC in production because of their highly similar morphology. However, the related metabolomic and bioactive information on the stems of DC and DT are largely deficient. Here, secondary metabolites of DC and DT stems were identified using an ultra-performance liquid chromatography-electrospray ionization-mass spectrometry, and their health-promoting functions were evaluated using several in vitro arrays. A total of 490 metabolites were identified in two stems, and 274 were significantly different. We screened out 10 key metabolites to discriminate the two species, and 36 metabolites were determined as health-promoting constituents. In summary, DT stems with higher extract yield, higher total phenolics and flavonoids, and stronger in vitro antioxidant activities demonstrated considerable potential in food and health fields.PMID:37630293 | DOI:10.3390/molecules28166039