PubMed

mSystems. 2023 Aug 24:e0058223. doi: 10.1128/msystems.00582-23. Online ahead of print.ABSTRACTCalf diarrhea is a multifactorial disease that affects the cattle industry and accounts for more than 50% of calf mortality. Although there is evidence of an association between altered gut microbiota and diarrhea, remarkably little is known about the microbial and metabolic mechanisms underlying the link between gut microbiota dysbiosis and the occurrence of calf diarrhea. Here, we performed fecal metagenomic and metabolomic studies on fecal samples from diarrheic and healthy calves of Xia-nan cattle breed. Results revealed that composition of the gut microbiome and metabolome was remarkably altered in diarrheic calves, and gut microbial alterations were associated with diarrhea and linked to the changes in metabolites. Metabolite profiles showed that diarrheic calves exhibited a marked decrease in some purines (adenosine, adenine, 2'-deoxyguanosine, allantoate, deoxyinosine, and deoxyguanosine) and arachidonic acid (prostaglandin F2α and prostaglandin E2) compared to healthy calves. Purine-producing microbial species, including Lactiplantibacillus plantarum, Campylobacter coli, Treponema porcinum, Klebsiella pneumoniae, and Phocaeicola coprophilus, were significantly reduced in diarrheic calves compared to healthy calves, whereas the arachidonic acid-producing species such as Neisseria gonorrhoeae, Staphylococcus aureus, and Clostridiales bacterium exhibited a marked increase. These microbial signatures were closely associated with the metabolic dysbiosis of purine and arachidonic acid in diarrhea calves. Our study showed that gut microbiota-driven metabolic disorders of purine or arachidonic acid were associated with calf diarrhea. The findings prove that altered gut microbiota plays a role in diarrhea pathogenesis and indicate that gut microbiota-targeted therapies could be useful for both prevention and treatment of diarrhea. IMPORTANCE Calf diarrhea is of great concern to the global dairy industry as it results in significant economic losses due to lower conception rates, reduced milk production, and early culling. Although there is evidence of an association between altered gut microbiota and diarrhea, remarkably little is known about the microbial and metabolic mechanisms underlying the link between gut microbiota dysbiosis and the occurrence of calf diarrhea. Here, we used fecal metagenomic and metabolomic analyses to demonstrate that gut microbiota-driven metabolic disorders of purine or arachidonic acid were associated with calf diarrhea. These altered gut microbiotas play vital roles in diarrhea pathogenesis and indicate that gut microbiota-targeted therapies could be useful for both prevention and treatment of diarrhea.PMID:37615434 | DOI:10.1128/msystems.00582-23

Chembiochem. 2023 Aug 24:e202300540. doi: 10.1002/cbic.202300540. Online ahead of print.ABSTRACTNatural deep eutectic solvents (NADESs) are emerging sustainable alternatives to conventional organic solvents. Beyond their role as laboratory solvents, NADESs are increasingly explored in drug delivery and as therapeutics. Their increasing applications notwithstanding, our understanding of how they interact with biomolecules at multiple levels - metabolome, proteome, and transcriptome - within human cell remain poor. Here, we deploy integrated metabolomics, proteomics, and transcriptomics to probe how NADESs perturb the molecular landscape of human cells. In a human cell line model, we found that an archetypal NADES derived from choline and geranic acid (CAGE) significantly altered the metabolome, proteome, and transcriptome. CAGE upregulated indole-3-lactic acid and 4-hydroxyphenyllactic acid levels, resulting in ligand-independent activation of aryl hydrocarbon receptor to signal the transcription of genes with implications for inflammation, immunomodulation, cell development, and chemical detoxification. Further, treating the cell line with CAGE downregulated glutamine biosynthesis, a nutrient rapidly proliferating cancer cells require. The ability of CAGE to attenuate glutamine levels is potentially relevant for cancer treatment. These findings suggest that NADESs, even when derived from natural components like choline, can indirectly modulate cell biology at multiple levels, expanding their applications beyond chemistry to biomedicine and biotechnology.PMID:37615422 | DOI:10.1002/cbic.202300540

J Agric Food Chem. 2023 Aug 24. doi: 10.1021/acs.jafc.3c01782. Online ahead of print.ABSTRACTUstilaginoidea virens, the causal agent of rice false smut, produces a large amount of mycotoxins, including ustilaginoidins and sorbicillinoids. However, little is known about the regulatory mechanism of mycotoxin biosynthesis inU. virens. Here, we demonstrate that the NAD+-dependent histone deacetylase UvHST2 negatively regulates ustilaginoidin biosynthesis. UvHst2 knockout caused retarded hypha growth and reduced conidiation and pathogenicity inU. virens. Transcriptome analysis revealed that the transcription factor genes, transporter genes, and other tailoring genes in eight biosynthetic gene clusters (BGCs) including ustilaginoidin and sorbicillinoid BGCs were upregulated in ΔUvhst2. Interestingly, the UvHst2 deletion affects alternative splicing. Metabolomics revealed that UvHST2 negatively regulates the biosynthesis of various mycotoxins including ustilaginoidins, sorbicillin, ochratoxin B, zearalenone, and O-M-sterigmatocystin. Combined transcriptome and metabolome analyses uncover that UvHST2 positively regulates pathogenicity but negatively modulates the expression of BGCs involved in secondary metabolism. Collectively, UvHST2 functions as a global regulator of secondary metabolism inU. virens.PMID:37615365 | DOI:10.1021/acs.jafc.3c01782

Gut Microbes. 2023 Dec;15(2):2247053. doi: 10.1080/19490976.2023.2247053.ABSTRACTThis study is to investigate whether dietary fiber intake prevents vascular and renal damage in a genetic mouse model of systemic lupus erythematosus (SLE), and the contribution of gut microbiota in the protective effects. Female NZBWF1 (SLE) mice were treated with resistant-starch (RS) or inulin-type fructans (ITF). In addition, inoculation of fecal microbiota from these experimental groups to recipient normotensive female C57Bl/6J germ-free (GF) mice was performed. Both fiber treatments, especially RS, prevented the development of hypertension, renal injury, improved the aortic relaxation induced by acetylcholine, and the vascular oxidative stress. RS and ITF treatments increased the proportion of acetate- and butyrate-producing bacteria, respectively, improved colonic inflammation and integrity, endotoxemia, and decreased helper T (Th)17 proportion in mesenteric lymph nodes (MLNs), blood, and aorta in SLE mice. However, disease activity (splenomegaly and anti-ds-DNA) was unaffected by both fibers. T cell priming and Th17 differentiation in MLNs and increased Th17 infiltration was linked to aortic endothelial dysfunction and hypertension after inoculation of fecal microbiota from SLE mice to GF mice, without changes in proteinuria and autoimmunity. All these effects were lower in GF mice after fecal inoculation from fiber-treated SLE mice. In conclusion, these findings support that fiber consumption prevented the development of hypertension by rebalancing of dysfunctional gut-immune system-vascular wall axis in SLE.PMID:37615336 | DOI:10.1080/19490976.2023.2247053

Arterioscler Thromb Vasc Biol. 2023 Aug 24. doi: 10.1161/ATVBAHA.122.318222. Online ahead of print.ABSTRACTBACKGROUND: Impaired cholesterol efflux capacity (CEC) is a novel lipid metabolism trait associated with atherosclerotic cardiovascular disease. Mechanisms underlying CEC variation are unknown. We evaluated associations of circulating metabolites with CEC to advance understanding of metabolic pathways involved in cholesterol efflux regulation.METHODS: Participants enrolled in the MESA (Multi-Ethnic Study of Atherosclerosis) who underwent nuclear magnetic resonance metabolome profiling and CEC measurement (N=3543) at baseline were included. Metabolite associations with CEC were evaluated using standard linear regression analyses. Repeated ElasticNet and multilayer perceptron regression were used to assess metabolite profile predictive performance for CEC. Features important for CEC prediction were identified using Shapley Additive Explanations values.RESULTS: Greater CEC was significantly associated with metabolite clusters composed of the largest-sized particle subclasses of VLDL (very-low-density lipoprotein) and HDL (high-density lipoprotein), as well as their constituent apo A1, apo A2, phospholipid, and cholesterol components (β=0.072-0.081; P<0.001). Metabolite profiles had poor accuracy for predicting in vitro CEC in linear and nonlinear analyses (R2<0.02; Spearman ρ<0.18). The most important feature for CEC prediction was race, with Black participants having significantly lower CEC compared with other races.CONCLUSIONS: We identified independent associations among CEC, the largest-sized particle subclasses of VLDL and HDL, and their constituent apolipoproteins and lipids. A large proportion of variation in CEC remained unexplained by metabolites and traditional clinical risk factors, supporting further investigation into genomic, proteomic, and phospholipidomic determinants of CEC.PMID:37615111 | DOI:10.1161/ATVBAHA.122.318222

PNAS Nexus. 2023 Aug 10;2(8):pgad262. doi: 10.1093/pnasnexus/pgad262. eCollection 2023 Aug.ABSTRACTThe cerebrospinal fluid (CSF) provides mechanical protection for the brain and serves as a brain dispersion route for nutrients, hormones, and metabolic waste. The CSF secretion rate is elevated in the dark phase in both humans and rats, which could support the CSF flow along the paravascular spaces that may be implicated in waste clearance. The similar diurnal CSF dynamics pattern observed in the day-active human and the nocturnal rat suggests a circadian regulation of this physiological variable, rather than sleep itself. To obtain a catalog of potential molecular drivers that could provide the day-night-associated modulation of the CSF secretion rate, we determined the diurnal fluctuation in the rat choroid plexus transcriptomic profile with RNA-seq and in the CSF metabolomics with ultraperformance liquid chromatography combined with mass spectrometry. We detected significant fluctuation of 19 CSF metabolites and differential expression of 2,778 choroid plexus genes between the light and the dark phase, the latter of which encompassed circadian rhythm-related genes and several choroid plexus transport mechanisms. The fluctuating components were organized with joint pathway analysis, of which several pathways demonstrated diurnal regulation. Our results illustrate substantial transcriptional and metabolic light-dark phase-mediated changes taking place in the rat choroid plexus and its encircling CSF. The combined data provide directions toward future identification of the molecular pathways governing the fluctuation of this physiological process and could potentially be harnessed to modulate the CSF dynamics in pathology.PMID:37614671 | PMC:PMC10443925 | DOI:10.1093/pnasnexus/pgad262

Front Microbiol. 2023 Aug 8;14:1145430. doi: 10.3389/fmicb.2023.1145430. eCollection 2023.ABSTRACTOBJECTIVE: The incidence of non-alcoholic fatty liver disease is increasing every year, and there is growing evidence that metabolites and intestinal bacteria play a causal role in NAFLD. Gentiopicroside, a major iridoids compound in gentian, has been reported to reduce hepatic lipid accumulation. However to date, no studies have confirmed whether the predominance of Gentiopicroside is related to metabolites and intestinal bacteria. Therefore, we sought to study whether the hypolipidemic effect of Gentiopicroside is related to metabolic function and intestinal flora regulation.METHODS: In the present study, C57BL/6J mice were fed a high-fat diet for 12 weeks, followed by a high-fat diet with or without Gentiopicroside for 8 weeks, respectively. The Gentiopicroside intervention reduced body weight gain, liver index, and decreased serum biochemical parameters such as alanine aminotransferase, aspartate aminotransferase, and triglycerides in high-fat fed mice. The effect of Gentiopicroside on non-alcoholic fatty liver disease was studied using serum untargeted metabolomics and 16S rDNA assay.RESULTS: Metabolomic analysis showed that the addition of Gentiopicroside significantly altered the levels of amino acids, unmetabolized Gentiopicroside after administration, and metabolites such as Cinnoline, Galabiosylceramide, and Tryptophyl-Tyrosine, which are involved in the pathways regulating bile secretion, tryptophan metabolism, and lipid metabolism. Analysis of intestinal bacteria showed that Gentiopicrosides altered the community composition structure of intestinal bacteria, characterized by an increase and a decrease in beneficial and harmful bacteria, respectively. In addition, correlation analysis showed that the effect of Gentiopicroside on metabolites was positively correlated with intestinal flora Bacteroides, Lactobacillus, Muribaculum, and Prevotellaceae_UCG_001. Finally, the combined analysis revealed that metabolites were associated with the regulation of Firmicutes and Actinobacteria and positively correlated with lipid levels.CONCLUSION: These results suggest that Gentiopicroside may be a potential agent for the prevention of intestinal disorders and the alleviation of non-alcoholic fatty liver disease.PMID:37614606 | PMC:PMC10443917 | DOI:10.3389/fmicb.2023.1145430

Front Mol Biosci. 2023 Aug 8;10:1215039. doi: 10.3389/fmolb.2023.1215039. eCollection 2023.ABSTRACTIntroduction: Systemic sclerosis (SSc) is a chronic autoimmune disease, marked by an unpredictable course, high morbidity, and increased mortality risk that occurs especially in the diffuse and rapidly progressive forms of the disease, characterized by fibrosis of the skin and internal organs and endothelial dysfunction. Recent studies suggest that the identification of altered metabolic pathways may play a key role in understanding the pathophysiology of the disease. Therefore, metabolomics might be pivotal in a better understanding of these pathogenic mechanisms. Methods: Through a systematic review of the literature following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Guidelines (PRISMA), searches were done in the PubMed, EMBASE, Web of Science, and Scopus databases from 2000 to September 2022. Three researchers independently reviewed the literature and extracted the data based on predefined inclusion and exclusion criteria. Results: Of the screened studies, 26 fulfilled the inclusion criteria. A total of 151 metabolites were differentially distributed between SSc patients and healthy controls (HC). The main deregulated metabolites were those derived from amino acids, specifically homocysteine (Hcy), proline, alpha-N-phenylacetyl-L-glutamine, glutamine, asymmetric dimethylarginine (ADMA), citrulline and ornithine, kynurenine (Kyn), and tryptophan (Trp), as well as acylcarnitines associated with long-chain fatty acids and tricarboxylic acids such as citrate and succinate. Additionally, differences in metabolic profiling between SSc subtypes were identified. The diffuse cutaneous systemic sclerosis (dcSSc) subtype showed upregulated amino acid-related pathways involved in fibrosis, endothelial dysfunction, and gut dysbiosis. Lastly, potential biomarkers were evaluated for the diagnosis of SSc, the identification of the dcSSc subtype, pulmonary arterial hypertension, and interstitial lung disease. These potential biomarkers are within amino acids, nucleotides, carboxylic acids, and carbohydrate metabolism. Discussion: The altered metabolite mechanisms identified in this study mostly point to perturbations in amino acid-related pathways, fatty acid beta-oxidation, and in the tricarboxylic acid cycle, possibly associated with inflammation, vascular damage, fibrosis, and gut dysbiosis. Further studies in targeted metabolomics are required to evaluate potential biomarkers for diagnosis, prognosis, and treatment response.PMID:37614441 | PMC:PMC10442829 | DOI:10.3389/fmolb.2023.1215039

Front Neurosci. 2023 Aug 8;17:1084813. doi: 10.3389/fnins.2023.1084813. eCollection 2023.ABSTRACTINTRODUCTION: Brain tissue damage caused by ischemic stroke can trigger changes in the body's metabolic response, and understanding the changes in the metabolic response of the gut after stroke can contribute to research on poststroke brain function recovery. Despite the increase in international research on poststroke metabolic mechanisms and the availability of powerful research tools in recent years, there is still an urgent need for poststroke metabolic studies. Metabolomic examination of feces from a cerebral ischemia-reperfusion rat model can provide new insights into poststroke metabolism and identify key metabolic pathways, which will help reveal diagnostic and therapeutic targets as well as inspire pathophysiological studies after stroke.METHODS: We randomly divided 16 healthy adult pathogen-free male Sprague-Dawley (SD) rats into the normal group and the study group, which received middle cerebral artery occlusion/reperfusion (MCAO/R). Ultra-performance liquid chromatography-tandem mass spectrometry (UPLCMS/MS) was used to determine the identities and concentrations of metabolites across all groups, and filtered high-quality data were analyzed for differential screening and differential metabolite functional analysis.RESULTS: After 1 and 14 days of modeling, compared to the normal group, rats in the study group showed significant neurological deficits (p < 0.001) and significantly increased infarct volume (day 1: p < 0.001; day 14: p = 0.001). Mass spectra identified 1,044 and 635 differential metabolites in rat feces in positive and negative ion modes, respectively, which differed significantly between the normal and study groups. The metabolites with increased levels identified in the study group were involved in tryptophan metabolism (p = 0.036678, p < 0.05), arachidonic acid metabolism (p = 0.15695), cysteine and methionine metabolism (p = 0.24705), and pyrimidine metabolism (p = 0.3413), whereas the metabolites with decreased levels were involved in arginine and proline metabolism (p = 0.15695) and starch and sucrose metabolism (p = 0.52256).DISCUSSION: We determined that UPLC-MS/MS could be employed for untargeted metabolomics research. Moreover, tryptophan metabolic pathways may have been disordered in the study group. Alterations in the tryptophan metabolome may provide additional theoretical and data support for elucidating stroke pathogenesis and selecting pathways for intervention.PMID:37614341 | PMC:PMC10442664 | DOI:10.3389/fnins.2023.1084813

Zhen Ci Yan Jiu. 2023 Aug 25;48(8):736-45. doi: 10.13702/j.1000⁃0607.20221276.ABSTRACTOBJECTIVE: To observe the effects of moxibustion at "Tianshu"（ST25） and "Shangjuxu"（ST37） on the colonic metabolites and inflammatory factors in rats with Crohn's disease（CD）, so as to explore the mechanisms of moxibustion in protecting colon of CD rats based on metabolomics.METHODS: Twelve rats were first randomly selected from 36 male SD rats as a normal group（NG）. The CD model was induced by 2, 4, 6 trinitrobenzene sulfonic acid（TNBS） enema on the rest 24 rats. After successful modeling, rats were randomly divided into model（TNBS） and moxibustion（TNBS+MOX） groups（n=10 rats/group）. Moxibustion was applied at bilateral ST25 and ST37 for 30 min, once daily for 7 consecutive days in the TNBS+MOX group, while rats in the NG and TNBS groups did not receive any interventions. Body weight of rats was recorded and disease activity index（DAI） was assessed during the experiment. After interventions, HE staining was performed to observe pathological damage of colon. Serum levels of inflammatory factors were measured by ELISA. NMR hydrogen spectroscopy was used to detect colonic metabolites of each group, and orthogonal partial least squares discriminant analysis（OPLS-DA） was used to screen differential colonic metabolites between groups, followed by pathway analysis using MetaboAnalyst 5.0 platform.RESULTS: After modeling, compared with the NG group, the body weight of the rats in the TNBS group was significantly decreased（P<0.05）, the DAI score was increased （P<0.05）, the colon had obvious inflammatory damage and the pathological injury index was increased（P<0.05）, and levels of serum tumor necrosis factor-α（TNF-α）, interleukin（IL）-1β and interferon-γ（IFN-γ） were significantly increased（P<0.05）. After moxibustion intervention, compared with the TNBS group, the body weight was significantly increased（P<0.05）, while the levels of serum TNF-α, IL-1β, IFN-γ, and DAI score of the rats in the TNBS+MOX group were significantly decreased（P<0.05）, with alleviated colonic inflammatory injury detected by HE staining. Compared with the NG group, the relative expressions of colonic hypoxanthine, betaine, creatine, inositol, taurine, uracil, and methanol of the TNBS group were decreased（P<0.05）, while the relative expressions of histidine, leucine, proline, lysine, isoleucine, phenylalanine, tyrosine, propionic acid, and valine were increased（P<0.05） in the TNBS group, among which, relative expressions of hypoxanthine, leucine, lysine, isoleucine, betaine, tyrosine, and taurine were reversed in the TNBS+MOX group relevant to the TNBS group, mainly involving phenylalanine, tyrosine and tryptophan biosynthesis, and taurine and subtaurine metabolism pathway.CONCLUSION: The mechanism of moxibustion at ST25 and ST37 for CD may be related to improving colon metabolic disorder state by regulating multiple metabolic metabolites and metabolic pathways, and reducing the level of inflammatory factors, so as to maintain intestinal immune homeostasis.PMID:37614131 | DOI:10.13702/j.1000⁃0607.20221276

Lipids Health Dis. 2023 Aug 23;22(1):133. doi: 10.1186/s12944-023-01862-8.ABSTRACTBACKGROUND: Desaturase enzymes play a key role in several pathways including biosynthesis of poly- and mono- unsaturated fatty acids (PUFAs, MUFA). In preterm infants, desaturase enzyme activity (DA) may be a rate-limiting step in maintaining PUFAs levels during this critical developmental window and impact on long term metabolic health. The study tested the hypothesis that DA is altered in preterm infants compared to term infants in early life and may be a marker of risk or contribute to later alterations in metabolic health.METHODS: Lipidomic analyses were conducted using blood samples from two established UK-based cohorts, involving very preterm (n = 105) and term (n = 259) infants. Blood samples were taken from term infants at birth, two and six weeks and from preterm infants when established on enteral feeds and at term corrected age. DA of the 2 groups of infants were estimated indirectly from product/precursor lipids ratios of phosphatidylcholine (PC) and triglycerides (TG) species and reported according to their postmenstrual and postnatal ages.RESULTS: There were changes in lipid ratios representing desaturase enzyme activity in preterm infants in the first weeks of life with higher delta 6 desaturases (D6D) triglyceride (TG) indices but significantly lower delta 9 desaturase (D9D) and D6D(PC) indices. In comparison to term infants, preterm have lower delta 5 desaturase (D5D) but higher D6D indices at all postnatal ages. Although point levels of desaturase indices were different, trajectories of changes in these indices over time were similar in preterm and term infants.CONCLUSIONS: This study findings suggest the patterns of desaturase indices in preterm infants differ from that of term infants but their trajectories of change in the first 10 weeks of life were similar. These differences of DA if they persist in later life could contribute to the mechanism of diseases in preterm adulthood and warrant further investigations.PMID:37612700 | DOI:10.1186/s12944-023-01862-8

BMC Cancer. 2023 Aug 23;23(1):789. doi: 10.1186/s12885-023-11239-w.ABSTRACTThis study aimed to evaluate the potential of exosomes from cancer cells to predict chemoresistance in pancreatic cancer (PC) and explore the molecular mechanisms through RNA-sequencing and mass spectrometry. We sought to understand the connection between the exosomal Medium-chain acyl-CoA dehydrogenase (ACADM) level and the reaction to gemcitabine in vivo and in patients with PC. We employed loss-of-function, gain-of-function, metabolome mass spectrometry, and xenograft models to investigate the effect of exosomal ACADM in chemoresistance in PC. Our results showed that the molecules involved in lipid metabolism in exosomes vary between PC cells with different gemcitabine sensitivity. Exosomal ACADM (Exo-ACADM) was strongly correlated with gemcitabine sensitivity in vivo, which can be used as a predictor for postoperative gemcitabine chemosensitivity in pancreatic patients. Moreover, ACADM was found to regulate the gemcitabine response by affecting ferroptosis through Glutathione peroxidase 4 (GPX4) and mevalonate pathways. It was also observed that ACADM increased the consumption of unsaturated fatty acids and decreased intracellular lipid peroxides and reactive oxygen species (ROS) levels. In conclusion, this research suggests that Exo-ACADM may be a viable biomarker for predicting the responsiveness of patients to chemotherapy.PMID:37612627 | DOI:10.1186/s12885-023-11239-w

Sci Rep. 2023 Aug 23;13(1):13752. doi: 10.1038/s41598-023-39737-8.ABSTRACTIntegration of the omics data, including metabolomics and proteomics, provides a unique opportunity to search for new associations within metabolic disorders, including Alzheimer's disease. Using metabolomics, we have previously profiled oxylipins, endocannabinoids, bile acids, and steroids in 293 CSF and 202 matched plasma samples from AD cases and healthy controls and identified both central and peripheral markers of AD pathology within inflammation-regulating cytochrome p450/soluble epoxide hydrolase pathway. Additionally, using proteomics, we have identified five cerebrospinal fluid protein panels, involved in the regulation of energy metabolism, vasculature, myelin/oligodendrocyte, glia/inflammation, and synapses/neurons, affected in AD, and reflective of AD-related changes in the brain. In the current manuscript, using metabolomics-proteomics data integration, we describe new associations between peripheral and central lipid mediators, with the above-described CSF protein panels. Particularly strong associations were observed between cytochrome p450/soluble epoxide hydrolase metabolites, bile acids, and proteins involved in glycolysis, blood coagulation, and vascular inflammation and the regulators of extracellular matrix. Those metabolic associations were not observed at the gene-co-expression level in the central nervous system. In summary, this manuscript provides new information regarding Alzheimer's disease, linking both central and peripheral metabolism, and illustrates the necessity for the "omics" data integration to uncover associations beyond gene co-expression.PMID:37612324 | DOI:10.1038/s41598-023-39737-8

Chin Med J (Engl). 2023 Aug 23. doi: 10.1097/CM9.0000000000002816. Online ahead of print.ABSTRACTBACKGROUND: Liver cancer is largely resistant to chemotherapy. This study aimed to identify the effective chemotherapeutics for β-catenin-activated liver cancer which is caused by gain-of-function mutation of catenin beta 1 (CTNNB1), the most frequently altered proto-oncogene in hepatic neoplasms.METHODS: Constitutive β-catenin-activated mouse embryonic fibroblasts (MEFs) were established by deleting exon 3 (β-cateninΔ(ex3)/+), the most common mutation site in CTNNB1 gene. A screening of 12 widely used chemotherapy drugs was conducted for the ones that selectively inhibited β-cateninΔ(ex3)/+ but not for wild-type MEFs. Untargeted metabolomics was carried out to examine the alterations of metabolites in nucleotide synthesis. The efficacy and selectivity of methotrexate (MTX) on β-catenin-activated human liver cancer cells were determined in vitro. Immuno-deficient nude mice subcutaneously inoculated with β-catenin wild-type or mutant liver cancer cells and hepatitis B virus (HBV); β-cateninlox(ex3)/+ mice were used, respectively, to evaluate the efficacy of MTX in the treatment of β-catenin mutant liver cancer.RESULTS: MTX was identified and validated as a preferential agent against the proliferation and tumor formation of β-catenin-activated cells. Boosted nucleotide synthesis was the major metabolic aberration in β-catenin-active cells, and this alteration was also the target of MTX. Moreover, MTX abrogated hepatocarcinogenesis of HBV; β-cateninlox(ex3)/+ mice, which stimulated concurrent Ctnnb1-activated mutation and HBV infection in liver cancer.CONCLUSION: MTX is a promising chemotherapeutic agent for β-catenin hyperactive liver cancer. Since repurposing MTX has the advantages of lower risk, shorter timelines, and less investment in drug discovery and development, a clinical trial is warranted to test its efficacy in the treatment of β-catenin mutant liver cancer.PMID:37612257 | DOI:10.1097/CM9.0000000000002816

J Biol Chem. 2023 Aug 21:105186. doi: 10.1016/j.jbc.2023.105186. Online ahead of print.ABSTRACTLoss of protein kinase Cδ (PKCδ) activity renders cells resistant to DNA damaging agents, including irradiation, however the mechanism(s) underlying resistance is poorly understood. Here we have asked if metabolic reprogramming by PKCδ contributes to radioprotection. Analysis of global metabolomics showed that depletion of PKCδ affects metabolic pathways that control energy production, and antioxidant, nucleotide, and amino acid biosynthesis. Increased NADPH and nucleotide production in PKCδ depleted cells is associated with upregulation of the pentose phosphate pathway (PPP) as evidenced by increased activation of G6PD and an increase in the nucleotide precursor, 5-phosphoribosyl-1-pyrophosphate. Stable isotope tracing with U-[13C6] glucose showed reduced utilization of glucose for glycolysis in PKCδ depleted cells, and no increase in U-[13C6] glucose incorporation into purines or pyrimidines. In contrast, isotope tracing with [13C5, 15N2] glutamine showed increased utilization of glutamine for synthesis of nucleotides, glutathione and TCA intermediates, and increased incorporation of labelled glutamine into pyruvate and lactate. Using a glycolytic rate assay, we confirmed that anaerobic glycolysis is increased in PKCδ depleted cells; this was accompanied by a reduction in oxidative phosphorylation, as assayed using a mitochondrial stress assay. Importantly, pretreatment of cells with specific inhibitors of the PPP or glutaminase prior to irradiation reversed radioprotection in PKCδ depleted cells, indicating that these cells have acquired co-dependency on the PPP and glutamine for survival. Our studies demonstrate that metabolic reprogramming to increase utilization of glutamine and nucleotide synthesis contributes to radioprotection in the context of PKCδ inhibition.PMID:37611829 | DOI:10.1016/j.jbc.2023.105186

Cell Rep. 2023 Aug 18:112997. doi: 10.1016/j.celrep.2023.112997. Online ahead of print.ABSTRACTColorectal cancer (CRC) is driven by genomic alterations in concert with dietary influences, with the gut microbiome implicated as an effector in disease development and progression. While meta-analyses have provided mechanistic insight into patients with CRC, study heterogeneity has limited causal associations. Using multi-omics studies on genetically controlled cohorts of mice, we identify diet as the major driver of microbial and metabolomic differences, with reductions in α diversity and widespread changes in cecal metabolites seen in high-fat diet (HFD)-fed mice. In addition, non-classic amino acid conjugation of the bile acid cholic acid (AA-CA) increased with HFD. We show that AA-CAs impact intestinal stem cell growth and demonstrate that Ileibacterium valens and Ruminococcus gnavus are able to synthesize these AA-CAs. This multi-omics dataset implicates diet-induced shifts in the microbiome and the metabolome in disease progression and has potential utility in future diagnostic and therapeutic developments.PMID:37611587 | DOI:10.1016/j.celrep.2023.112997

Ecotoxicol Environ Saf. 2023 Aug 21;263:115393. doi: 10.1016/j.ecoenv.2023.115393. Online ahead of print.ABSTRACTChildren are disproportionately represented among those who suffer asthma, which is a kind of chronic airway inflammation. Asthma symptoms might worsen when exposed to the air pollutant particulate matter 2.5 (PM2.5). However, it is becoming more prevalent among older adults, with more asthma-related deaths occurring in this pollution than in any other age group, and symptoms caused by asthma can reduce the quality of life of the elderly, whose asthma is underdiagnosed due to physiological factors. Therefore, in an effort to discover a therapy for older asthma during exposure to air pollution, we sought to ascertain the effects of pre-exposure (PA) and persistent exposure (PAP) to PM2.5 in aged asthma rats. In this study, we exposed aged rats to PM2.5 at different times (PA and PAP) and established an ovalbumin-mediated allergic asthma model. The basic process of elderly asthma caused by PM2.5 exposure was investigated by lung function detection, enzyme-linked immunosorbent assay (ELISA), histopathology, cytology, cytokine microarray, untargeted metabolomics, and gut microbiota analysis. Our findings demonstrated that in the PA and PAP groups, exposure to PM2.5 reduced lung function and exacerbated lung tissue damage, with varying degrees of effect on immunoglobulin levels, the findings of a cytological analysis, cytokines, and chemokines. The PA and PAP rats had higher amounts of polycyclic aromatic hydrocarbons (PAHs), such as naphthalene, 2-methylNaphthalene, 1-methylNaphthalene and flourene. Moreover, exposure to PM2.5 at different times showed different effects on plasma metabolism and gut microbiota. Bioinformatics analysis showed a strong correlation between PAHs, cytokines, and gut microbiota, and PAHs may cause metabolic disorders through the gut microbiota. These findings point to a possible mechanism for the development of asthma in older people exposure to PM2.5 that may be related to past interactions between PAHs, cytokines, gut microbiota, and plasma metabolites.PMID:37611479 | DOI:10.1016/j.ecoenv.2023.115393

Phytomedicine. 2023 Aug 16;120:155037. doi: 10.1016/j.phymed.2023.155037. Online ahead of print.ABSTRACTBACKGROUND: Pudilan Xiaoyan Oral Liquid (PDL) is a famous traditional Chinese prescription recorded in the Chinese Pharmacopeia, which is widely used to treat inflammatory diseases of the respiratory tract in children and adults. However, the endogenous changes in children and adults with PDL in the treatment of acute pharyngitis remain unclear.PURPOSE: The differential regulatory roles of PDL in endogenous metabolism and gut microbes in young and adult rats were investigated with a view to providing a preclinical data reference for PDL in medication for children.METHODS: An acute pharyngitis model was established, and serum levels of inflammatory factors and histopathology were measured. This study simulated the growth and development of children in young rats and explored the endogenous metabolic characteristics and intestinal microbial composition after the intervention of PDL by using serum metabolomic technique and 16S rRNA high-throughput sequencing technique.RESULTS: The results showed that PDL had therapeutic effects on young and adult rats with acute pharyngitis. Sixteen biomarkers were identified by metabolomics in the serum of young rats and 23 in adult rats. PDL can also affect intestinal microbial diversity and community richness in young and adult rats. Alloprevotella, Allobaculum, Alistipes, Bifidobacterium, and Enterorhabdus were prominent bacteria in young rats. Bacteria from the phylum Firmicutes of the adult rats changed more significantly under the treatment of PDL. In young rats, amino acid metabolism was the primary regulatory mode of PDL, whereas, in adult rats, glycerophospholipid metabolism was studied.CONCLUSION: The regulation of PDL on the serum metabolite group and intestinal microflora in young rats was different from that in adult rats, indicating the necessity of an independent study on children's medication. PDL may also exert therapeutic effects on young and adult rats by regulating gut microbial homeostasis. The results support the clinical application of PDL.PMID:37611464 | DOI:10.1016/j.phymed.2023.155037

Comput Biol Med. 2023 Aug 10;165:107329. doi: 10.1016/j.compbiomed.2023.107329. Online ahead of print.ABSTRACTScreening potential drug-drug interactions, drug-gene interactions, contraindications, and other factors is crucial in clinical practice. However, implementing these screening concepts in real-world settings poses challenges. This work proposes an approach towards precision medicine that combines genetic and nongenetic factors to facilitate clinical decision-making. The approach focuses on raising the performance of four potential interaction screenings in the prescribing process, including drug-drug interactions, drug-gene interactions, drug-herb interactions, drug-social lifestyle interactions, and two potential considerations for patients with liver or renal impairment. The work describes the design of a curated knowledge-based model called the knowledge model for potential interaction and consideration screening, the screening logic for both the detection module and inference module, and the personalized prescribing report. Three case studies have demonstrated the proof-of-concept and effectiveness of this approach. The proposed approach aims to reduce decision-making processes for healthcare professionals, reduce medication-related harm, and enhance treatment effectiveness. Additionally, the recommendation with a semantic network is suggested to assist in risk-benefit analysis when health professionals plan therapeutic interventions with new medicines that have insufficient evidence to establish explicit recommendations. This approach offers a promising solution to implementing precision medicine in clinical practice.PMID:37611418 | DOI:10.1016/j.compbiomed.2023.107329

J Hazard Mater. 2023 Aug 19;460:132344. doi: 10.1016/j.jhazmat.2023.132344. Online ahead of print.ABSTRACTAlgal-bacterial symbiosis systems have emerged as sustainable methods for the treatment of new pollutants and the recovery of resources. However, the bio-refinery of biomass derived from microalgae is inefficient and expensive. In order to simultaneously degrade antibiotic and recover resources efficiently, two algal-bacterial symbiosis systems were constructed using Pseudomonas aeruginosa (alginate overproduction) and Bacillus subtilis (poly-γ-glutamic acid overproduction) with amoxicillin-degrading-microalga Prototheca zopfii W1. The optimal conditions for W1 to degrade amoxicillin are 35 °C, pH 7, and 180 rpm. In the presence of 5-50 mg/L of amoxicillin, W1-P. aeruginosa and W1-B. subtilis exhibit higher amoxicillin degradation and produce more extracellular polymers than W1 or bacteria alone. The metabolomic analysis demonstrates that the algal-bacterial symbiosis enhances the tolerance of W1 to amoxicillin by altering carbohydrate metabolism and promotes the production of biopolymers by upregulating the precursors synthesis. Moreover, the removal of amoxicillin (10 mg/L) from livestock effluent by W1-P. aeruginosa and W1-B. subtilis is greater than 90 % in 3 days, and the maximum yields of alginate and poly-γ-glutamate are 446.1 and 254.3 mg/g dry cell weight, respectively. These outcomes provide theoretical support for the application of algal-bacterial symbiosis systems to treatment of amoxicillin wastewater and efficient production of biopolymers.PMID:37611392 | DOI:10.1016/j.jhazmat.2023.132344