PubMed

Front Pharmacol. 2023 May 22;14:1197847. doi: 10.3389/fphar.2023.1197847. eCollection 2023.ABSTRACTBackground: Farnesoid X receptor (FXR) is a key metabolic target of bile acids (BAs) and is also a target for drugs against several liver diseases. However, the contribution of FXR in the pathogenesis of cholestasis is still not fully understood. The purpose of this study is to provide a comprehensive insight into the metabolic properties of FXR-involved cholestasis in mice. Materials and methods: In this study, an alpha-naphthylisothiocyanate (ANIT)-induced cholestasis mouse model and FXR-/- mice were established to investigate the effect of FXR on cholestasis. The effect of FXR on liver and ileal pathology was evaluated. Simultaneously, Untargeted metabolomics combined with 16s rRNA gene sequencing analysis was applied to reveal the involvement of FXR in the pathogenesis of cholestasis. Results: The results showed that ANIT (75 mg/kg) induced marked cholestasis in WT and FXR -/- mice. It is noteworthy that FXR-/- mice developed spontaneous cholestasis. Compared with WT mice, significant liver and ileal tissue damage were found. In addition, 16s rRNA gene sequencing analysis revealed gut microbiota dysbiosis in FXR-/- mice and ANIT-induced cholestasis mice. Differential biomarkers associated with the pathogenesis of cholestasis caused by FXR knockout were screened using untargeted metabolomics. Notably, Lactobacillus_ johnsonii_FI9785 has a high correlation with the differential biomarkers associated with the pathogenesis and progression of cholestasis caused by FXR knockout. Conclusion: Our results implied that the disorder of the intestinal flora caused by FXR knockout can also interfere with the metabolism. This study provides novel insights into the FXR-related mechanisms of cholestasis.PMID:37284301 | PMC:PMC10239812 | DOI:10.3389/fphar.2023.1197847

Plant Environ Interact. 2021 Nov 22;2(6):277-289. doi: 10.1002/pei3.10066. eCollection 2021 Dec.ABSTRACTTall fescue (Festuca arundinacea) is an important cool-season perennial forage grass that forms mutualistic symbioses with fungal endophytes. Physiological, biochemical and transcriptional comparisons were made between two tall fescue genotypes with contrasting drought tolerance (tolerant, T400, and sensitive, S279), either with or without endophyte (Epichloë coenophiala). Drought stress was applied by withholding watering until plants reached mild, moderate and severe stresses. Physiological characterization showed that T400 had narrower, thicker leaves, and lower leaf conductance under well-watered conditions, compared to S279. After severe drought and recovery, endophytic T400 had greater shoot and root biomass than other plant types. Under drought, leaf osmotic pressure increased much more in T400 than S279, consistent with accumulation of metabolites/osmolytes, especially proline. Gene Ontology enrichment analysis indicated that T400 had more active organic acid metabolism than S279 under drought, and implicated the role of endophyte in stimulating protein metabolism in both genotypes. Overall T400 and S279 responded to endophyte differently in aspects of physiology, gene transcription and metabolites, indicating plant genotype-specific reactions to endophyte infection.PMID:37284176 | PMC:PMC10168078 | DOI:10.1002/pei3.10066

Front Immunol. 2023 May 22;14:1177580. doi: 10.3389/fimmu.2023.1177580. eCollection 2023.ABSTRACTBACKGROUND: Recent observational studies and meta-analyses have shown that vitamin C reduces cancer incidence and mortality, but the underlying mechanisms remain unclear. We conducted a comprehensive pan-cancer analysis and biological validation in clinical samples and animal tumor xenografts to understand its prognostic value and association with immune characteristics in various cancers.METHODS: We used the Cancer Genome Atlas gene expression data involving 5769 patients and 20 cancer types. Vitamin C index (VCI) was calculated using the expression of 11 genes known to genetically predict vitamin C levels, which were classified into high and low subgroups. The correlation between VCI and patient overall survival (OS), tumor mutational burden (TMB), microsatellite instability (MSI), and immune microenvironment was evaluated, using Kaplan-Meier analysis method and ESTIMATE (https://bioinformatics.mdanderson.org/estimate/). Clinical samples of breast cancer and normal tissues were used to validate the expression of VCI-related genes, and animal experiments were conducted to test the impact of vitamin C on colon cancer growth and immune cell infiltration.RESULTS: Significant changes in expression of VCI-predicted genes were observed in multiple cancer types, especially in breast cancer. There was a correlation of VCI with prognosis in all samples (adjusted hazard ratio [AHR] = 0.87; 95% confidence interval [CI] = 0.78-0.98; P = 0.02). The specific cancer types that exhibited significant correlation between VCI and OS included breast cancer (AHR = 0.14; 95% CI = 0.05-0.40; P < 0.01), head and neck squamous cell carcinoma (AHR = 0.20; 95% CI = 0.07-0.59; P < 0.01), kidney clear cell carcinoma (AHR = 0.66; 95% CI = 0.48-0.92; P = 0.01), and rectum adenocarcinoma (AHR = 0.01; 95% CI = 0.001-0.38; P = 0.02). Interestingly, VCI was correlated with altered immunotypes and associated with TMB and MSI negatively in colon and rectal adenocarcinoma (P < 0.001) but positively in lung squamous cell carcinoma (P < 0.05). In vivo study using mice bearing colon cancer xenografts demonstrated that vitamin C could inhibit tumor growth with significant impact on immune cell infiltration.CONCLUSION: VCI is significantly correlated with OS and immunotypes in multiple cancers, and vitamin C might have therapeutic potential in colon cancer.PMID:37283769 | PMC:PMC10239825 | DOI:10.3389/fimmu.2023.1177580

Neurosurg Focus. 2023 Jun;54(6):E4. doi: 10.3171/2023.3.FOCUS2379.ABSTRACTOBJECTIVE: Gliomas exhibit high intratumor and interpatient heterogeneity. Recently, it has been shown that the microenvironment and phenotype differ significantly between the glioma core (inner) and edge (infiltrating) regions. This proof-of-concept study differentiates metabolic signatures associated with these regions, with the potential for prognosis and targeted therapy that could improve surgical outcomes.METHODS: Paired glioma core and infiltrating edge samples were obtained from 27 patients after craniotomy. Liquid-liquid metabolite extraction was performed on the samples and metabolomic data were obtained via 2D liquid chromatography-mass spectrometry/mass spectrometry. To gauge the potential of metabolomics to identify clinically relevant predictors of survival from tumor core versus edge tissues, a boosted generalized linear machine learning model was used to predict metabolomic profiles associated with O6-methylguanine DNA methyltransferase (MGMT) promoter methylation.RESULTS: A panel of 66 (of 168) metabolites was found to significantly differ between glioma core and edge regions (p ≤ 0.05). Top metabolites with significantly different relative abundances included DL-alanine, creatine, cystathionine, nicotinamide, and D-pantothenic acid. Significant metabolic pathways identified by quantitative enrichment analysis included glycerophospholipid metabolism; butanoate metabolism; cysteine and methionine metabolism; glycine, serine, alanine, and threonine metabolism; purine metabolism; nicotinate and nicotinamide metabolism; and pantothenate and coenzyme A biosynthesis. The machine learning model using 4 key metabolites each within core and edge tissue specimens predicted MGMT promoter methylation status, with AUROCEdge = 0.960 and AUROCCore = 0.941. Top metabolites associated with MGMT status in the core samples included hydroxyhexanoycarnitine, spermine, succinic anhydride, and pantothenic acid, and in the edge samples metabolites included 5-cytidine monophosphate, pantothenic acid, itaconic acid, and uridine.CONCLUSIONS: Key metabolic differences are identified between core and edge tissue in glioma and, furthermore, demonstrate the potential for machine learning to provide insight into potential prognostic and therapeutic targets.PMID:37283447 | DOI:10.3171/2023.3.FOCUS2379

Alzheimers Dement. 2023 Jun 7. doi: 10.1002/alz.13076. Online ahead of print.ABSTRACTMicrobial infections of the brain can lead to dementia, and for many decades microbial infections have been implicated in Alzheimer's disease (AD) pathology. However, a causal role for infection in AD remains contentious, and the lack of standardized detection methodologies has led to inconsistent detection/identification of microbes in AD brains. There is a need for a consensus methodology; the Alzheimer's Pathobiome Initiative aims to perform comparative molecular analyses of microbes in post mortem brains versus cerebrospinal fluid, blood, olfactory neuroepithelium, oral/nasopharyngeal tissue, bronchoalveolar, urinary, and gut/stool samples. Diverse extraction methodologies, polymerase chain reaction and sequencing techniques, and bioinformatic tools will be evaluated, in addition to direct microbial culture and metabolomic techniques. The goal is to provide a roadmap for detecting infectious agents in patients with mild cognitive impairment or AD. Positive findings would then prompt tailoring of antimicrobial treatments that might attenuate or remit mounting clinical deficits in a subset of patients.PMID:37283269 | DOI:10.1002/alz.13076

Crit Rev Food Sci Nutr. 2023 Jun 7:1-25. doi: 10.1080/10408398.2023.2217451. Online ahead of print.ABSTRACTExposure to mycotoxins through the dietary route occurs on a daily basis while their deleterious effects are exhibited in the form of ailments, such as inflammation, cancer, and hormonal imbalance. The negative impact of mycotoxins can be attributed to their interaction with various biomolecules and their interference in metabolic pathways. The activity of biomolecules, such as enzymes/receptors, which engage the intricate mechanism of endogenous metabolism, is more susceptible to disruption by metabolites of high toxicity, which gives rise to adverse health effects. Metabolomics is a useful analytical approach that can assist in unraveling such information. It can simultaneously and comprehensively analyze a large number of endogenous and exogenous molecules present in biofluids and can, thus, reveal biologically relevant perturbations following mycotoxin exposure. Information provided by genome, transcriptome and proteome analyses, which have been utilized for the elucidation of biological mechanisms so far, are further complemented by the addition of metabolomics in the available bioanalytics toolbox. Metabolomics can offer insight into complex biological processes and their respective response to several (co-)exposures. This review focuses on the most extensively studied mycotoxins reported in literature and their respective impact on the metabolome upon exposure.PMID:37283072 | DOI:10.1080/10408398.2023.2217451

Zhongguo Zhong Yao Za Zhi. 2023 May;48(10):2792-2802. doi: 10.19540/j.cnki.cjcmm.20230111.401.ABSTRACTGenkwa Fols, Kansui Radix, and Euphorbiae Pekinensis Radix in Shizao Decoction(SZD) are toxic to intestinal tract. Jujubae Fructus in this prescription can alleviate the toxicity, but the mechanism is still unclear. Therefore, this study aims to explore the mechanism. To be specific, 40 normal Sprague-Dawley(SD) rats were classified into the normal group, high-dose and low-dose SZD groups, and high-dose and low-dose SZD without Jujubae Fructus(SZD-JF) groups. The SZD groups were given(ig) SZD, while SZD-JF groups received the decoction without Jujubae Fructus. The variation of body weight and spleen index were recorded. The patho-logical changes of intestinal tissue were observed based on hematoxylin and eosin(HE) staining. The content of malondialdehyde(MDA) and glutathione(GSH) and activity of superoxide dismutase(SOD) in intestinal tissue were measured to evaluate the intestinal injury. Fresh feces of rats were collected to detect intestinal flora structure by 16S ribosomal RNA gene(16S rDNA) sequencing technology. The content of fecal short chain fatty acids and fecal metabolites was determined by gas chromatography-mass spectrometer(GC-MS) and liquid chromatography-mass spectrometer ultra-fast liquid chromatography-quadrupole-time-of-flight mass spectrometer(UFLC-Q-TOF-MS), separately. Spearman's correlation analysis was employed to analyze the differential bacteria genera and differential metabolites. RESULTS:: showed that high-dose and low-dose SZD-JF groups had high content of MDA in intestinal tissue, low GSH content and SOD activity, short intestinal villi(P&lt;0.05), low diversity and abundance of intestinal flora, variation in the intestinal flora structure, and low content of short chain fatty acids(P&lt;0.05) compared with the normal group. Compared with high-dose and low-dose SZD-JF groups, high-dose and low-dose SZD groups displayed low content of MDA in intestinal tissue, high GSH content and SOD activity, recovery of the length of intestinal villi, increased abundance and diversity of intestinal flora, alleviation of dysbacteria, and recovery of the content of short chain fatty acids(P&lt;0.05). According to the variation of intestinal flora and fecal metabolites after the addition of Jujubae Fructus, 6 differential bacterial genera(Lactobacillus, Butyricimonas, Clostridia＿UCG-014, Prevotella, Escherichia-Shigella, Alistipes),4 differential short chain fatty acids(such as acetic acid, propionic acid, butyric acid, valeric acid) and 18 differential metabolites(such as urolithin A, lithocholic acid, and creatinine) were screened out. Beneficial bacteria such as Lactobacillus were in positive correlation with butyric acid and urolithin A(P&lt;0.05). The pathogenic bacteria such as Escherichia-Shigella were in negative correlation with propionic acid and urolithin A(P&lt;0.05). In summary, SZD-JF caused obvious intestinal injury to normal rats, which could lead to intestinal flora disorder. The addition of Jujubae Fructus can alleviate the disorder and relieve the injury by regulating intestinal flora and the metabolites. This study discusses the effect of Jujubae Fructus in relieving the intestinal injury caused by SZD and the mechanism from the perspective of intestinal flora-host metabolism, which is expected to serve as a reference for clinical application of this prescription.PMID:37282939 | DOI:10.19540/j.cnki.cjcmm.20230111.401

Zhongguo Zhong Yao Za Zhi. 2023 Apr;48(8):2193-2202. doi: 10.19540/j.cnki.cjcmm.20221213.401.ABSTRACTThis study aims to explore the effect of tryptanthrin on potential metabolic biomarkers in the serum of mice with ulcerative colitis(UC) induced by dextran sulfate sodium(DSS) based on liquid chromatography-mass spectrometry(LC-MS) and predict the related metabolic pathways. C57BL/6 mice were randomly assigned into a tryptanthrin group, a sulfasalazine group, a control group, and a model group. The mouse model of UC was established by free drinking of 3% DSS solution for 11 days, and corresponding drugs were adminsitrated at the same time. The signs of mice were observed and the disease activity index(DAI) score was recorded from the first day. Colon tissue samples were collected after the experiment and observed by hematoxylin-eosin(HE) staining. The levels of interleukin-4(IL-4), interleukin-10(IL-10), tumor necrosis factor-α(TNF-α), interleukin-6(IL-6), and interleukin-8(IL-8) in the serum were measured by enzyme linked immunosorbent assay(ELISA). The serum samples were collected from 6 mice in each group for widely targeted metabolomics. The metabolic pathways were enriched by MetaboAnalyst 5.0. The results showed that compared with the model group, tryptanthrin treatment decreased the DAI score(P&lt;0.05), alleviated the injury of the colon tissue and the infiltration of inflammatory cells, lowered the levels of proinflammatory cytokines, and elevated the levels of anti-inflammatory cytokines in the serum. The metabolomic analysis revealed 28 differential metabolites which were involved in 3 metabolic pathways including purine metabolism, arachidonic acid metabolism, and tryptophan metabolism. Tryptanthrin may restore the metabolism of the mice with UC induced by DSS to the normal level by regulating the purine metabolism, arachidonic acid metabolism, and tryptophan metabolism. This study employed metabolomics to analyze the mechanism of tryptanthrin in the treatment of UC, providing an experimental basis for the utilization and development of tryptanthrin.PMID:37282907 | DOI:10.19540/j.cnki.cjcmm.20221213.401

Zhongguo Zhong Yao Za Zhi. 2023 May;48(9):2490-2499. doi: 10.19540/j.cnki.cjcmm.20230130.401.ABSTRACTThe effect of Tujia medicine Berberidis Radix on endogenous metabolites in the serum and feces of mice with ulcerative colitis(UC) induced by dextran sulfate sodium(DSS) was analyzed by metabolomics technology to explore the metabolic pathway and underlying mechanism of Berberidis Radix in the intervention of UC. The UC model was induced in mice by DSS. Body weight, disease activity index(DAI), and colon length were recorded. The levels of tumor necrosis factor-α(TNF-α) and interleukin-10(IL-10) in colon tissues were determined by ELISA. The levels of endogenous metabolites in the serum and feces were detected by ultra-high-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry(UPLC-Q-TOF-MS). Principal component analysis(PCA) and orthogonal partial least squares-discriminant analysis(OPLS-DA) were employed to characterize and screen differential metabolites. The potential metabolic pathways were analyzed by MetaboAnalyst 5.0. The results showed that Berberidis Radix could significantly improve the symptoms of UC mice and increase the level of the anti-inflammatory factor IL-10. A total of 56 and 43 differential metabolites were identified in the serum and feces, respectively, belonging to lipids, amino acids, fatty acids, etc. After the intervention by Berberidis Radix, the metabolic disorder gradually recovered. The involved metabolic pathways included biosynthesis of phenylalanine, tyrosine, and tryptophan, linoleic acid metabolism, phenylalanine metabolism, and glycerophospholipid metabolism. Berberidis Radix can alleviate the symptoms of mice with DSS-induced UC, and the mechanism may be closely related to the re-gulation of lipid metabolism, amino acid metabolism, and energy metabolism.PMID:37282878 | DOI:10.19540/j.cnki.cjcmm.20230130.401

Zhongguo Zhong Yao Za Zhi. 2023 May;48(9):2325-2333. doi: 10.19540/j.cnki.cjcmm.20221122.402.ABSTRACTThe study aimed to investigate the effect of anemoside B4(B4) on fatty acid metabolism in mice with colitis-associated cancer(CAC). The CAC model was established by azoxymethane(AOM)/dextran sodium sulfate(DSS) in mice. Mice were randomly divided into a normal group, a model group, and low-, medium-, and high-dose anemoside B4 groups. After the experiment, the length of the mouse colon and the size of the tumor were measured, and the pathological alterations in the mouse colon were observed using hematoxylin-eosin(HE) staining. The slices of the colon tumor were obtained for spatial metabolome analysis to analyze the distribution of fatty acid metabolism-related substances in the tumor. The mRNA levels of SREBP-1, FAS, ACCα, SCD-1, PPARα, ACOX, UCP-2, and CPT-1 were determined by real-time quantitative PCR(RT-qPCR). The results revealed that the model group showed decreased body weight(P&lt;0.05) and colon length(P&lt;0.001), increased number of tumors, and increased pathological score(P&lt;0.01). Spatial metabolome analysis revealed that the content of fatty acids and their derivatives, carnitine, and phospholipid in the colon tumor was increased. RT-qPCR results indicated that fatty acid de novo synthesis and β-oxidation-related genes, such as SREBP-1, FASN, ACCα, SCD-1, ACOX, UCP-2, and CPT-1 mRNA expression levels increased considerably(P&lt;0.05, P&lt;0.001). After anemoside B4 administration, the colon length increased(P&lt;0.01), and the number of tumors decreased in the high-dose anemoside B4 group(P&lt;0.05). Additionally, spatial metabolome analysis showed that anemoside B4 could decrease the content of fatty acids and their derivatives, carnitine, and phospholipids in colon tumors. Meanwhile, anemoside B4 could also down-regulate the expression of FASN, ACCα, SCD-1, PPARα, ACOX, UCP-2, and CPT-1 in the colon(P&lt;0.05, P&lt;0.01, P&lt;0.001). The findings of this study show that anemoside B4 may inhibit CAC via regulating fatty acid metabolism reprogramming.PMID:37282861 | DOI:10.19540/j.cnki.cjcmm.20221122.402

Clin Transl Med. 2023 Jun;13(6):e1302. doi: 10.1002/ctm2.1302.NO ABSTRACTPMID:37282796 | DOI:10.1002/ctm2.1302

Plant Cell. 2023 Jun 7:koad164. doi: 10.1093/plcell/koad164. Online ahead of print.ABSTRACTLeaf and floral tissue degeneration are common features in plants. In cereal crops such as barley (Hordeum vulgare L.), pre-anthesis tip degeneration (PTD) starts with growth arrest of the inflorescence meristem dome, which is followed basipetally by the degeneration of floral primordia and the central axis. Due to its quantitative nature and environmental sensitivity, inflorescence PTD constitutes a complex, multilayered trait affecting final grain number. This trait appears to be highly predictable and heritable under standardized growth conditions, consistent with a developmentally programmed mechanism. To elucidate the molecular underpinnings of inflorescence PTD, we combined metabolomic, transcriptomic, and genetic approaches to show that barley inflorescence PTD is accompanied by sugar depletion, amino acid degradation, and abscisic acid responses involving transcriptional regulators of senescence, defense, and light signaling. Based on transcriptome analyses, we identified GRASSY TILLERS1 (HvGT1), encoding an HD-ZIP transcription factor, as an important modulator of inflorescence PTD. A gene-edited knockout mutant of HvGT1 delayed PTD and increased differentiated apical spikelets and final spikelet number, suggesting a possible strategy to increase grain number in cereals. We propose a molecular framework that leads to barley PTD, the manipulation of which may increase yield potential in barley and other related cereals.PMID:37282730 | DOI:10.1093/plcell/koad164

Neural Regen Res. 2023 Nov;18(11):2443-2448. doi: 10.4103/1673-5374.371375.ABSTRACTMaternal one-carbon metabolism plays an important role in early life programming. There is a well-established connection between the fetal environment and the health status of the offspring. However, there is a knowledge gap on how maternal nutrition impacts stroke outcomes in offspring. The aim of our study was to investigate the role of maternal dietary deficiencies in folic acid or choline on stroke outcomes in 3-month-old offspring. Adult female mice were fed a folic acid-deficient diet, choline-deficient diet, or control diet 4 weeks before pregnancy. They were continued on diets during pregnancy and lactation. Male and female offspring were weaned onto a control diet and at 2 months of age were subjected to ischemic stroke within the sensorimotor cortex via photothrombotic damage. Mothers maintained on either a folic acid-deficient diet or choline-deficient diet had reduced levels of S-adenosylmethionine in the liver and S-adenosylhomocysteine in the plasma. After ischemic stroke, motor function was impaired in 3-month-old offspring from mothers receiving either a folic acid-deficient diet or choline-deficient diet compared to the animals receiving a control diet. In brain tissue, there was no difference in ischemic damage volume. When protein levels were assessed in ischemic brain tissue, there were lower levels of active caspase-3 and hypoxia-inducible factor 1α in males compared to females and betaine levels were reduced in offspring from the mothers receiving a choline-deficient diet. Our results demonstrate that a deficient maternal diet at critical time points in neurodevelopment results in worse stroke outcomes. This study emphasizes the importance of maternal diet and the impact it can have on offspring health.PMID:37282475 | DOI:10.4103/1673-5374.371375

Neuro Oncol. 2023 Jun 5:noad103. doi: 10.1093/neuonc/noad103. Online ahead of print.ABSTRACTBACKGROUND: Resistance to existing therapies is a significant challenge in improving outcomes for glioblastoma (GBM) patients. Metabolic plasticity has emerged as an important contributor to therapy resistance, including radiation therapy (RT). Here, we investigated how GBM cells reprogram their glucose metabolism in response to RT to promote radiation resistance.METHODS: Effects of radiation on glucose metabolism of human GBM specimens were examined in vitro and in vivo with the use of metabolic and enzymatic assays, targeted metabolomics, and FDG-PET. Radiosensitization potential of interfering with PKM2 activity was tested via gliomasphere formation assays and in vivo human GBM models.RESULTS: Here, we show that RT induces increased glucose utilization by GBM cells, and this is accompanied with translocation of GLUT3 transporters to the cell membrane. Irradiated GBM cells route glucose carbons through the pentose phosphate pathway (PPP) to harness the antioxidant power of the PPP and support survival after radiation. This response is regulated in part by the M2 isoform of pyruvate kinase (PKM2). Activators of PKM2 can antagonize the radiation-induced rewiring of glucose metabolism and radiosensitize GBM cells in vitro and in vivo.CONCLUSIONS: These findings open the possibility that interventions designed to target cancer-specific regulators of metabolic plasticity, such as PKM2, rather than specific metabolic pathways, have the potential to improve the radiotherapeutic outcomes in GBM patients.PMID:37279645 | DOI:10.1093/neuonc/noad103

Genes Nutr. 2023 Jun 6;18(1):10. doi: 10.1186/s12263-023-00729-y.ABSTRACTBACKGROUND: Glycogen storage disease type Ia (GSDIa) is an inborn metabolic disorder caused by the deficiency of glucose-6-phospatase-α (G6Pase-α) leading to mitochondrial dysfunction. It remains unclear whether mitochondrial dysfunction is present in patients' peripheral blood mononuclear cells (PBMC) and whether dietary treatment can play a role. The aim of this study was to investigate mitochondrial function in PBMC of GSDIa patients.METHODS: Ten GSDIa patients and 10 age-, sex- and fasting-time matched controls were enrolled. Expression of genes involved in mitochondrial function and activity of key fatty acid oxidation (FAO) and Krebs cycle proteins were assessed in PBMC. Targeted metabolomics and assessment of metabolic control markers were also performed.RESULTS: Adult GSDIa patients showed increased CPT1A, SDHB, TFAM, mTOR expression (p < 0.05) and increased VLCAD, CPT2 and citrate synthase activity in PBMC (p < 0.05). VLCAD activity directly correlated with WC (p < 0.01), BMI (p < 0.05), serum malonycarnitine levels (p < 0.05). CPT2 activity directly correlated with BMI (p < 0.05).CONCLUSION: Mitochondrial reprogramming is detectable in PBMC of GSDIa patients. This feature may develop as an adaptation to the liver enzyme defect and may be triggered by dietary (over)treatment in the frame of G6Pase-α deficiency. PBMC can represent an adequate mean to assess (diet-induced) metabolic disturbances in GSDIa.PMID:37280548 | DOI:10.1186/s12263-023-00729-y

Nat Rev Mol Cell Biol. 2023 Jun 6. doi: 10.1038/s41580-023-00615-w. Online ahead of print.ABSTRACTSingle-cell multi-omics technologies and methods characterize cell states and activities by simultaneously integrating various single-modality omics methods that profile the transcriptome, genome, epigenome, epitranscriptome, proteome, metabolome and other (emerging) omics. Collectively, these methods are revolutionizing molecular cell biology research. In this comprehensive Review, we discuss established multi-omics technologies as well as cutting-edge and state-of-the-art methods in the field. We discuss how multi-omics technologies have been adapted and improved over the past decade using a framework characterized by optimization of throughput and resolution, modality integration, uniqueness and accuracy, and we also discuss multi-omics limitations. We highlight the impact that single-cell multi-omics technologies have had in cell lineage tracing, tissue-specific and cell-specific atlas production, tumour immunology and cancer genetics, and in mapping of cellular spatial information in fundamental and translational research. Finally, we discuss bioinformatics tools that have been developed to link different omics modalities and elucidate functionality through the use of better mathematical modelling and computational methods.PMID:37280296 | DOI:10.1038/s41580-023-00615-w

ISME Commun. 2023 Jun 7;3(1):57. doi: 10.1038/s43705-023-00263-3.ABSTRACTCyanobacteria are oxygenic photosynthetic bacteria that perform a substantial part of the global primary production. Some species are responsible for catastrophic environmental events, called blooms, which have become increasingly common in lakes and freshwater bodies as a consequence of global changes. Genotypic diversity is considered essential for marine cyanobacterial population, allowing it to cope with spatio-temporal environmental variations and to adapt to specific micro-niches in the ecosystem. This aspect is underestimated in the study of bloom development, however, and given little notice in studies of the ecology of harmful cyanobacteria. Here we compared the genomes of four strains of Aphanizomenon gracile, a species of filamentous toxinogenic cyanobacteria (Nostocales) found worldwide in fresh and brackish water. Millimeter-sized fascicles were isolated from a single water sample and have been maintained in culture since 2010. A comparative study revealed extensive heterogeneity in gene contents, despite similar genome size and high similarity indices. These variations were mainly associated with mobile genetic elements and biosynthetic gene clusters. For some of the latter, metabolomic analysis confirmed the production of related secondary metabolites, such as cyanotoxins and carotenoids, which are thought to play a fundamental role in the cyanobacterial fitness. Altogether, these results demonstrated that an A. gracile bloom could be a highly diverse population at low spatial scale and raised questions about potential exchanges of essential metabolites between individuals.PMID:37280295 | DOI:10.1038/s43705-023-00263-3

Sci Rep. 2023 Jun 6;13(1):9177. doi: 10.1038/s41598-023-36475-9.ABSTRACTCarbapenem-resistant Acinetobacter baumannii (CRAb) is an urgent public health threat, according to the CDC. This pathogen has few treatment options and causes severe nosocomial infections with > 50% fatality rate. Although previous studies have examined the proteome of CRAb, there have been no focused analyses of dynamic changes to β-lactamase expression that may occur due to drug exposure. Here, we present our initial proteomic study of variation in β-lactamase expression that occurs in CRAb with different β-lactam antibiotics. Briefly, drug resistance to Ab (ATCC 19606) was induced by the administration of various classes of β-lactam antibiotics, and the cell-free supernatant was isolated, concentrated, separated by SDS-PAGE, digested with trypsin, and identified by label-free LC-MS-based quantitative proteomics. Thirteen proteins were identified and evaluated using a 1789 sequence database of Ab β-lactamases from UniProt, the majority of which were Class C β-lactamases (≥ 80%). Importantly, different antibiotics, even those of the same class (e.g. penicillin and amoxicillin), induced non-equivalent responses comprising various isoforms of Class C and D serine-β-lactamases, resulting in unique resistomes. These results open the door to a new approach of analyzing and studying the problem of multi-drug resistance in bacteria that rely strongly on β-lactamase expression.PMID:37280269 | DOI:10.1038/s41598-023-36475-9

Adv Mater. 2023 Jun 6:e2301664. doi: 10.1002/adma.202301664. Online ahead of print.ABSTRACTDue to the emergence of drug resistance in bacteria and biofilm protection, achieving a satisfactory therapeutic effect for bacteria-infected open wounds with conventional measures is problematic. Here, we construct a photothermal cascade nano-reactor (CPNC@GOx-Fe2+ ) through a supramolecular strategy through hydrogen bonding and coordination interactions between chitosan-modified palladium nano-cube (CPNC), glucose oxidase (GOx), and ferrous iron (Fe2+ ). CPNC@GOx-Fe2+ exhibits excellent photothermal effect and powers the GOx-assisted cascade reaction to generate hydroxyl radicals, enabling photothermal and chemodynamic combination therapy against bacteria and biofilms. Further proteomics, metabolomics, and all-atom simulation results indicate that the damage of hydroxyl radical to the function and structure of the cell membrane and the thermal effect enhances the fluidity and inhomogeneity of the bacterial cell membrane, resulting in the synergistic anti-bacterial effect. In the biofilm-associated tooth extraction wound model, hydroxyl radical generated from the cascade reaction process could initiate the radical polymerization process to form a hydrogel in situ for wound protection. In vivo experiments confirm synergistic anti-bacterial and wound protection can accelerate the healing of infected tooth-extraction wounds without affecting the oral commensal microbiota. This study provides a way to propose a multifunctional supramolecular system for the treatment of open wound infection. This article is protected by copyright. All rights reserved.PMID:37279172 | DOI:10.1002/adma.202301664

IEEE/ACM Trans Comput Biol Bioinform. 2023 Jun 6;PP. doi: 10.1109/TCBB.2023.3283221. Online ahead of print.ABSTRACTAntimicrobial resistance is a global public health concern. The lack of innovations in antibiotic development has led to renewed interest in antibiotic adjuvants. However, there is no database to collect antibiotic adjuvants. Herein, we build a comprehensive database named Antibiotic Adjuvant DataBase (AADB) by manually collecting relevant literature. Specifically, AADB includes 3,035 combinations of antibiotics with adjuvants, covering 83 antibiotics, 226 adjuvants, and 325 bacterial strains. AADB provides user-friendly interfaces for searching and downloading. Users can easily obtain these datasets for further analysis. In addition, we also collected related datasets (e.g., chemogenomic and metabolomic data) and proposed a computational strategy to dissect these datasets. As a test case, we identified 10 candidates for minocycline, and 6 of 10 candidates are the known adjuvants that synergize with minocycline to inhibit the growth of E. coli BW25113. We hope that AADB can help users to identify effective antibiotic adjuvants. AADB is freely available at http://www.acdb.plus/AADB.PMID:37279138 | DOI:10.1109/TCBB.2023.3283221