PubMed

Front Plant Sci. 2022 Sep 15;13:919151. doi: 10.3389/fpls.2022.919151. eCollection 2022.ABSTRACTChrysanthemum indicum var. aromaticum (CIA) is an endemic plant that occurs only in the high mountain areas of the Shennongjia Forest District in China. The whole plant, in particular the flowers of CIA, have intense fragrance, making it a novel resource plant for agricultural, medicinal, and industrial applications. However, the volatile metabolite emissions in relation to CIA flower development and the molecular mechanisms underlying the generation of floral scent remain poorly understood. Here, integrative metabolome and transcriptome analyses were performed to investigate floral scent-related volatile compounds and genes in CIA flowers at three different developmental stages. A total of 370 volatile metabolites, mainly terpenoids and esters, were identified, of which 89 key differential metabolites exhibited variable emitting profiles during flower development. Transcriptome analysis further identified 8,945 differentially expressed genes (DEGs) between these samples derived from different flower developmental stages and KEGG enrichment analyses showed that 45, 93, and 101 candidate DEGs associated with the biosynthesis of phenylpropanoids, esters, and terpenes, respectively. Interestingly, significant DEGs involved into the volatile terpenes are only present in the MEP and its downstream pathways, including those genes encoding ISPE, ISPG, FPPS, GPPS, GERD, ND and TPS14 enzymes. Further analysis showed that 20 transcription factors from MYB, bHLH, AP2/EFR, and WRKY families were potentially key regulators affecting the expressions of floral scent-related genes during the CIA flower development. These findings provide insights into the molecular basis of plant floral scent metabolite biosynthesis and serve as an important data resources for molecular breeding and utilization of CIA plants in the future.PMID:36733600 | PMC:PMC9889088 | DOI:10.3389/fpls.2022.919151

Front Mol Biosci. 2023 Jan 17;9:1070394. doi: 10.3389/fmolb.2022.1070394. eCollection 2022.ABSTRACTKODAMA is a valuable tool in metabolomics research to perform exploratory analysis. The advanced analytical technologies commonly used for metabolic phenotyping, mass spectrometry, and nuclear magnetic resonance spectroscopy push out a bunch of high-dimensional data. These complex datasets necessitate tailored statistical analysis able to highlight potentially interesting patterns from a noisy background. Hence, the visualization of metabolomics data for exploratory analysis revolves around dimensionality reduction. KODAMA excels at revealing local structures in high-dimensional data, such as metabolomics data. KODAMA has a high capacity to detect different underlying relationships in experimental datasets and correlate extracted features with accompanying metadata. Here, we describe the main application of KODAMA exploratory analysis in metabolomics research.PMID:36733493 | PMC:PMC9887019 | DOI:10.3389/fmolb.2022.1070394

Front Neurol. 2023 Jan 17;13:1026904. doi: 10.3389/fneur.2022.1026904. eCollection 2022.ABSTRACTOBJECTIVE: Through transcriptomic and metabolomic analyses, this study examined the role of high-fiber diet in obesity complicated by diabetes and neurodegenerative symptoms.METHOD: The expression matrix of high-fiber-diet-related metabolites, blood methylation profile associated with pre-symptomatic dementia in elderly patients with type 2 diabetes mellitus (T2DM), and high-throughput single-cell sequencing data of hippocampal samples from patients with Alzheimer's disease (AD) were retrieved from the Gene Expression Omnibus (GEO) database and through a literature search. Data were analyzed using principal component analysis (PCA) after quality control and data filtering to identify different cell clusters and candidate markers. A protein-protein interaction network was mapped using the STRING database. To further investigate the interaction among high-fiber-diet-related metabolites, methylation-related DEGs related to T2DM, and single-cell marker genes related to AD, AutoDock was used for semi-flexible molecular docking.RESULT: Based on GEO database data and previous studies, 24 marker genes associated with high-fiber diet, T2DM, and AD were identified. Top 10 core genes include SYNE1, ANK2, SPEG, PDZD2, KALRN, PTPRM, PTPRK, BIN1, DOCK9, and NPNT, and their functions are primarily related to autophagy. According to molecular docking analysis, acetamidobenzoic acid, the most substantially altered metabolic marker associated with a high-fiber diet, had the strongest binding affinity for SPEG.CONCLUSION: By targeting the SPEG protein in the hippocampus, acetamidobenzoic acid, a metabolite associated with high-fiber diet, may improve diabetic and neurodegenerative diseases in obese people.PMID:36733447 | PMC:PMC9888315 | DOI:10.3389/fneur.2022.1026904

Front Vet Sci. 2023 Jan 17;9:1023650. doi: 10.3389/fvets.2022.1023650. eCollection 2022.ABSTRACTBone tissue engineering is an emerging field of regenerative medicine, with a wide array of biomaterial technologies and therapeutics employed. However, it is difficult to objectively compare these various treatments during various stages of tissue response. Metabolomics is rapidly emerging as a powerful analytical tool to establish broad-spectrum metabolic signatures for a target biological system. Developing an effective biomarker panel for bone repair from small molecule data would provide an objective metric to readily assess the efficacy of novel therapeutics in relation to natural healing mechanisms. In this study we utilized a large segmental bone defect in goats to reflect trauma resulting in substantial volumetric bone loss. Characterization of the native repair capacity was then conducted over a period of 12 months through the combination of standard (radiography, computed tomography, histology, biomechanics) data and ultra-high-performance liquid chromatography-high resolution mass spectrometry (UHPLC-HRMS) metabolic profiling. Standard metrics demonstrated that samples formed soft callus structures that later mineralized. Small molecule profiles showed distinct temporal patterns associated with the bone tissue repair process. Specifically, increased lactate and amino acid levels at early time points indicated an environment conducive to osteoblast differentiation and extracellular matrix formation. Citrate and pyruvate abundances increased at later time points indicating increasing mineral content within the defect region. Taurine, shikimate, and pantothenate distribution profiles appeared to represent a shift toward a more homeostatic remodeling environment with the differentiation and activity of osteoclasts offsetting the earlier deposition phases of bone repair. The generation of a comprehensive metabolic reference portfolio offers a potent mechanism for examining novel biomaterials and can serve as guide for the development of new targeted therapeutics to improve the rate, magnitude, and quality of bone regeneration.PMID:36733424 | PMC:PMC9886884 | DOI:10.3389/fvets.2022.1023650

Front Oncol. 2023 Jan 17;12:1025046. doi: 10.3389/fonc.2022.1025046. eCollection 2022.ABSTRACTBACKGROUND: To explore potential metabolomics biomarker in predicting the efficiency of the chemo-immunotherapy in patients with advanced non-small cell lung cancer (NSCLC).METHODS: A total of 83 eligible patients were assigned to receive chemo-immunotherapy. Serum samples were prospectively collected before the treatment to perform metabolomics profiling analyses under the application of gas chromatography mass spectrometry (GC-MS). The key metabolites were identified using projection to latent structures discriminant analysis (PLS-DA). The key metabolites were used for predicting the chemo-immunotherapy efficiency in advanced NSCLC patients.RESULTS: Seven metabolites including pyruvate, threonine, alanine, urea, oxalate, elaidic acid and glutamate were identified as the key metabolites to the chemo-immunotherapy response. The receiver operating characteristic curves (AUC) were 0.79 (95% CI: 0.69-0.90), 0.60 (95% CI: 0.48-0.73), 0.69 (95% CI: 0.57-0.80), 0.63 (95% CI: 0.51-0.75), 0.60 (95% CI: 0.48-0.72), 0.56 (95% CI: 0.43-0.67), and 0.67 (95% CI: 0.55-0.80) for the key metabolites, respectively. A binary logistic regression was used to construct a combined biomarker model to improve the discriminating efficiency. The AUC was 0.86 (95% CI: 0.77-0.94) for the combined biomarker model. Pathway analyses showed that urea cycle, glucose-alanine cycle, glycine and serine metabolism, alanine metabolism, and glutamate metabolism were the key metabolic pathway to the chemo-immunotherapy response in patients with advanced NSCLC.CONCLUSION: Metabolomics analyses of key metabolites and pathways revealed that GC-MS could be used to predict the efficiency of chemo-immunotherapy. Pyruvate, threonine, alanine, urea, oxalate, elaidic acid and glutamate played a central role in the metabolic of PD patients with advanced NSCLC.PMID:36733356 | PMC:PMC9887290 | DOI:10.3389/fonc.2022.1025046

Eur J Med Res. 2023 Feb 2;28(1):58. doi: 10.1186/s40001-023-01021-w.ABSTRACTBACKGROUND: Aging is an inevitable process associated with impairments in multiple organ systems, which increases the risk of comorbidity and disability, and reduces the health-span. Metabolomics is a powerful tool in aging research, which can reflect the characteristics of aging at the level of terminal metabolism, and may contribute to the exploration of aging mechanisms and the formulation of anti-aging strategies.METHODS: To identify possible biomarkers and pathways associated with aging using untargeted metabolomics methods, we performed liquid chromatography-mass spectrometry (LC-MS)-based untargeted metabolomics profiling on serum samples from 32 older adults and 32 sex-matched young controls.RESULTS: Metabolite profiling could distinguish the two groups. Among the 349 metabolites identified, 80-including lysophospholipids whose levels gradually decline-are possible candidate aging biomarkers. Valine, leucine and isoleucine degradation and biosynthesis were important pathways in aging, with reduced levels of L-isoleucine (r = - 0.30, p = 0.017) and L-leucine (r = - 0.32, p = 0.010) observed in older adults.CONCLUSIONS: We preliminarily revealed the metabolite changes associated with aging in Chinese adults. Decreases in mitochondrial membrane-related lysophospholipids and dysfunction of branched-chain amino acid metabolism were determined to be the characteristics and promising research targets for aging.PMID:36732870 | DOI:10.1186/s40001-023-01021-w

Nat Cancer. 2023 Feb 2. doi: 10.1038/s43018-022-00510-x. Online ahead of print.ABSTRACTDespite producing a panoply of potential cancer-specific targets, the proteogenomic characterization of human tumors has yet to demonstrate value for precision cancer medicine. Integrative multi-omics using a machine-learning network identified master kinases responsible for effecting phenotypic hallmarks of functional glioblastoma subtypes. In subtype-matched patient-derived models, we validated PKCδ and DNA-PK as master kinases of glycolytic/plurimetabolic and proliferative/progenitor subtypes, respectively, and qualified the kinases as potent and actionable glioblastoma subtype-specific therapeutic targets. Glioblastoma subtypes were associated with clinical and radiomics features, orthogonally validated by proteomics, phospho-proteomics, metabolomics, lipidomics and acetylomics analyses, and recapitulated in pediatric glioma, breast and lung squamous cell carcinoma, including subtype specificity of PKCδ and DNA-PK activity. We developed a probabilistic classification tool that performs optimally with RNA from frozen and paraffin-embedded tissues, which can be used to evaluate the association of therapeutic response with glioblastoma subtypes and to inform patient selection in prospective clinical trials.PMID:36732634 | DOI:10.1038/s43018-022-00510-x

Sci Rep. 2023 Feb 2;13(1):1942. doi: 10.1038/s41598-023-29060-7.ABSTRACTFetal bovine serum (FBS) is a natural medium used in cell cultures containing the large amount of nutrients necessary for cell growth and is often used for in vitro cultures of animal cells. Although FBS plays a vital role in cell cultures, there are small molecules contained within FBS that remain unidentified, and their effects on cultured cells is poorly understood. Here, we report that different brands of FBS have varying influences on the background expression of IL-8, not TNFα and IL1β in epithelial cells. The endogenous small molecules in FBS and ERK pathways may contribute to these effects. In addition, FBS form the IL-8 stimulation and IL-8 non-responsive groups have different metabolome profiles. Overall, our study suggests that metabolites in FBS should be included in the quantitative considerations when conducting cell experiments, especially immune-related experiments, to improve the repeatability of experimental results in scientific papers; IL-8 could thus be an important factor in selecting FBS.PMID:36732616 | DOI:10.1038/s41598-023-29060-7

Sci Rep. 2023 Feb 2;13(1):1891. doi: 10.1038/s41598-023-28712-y.ABSTRACTPlastic pollution, especially by nanoplastics (NPs), has become an emerging topic due to the widespread existence and accumulation in the environment. The research on bioaccumulation and toxicity mechanism of NPs from polyethylene terephthalate (PET), which is widely used for packaging material, have been poorly investigated. Herein, we report the first use of high-resolution magic-angle spinning (HRMAS) NMR based metabolomics in combination with toxicity assay and behavioural end points to get systems-level understanding of toxicity mechanism of PET NPs in intact zebrafish embryos. PET NPs exhibited significant alterations on hatching and survival rate. Accumulation of PET NPs in larvae were observed in liver, intestine, and kidney, which coincide with localization of reactive oxygen species in these areas. HRMAS NMR data reveal that PET NPs cause: (1) significant alteration of metabolites related to targeting of the liver and pathways associated with detoxification and oxidative stress; (2) impairment of mitochondrial membrane integrity as reflected by elevated levels of polar head groups of phospholipids; (3) cellular bioenergetics as evidenced by changes in numerous metabolites associated with interrelated pathways of energy metabolism. Taken together, this work provides for the first time a comprehensive system level understanding of toxicity mechanism of PET NPs exposure in intact larvae.PMID:36732581 | DOI:10.1038/s41598-023-28712-y

Sci Rep. 2023 Feb 2;13(1):1886. doi: 10.1038/s41598-023-28862-z.ABSTRACTDuring the first 2 years of life, the infant gut microbiome is rapidly developing, and gut bacteria may impact host health through the production of metabolites that can have systemic effects. Thus, the fecal metabolome represents a functional readout of gut bacteria. Despite the important role that fecal metabolites may play in infant health, the development of the infant fecal metabolome has not yet been thoroughly characterized using frequent, repeated sampling during the first 2 years of life. Here, we described the development of the fecal metabolome in a cohort of 101 Latino infants with data collected at 1-, 6-, 12-, 18-, and 24-months of age. We showed that the fecal metabolome is highly conserved across time and highly personalized, with metabolic profiles being largely driven by intra-individual variability. Finally, we also identified several novel metabolites and metabolic pathways that changed significantly with infant age, such as valerobetaine and amino acid metabolism, among others.PMID:36732537 | DOI:10.1038/s41598-023-28862-z

Nat Commun. 2023 Feb 2;14(1):571. doi: 10.1038/s41467-023-36256-y.ABSTRACTBlood metabolome is commonly used in human studies to explore the associations of gut microbiota-derived metabolites with cardiometabolic diseases. Here, in a cohort of 1007 middle-aged and elderly adults with matched fecal metagenomic (149 species and 214 pathways) and paired fecal and blood targeted metabolomics data (132 metabolites), we find disparate associations with taxonomic composition and microbial pathways when using fecal or blood metabolites. For example, we observe that fecal, but not blood butyric acid significantly associates with both gut microbiota and prevalent type 2 diabetes. These findings are replicated in an independent validation cohort involving 103 adults. Our results suggest that caution should be taken when inferring microbiome-cardiometabolic disease associations from either blood or fecal metabolome data.PMID:36732517 | DOI:10.1038/s41467-023-36256-y

Metabolomics. 2023 Feb 2;19(2):9. doi: 10.1007/s11306-023-01973-4.ABSTRACTINTRODUCTION: To decrease antibiotic resistance, their use as growth promoters in the agricultural sector has been largely abandoned. This may lead to decreased health due to infectious disease or microbiome changes leading to gut inflammation.OBJECTIVES: We aimed to generate a m/z signature classifying chicken health in blood, and obtain biological insights from the resulting m/z signature.METHODS: We used direct infusion mass-spectrometry to determine a machine-learned metabolomics signature that classifies chicken health from a blood sample. We then challenged the resulting models by investigating the classification capability of the signature on novel data obtained at poultry houses in previously unseen countries using a Leave-One-Country-Out (LOCO) cross-validation strategy. Additionally, we optimised the number of mass/charge (m/z) values required to maximise the classification capability of Random Forest models, by developing a novel ranking system based on combined univariate t-test and fold-change analyses and building models based on this ranking through forward and reverse feature selection.RESULTS: The multi-country and LOCO models could classify chicken health. Both resulting 25-m/z and 3784-m/z signatures reliably classified chicken health in multiple countries. Through mummichog enrichment analysis on the large m/z signature, we found changes in amino acid metabolism, including branched chain amino acids and polyamines.CONCLUSION: We reliably classified chicken health from blood, independent of genetic-, farm-, feed- and country-specific confounding factors. The 25-m/z signature can be used to aid development of a per-metabolite panel. The extended 3784-m/z version can be used to gain a deeper understanding of the metabolic causes and consequences of low chicken health. Together, they may facilitate future treatment, prevention and intervention.PMID:36732451 | DOI:10.1007/s11306-023-01973-4

J Neurol Neurosurg Psychiatry. 2023 Feb 2:jnnp-2022-330259. doi: 10.1136/jnnp-2022-330259. Online ahead of print.ABSTRACTBACKGROUND: There are currently no specific biomarkers for multiple sclerosis (MS). Identifying robust biomarkers for MS is crucial to improve disease diagnosis and management.METHODS: This study first used six Mendelian randomisation methods to assess causal relationship of 174 metabolites with MS, incorporating data from European-ancestry metabolomics (n=8569-86 507) and MS (n=14 802 MS cases, 26 703 controls) genomewide association studies. Genetic scores for identified causal metabolite(s) were then computed to predict MS disability progression in an independent longitudinal cohort (AusLong study) of 203 MS cases with up to 15-year follow-up.RESULTS: We found a novel genetic causal effect of serine on MS onset (OR=1.67, 95% CI 1.51 to 1.84, p=1.73×10-20), such that individuals whose serine level is 1 SD above the population mean will have 1.67 times the risk of developing MS. This is robust across all sensitivity methods (OR ranges from 1.49 to 1.67). In an independent longitudinal MS cohort, we then constructed time-dynamic and time-fixed genetic scores based on serine genetic instrument single-nucleotide polymorphisms, where higher scores for raised serum serine level were associated with increased risk of disability worsening, especially in the time-dynamic model (RR=1.25, 95% CI 1.10 to 1.42, p=7.52×10-4).CONCLUSIONS: These findings support investigating serine as an important candidate biomarker for MS onset and disability progression.PMID:36732044 | DOI:10.1136/jnnp-2022-330259

Life Sci Alliance. 2023 Feb 2;6(4):e202201692. doi: 10.26508/lsa.202201692. Print 2023 Apr.ABSTRACTThe initial dissemination of cancer cells from many primary tumors implies intravasation to lymphatic nodes or blood vessels. To investigate the mechanisms involved, we analyzed the expression of small non-coding RNAs in cutaneous squamous cell carcinoma (cSCC), a prevalent tumor that mainly spreads to lymph nodes. We report the reduced expression of small nucleolar RNAs in primary cSCCs that metastasized when compared to non-metastasizing cSCCs, and the progressive loss of DKC1 (dyskerin, which stabilizes the small nucleolar RNAs) along the metastasis. DKC1 depletion in cSCC cells triggered lipid metabolism by altering the mevalonate pathway and the acquisition of metastatic traits. Treatment of DKC1-depleted cells with simvastatin, an inhibitor of the mevalonate pathway, blocked the expression of proteins involved in the epithelial-to-mesenchymal transition. Consistently, the expression of the enzyme 3-hydroxy-3-methylglutaryl-CoA synthase 1 was associated with pathological features of high metastatic risk in cSCC patients. Our data underpin the relevance of the mevalonate metabolism in metastatic dissemination and pave the possible incorporation of therapeutic approaches among the antineoplastic drugs used in routine patient care.PMID:36732018 | DOI:10.26508/lsa.202201692

Exp Cell Res. 2023 Jan 30:113503. doi: 10.1016/j.yexcr.2023.113503. Online ahead of print.ABSTRACTMost lung adenocarcinoma-associated EGFR tyrosine kinase mutations are either an exon 19 deletion (19Del) or L858R point mutation in exon 21. Although patients whose tumors contain either of these mutations exhibit increased sensitivity to tyrosine kinase inhibitors, progression-free and overall survival appear to be longer in patients with 19Del than in those with L858R. In mutant-transfected Ba/F3 cells, 19Del and L858R were compared by multi-omics analyses including proteomics, transcriptomics, and metabolomics. Proteome analysis identified increased plastin-2, TKT, PDIA5, and ENO1 expression in L858R cells, and increased EEF1G expression in 19Del cells. RNA sequencing showed significant differences between 19Del and L858R cells in 112 genes. Metabolome analysis showed that amino acids, adenylate, guanylate, NADPH, lactic acid, pyruvic acid glucose 6-phosphate, and ribose 5-phosphate were significantly different between the two mutant cells. Because GSH was increased with L858R, we combined osimertinib with the GSH inhibitor buthionine sulfoximine in L858R cells and observed synergistic effects. The complexity of EGFR 19Del and L858R mutant cells was demonstrated by proteomics, transcriptomics, and metabolomics analyses. Therapeutic strategies for lung cancer with different EGFR mutations could be considered because of their different metabolic phenotypes.PMID:36731710 | DOI:10.1016/j.yexcr.2023.113503

Int J Biol Macromol. 2023 Jan 30:123488. doi: 10.1016/j.ijbiomac.2023.123488. Online ahead of print.ABSTRACTSchisandra chinensis (S. chinensis) is an herbal medicine used for the treatment of Alzheimer's disease (AD). The purified polysaccharide fraction, namely SCP2, was previously isolated from S. chinensis crude polysaccharide (SCP) and its structure and in vitro activity were investigated. However, the in vivo activity of SCP2 and its potential mechanism for the treatment of AD have yet to be determined. This study used a combination of microbiomics and metabolomics to comprehensively explore the microbiota and metabolic changes in AD rats under SCP2 intervention, with the aim of elucidating the potential mechanisms of SCP2 in the treatment of AD. SCP2 showed significant therapeutic effects in AD rats, as evidenced by improved learning and memory capacity, reduced neuroinflammation, and restoration of the integrity of the intestinal barrier. Fecal metabolomic and microbiomic analyses revealed that SCP2 significantly modulated 19 endogenous metabolites and reversed gut microbiota disorders in AD rats. Moreover, SCP2 significantly increased the content of short-chain fatty acid (SCFAs) in the AD rats. Correlation analysis showed a significant correlation between gut microbes, metabolites and the content of SCFAs. Collectively, these findings will provide the basis for further development of SCP2.PMID:36731694 | DOI:10.1016/j.ijbiomac.2023.123488

Int J Biol Macromol. 2023 Jan 30:123481. doi: 10.1016/j.ijbiomac.2023.123481. Online ahead of print.ABSTRACTThis study aimed at investigating the gastroprotective effect of Evodiae fructus polysaccharide (EFP) against ethanol-induced gastric ulcer in mice. Biochemical indexes along with untargeted serum and liver metabolomics were determined. Results showed that pre-treatment of EFP alleviated ethanol-induced gastric ulcer in mice. EFP lessened oxidative stress and inflammation levels of stomachs, showing as increments of SOD and GSH-Px activities, GSH content and IL-10 level, and reductions of MDA and IL-6 levels. Meanwhile, EFP activated the Keap1/Nrf2/HO-1 signaling pathway through increasing Nrf2 and HO-1 protein expressions, and decreasing Keap1 protein expression. Serum and liver metabolomics analyses indicated that 10 metabolic potential biomarkers were identified among normal control, ulcer control and 200 mg/kg·bw of EFP groups, which were related to 5 enriched metabolic pathways including vitamin B6 metabolism, nicotinate and nicotinamide metabolism, pentose phosphate pathway, bile secretion and ascorbate and aldarate metabolism. Further pearson's correlation analysis indicated that there were some positive and negative correlations between the biomarkers and the biochemical indexes. It could be concluded that the gastroprotection of EFP might be related to anti-oxidative stress, anti-inflammation, activation of Keap1/Nrf2/HO-1 signaling pathway and alteration of metabolic pathways. This study supports the potential application of EFP in preventing ethanol-induced gastric ulcer.PMID:36731690 | DOI:10.1016/j.ijbiomac.2023.123481

Mol Metab. 2023 Jan 30:101684. doi: 10.1016/j.molmet.2023.101684. Online ahead of print.ABSTRACTOBJECTIVE: Calorie restriction is a first-line treatment for overweight individuals with metabolic impairments. However, few patients can adhere to long-term calorie restriction. An alternative approach to calorie restriction that also causes negative energy balance is mitochondrial uncoupling, which decreases the amount of energy that can be extracted from food. Herein we compare the metabolic effects of calorie restriction with the mitochondrial uncoupler BAM15 in the db/db mouse model of severe hyperglycemia, obesity, hypertriglyceridemia, and fatty liver.METHODS: Male db/db mice were treated with ∼50% calorie restriction, BAM15 at two doses of 0.1% and 0.2% (w/w) admixed in diet, or 0.2% BAM15 with time-restricted feeding from 5 weeks of age. Mice were metabolically phenotyped over 4 weeks with assessment of key readouts including body weight, glucose tolerance, and liver steatosis. At termination, liver tissues were analysed by metabolomics and qPCR.RESULTS: Calorie restriction and high-dose 0.2% BAM15 decreased body weight to a similar extent, but mice treated with BAM15 had far better improvement in glucose control. High-dose BAM15 treatment completely normalized fasting glucose and glucose tolerance to levels similar to lean db/+ control mice. Low-dose 0.1% BAM15 did not affect body mass but partially improved glucose tolerance to a similar degree as 50% calorie restriction. Both calorie restriction and high-dose BAM15 significantly improved hyperglucagonemia and liver and serum triglyceride levels. Combining high-dose BAM15 with time-restricted feeding to match the time that calorie restricted mice were fed resulted in the best metabolic phenotype most similar to lean db/+ controls. BAM15-mediated improvements in glucose control were associated with decreased glucagon levels and decreased expression of enzymes involved in hepatic gluconeogenesis.CONCLUSIONS: BAM15 and calorie restriction treatments improved most metabolic disease phenotypes in db/db mice. However, mice fed BAM15 had superior effects on glucose control compared to the calorie restricted group that consumed half as much food. Submaximal dosing with BAM15 demonstrated that its beneficial effects on glucose control are independent of weight loss. These data highlight the potential for mitochondrial uncoupler pharmacotherapies in the treatment of metabolic disease.PMID:36731653 | DOI:10.1016/j.molmet.2023.101684

Life Sci. 2023 Jan 30:121439. doi: 10.1016/j.lfs.2023.121439. Online ahead of print.ABSTRACTStress plays a critical role in hair loss, although the underlying mechanisms are largely unknown. γ-aminobutyric acid (GABA) has been reported to be associated with stress; however, whether it affects stress-induced hair growth inhibition is unclear. This study aimed to investigate the potential roles and mechanisms of action of GABA in chronic restraint stress (CRS)-induced hair growth inhibition. We performed RNA-seq analysis and found that differentially expressed genes (DEGs) associated with neuroactive ligand-receptor interaction, including genes related to GABA receptors, significantly changed after mice were treated with CRS. Targeted metabolomics analysis and enzyme-linked immunosorbent assay (ELISA) also showed that GABA levels in back skin tissues and serum significantly elevated in the CRS group. Notably, CRS-induced hair growth inhibition got aggravated by GABA and alleviated through GABAA antagonists, such as picrotoxin and ginkgolide A. RNA sequencing analysis revealed that DEGs related to the cell cycle, DNA replication, purine metabolism, and pyrimidine metabolism pathways were significantly downregulated in dermal papilla (DP) cells after GABA treatment. Moreover, ginkgolide A, a GABAA antagonist extracted from the leaves of Ginkgo biloba, promoted the cell cycle of DP cells. Therefore, the present study demonstrated that the increase in GABA could promote CRS-induced hair growth inhibition by downregulating the cell cycle of DP cells and suggested that ginkgolide A may be a promising therapeutic drug for hair loss.PMID:36731645 | DOI:10.1016/j.lfs.2023.121439

Metab Eng. 2023 Jan 30:S1096-7176(23)00019-8. doi: 10.1016/j.ymben.2023.01.011. Online ahead of print.ABSTRACTEthylene glycol (EG) is a promising next generation feedstock for bioprocesses. It is a key component of the ubiquitous plastic polyethylene terephthalate (PET) and other polyester fibers and plastics, used in antifreeze formulations, and can also be generated by electrochemical conversion of syngas, which makes EG a key compound in a circular bioeconomy. The majority of biotechnologically relevant bacteria assimilate EG via the glycerate pathway, a wasteful metabolic route that releases CO2 and requires reducing equivalents as well as ATP. In contrast, the recently characterized β-hydroxyaspartate cycle (BHAC) provides a more efficient, carbon-conserving route for C2 assimilation. Here we aimed at overcoming the natural limitations of EG metabolism in the industrially relevant strain Pseudomonas putida KT2440 by replacing the native glycerate pathway with the BHAC. We first prototyped the core reaction sequence of the BHAC in Escherichia coli before establishing the complete four-enzyme BHAC in Pseudomonas putida. Directed evolution on EG resulted in an improved strain that exhibits 35% faster growth and 20% increased biomass yield compared to a recently reported P. putida strain that was evolved to grow on EG via the glycerate pathway. Genome sequencing and proteomics highlight plastic adaptations of the genetic and metabolic networks in response to the introduction of the BHAC into P. putida and identify key mutations for its further integration during evolution. Taken together, our study shows that the BHAC can be utilized as 'plug-and-play' module for the metabolic engineering of two important microbial platform organisms, paving the way for multiple applications for a more efficient and carbon-conserving upcycling of EG in the future.PMID:36731627 | DOI:10.1016/j.ymben.2023.01.011