PubMed

Clin Pharmacol Ther. 2023 May 7. doi: 10.1002/cpt.2932. Online ahead of print.ABSTRACTTrimethoprim is predicted to inhibit several thiamine transporters, including the primary thiamine intestinal absorptive transporter, ThTR-2, and the hepatic and renal organic cation transporters, OCT1, OCT2, and MATEs. To investigate the effect of trimethoprim on thiamine absorption, studies were conducted in cells, mice, and healthy volunteers and supported by use of real-world data. In a randomized, crossover clinical study, seven healthy volunteers were given a single oral dose of thiamine or thiamine plus trimethoprim, followed by blood sampling. The thiamine area under the curve (AUC) increased with trimethoprim co-administration (p-value =0.031), similar results were seen in mice. Trimethoprim appeared to act on thiamine absorption through inhibition of hepatic OCT1 as evidenced from its ability to modulate levels of isobutyrylcarnitine and propionylcarnitine, OCT1 biomarkers identified from metabolomic analyses. Real-world data further supported this finding, showing an association between trimethoprim use and higher levels of triglyceride, LDL cholesterol, and total cholesterol, consistent with OCT1 inhibition (p-values: 2.2 x 10-16 , 5.75 x 10-7 , 5.82 x 10-7 , respectively). Trimethoprim also reduced urinary excretion and clearance of biomarkers for OCT2 and MATEs, N-methylnicotinamide and N1 -methyladenosine. These findings suggest that trimethoprim increases plasma levels of thiamine by inhibiting hepatic OCT1. Trimethoprim also inhibited renal cation transporters, but that inhibition did not appear to play a role in the observed increases in thiamine levels. This study highlights the potential for drug-nutrient interactions involving transporters, in addition to transporters' established role in drug-drug interactions.PMID:37151050 | DOI:10.1002/cpt.2932

J Agric Food Chem. 2023 May 7. doi: 10.1021/acs.jafc.2c08731. Online ahead of print.ABSTRACTThis study investigated the beneficial effects of a Laminaria japonica polysaccharide (LJPS) on the systemic health of ducks by modulating the gut microbiome and metabolome. Our findings demonstrated that the LJPS supplementation enhanced the overall growth performance and physiological immune and antioxidant index of ducks. In addition, the LJPS-fed group significantly increased abundances of intestinal Bacteroides and Prevotellaceae with decreased α-diversity than that in the control group. Among the total of 1840 intestinal metabolites, 186 metabolites were identified to be differentially regulated by LJPS feeding (upregulated 143 metabolites and downregulated 43 metabolites), which is closely associated with some of the growth-related metabolic pathways. Lastly, the correlation analysis recapitulates that the beneficial effects of LJPS underlie the alterations in intestinal microbiota and metabolites. Taken together, LJPS supplementation improved the physiological parameters and richness of some beneficial microbes and upregulated certain metabolic pathways, which facilitated better productivities and systemic health of ducks.PMID:37150978 | DOI:10.1021/acs.jafc.2c08731

Pharmacol Ther. 2023 May 5:108436. doi: 10.1016/j.pharmthera.2023.108436. Online ahead of print.ABSTRACTIdiopathic pulmonary fibrosis (IPF) is a chronic progressive disorder of unknown origin and the most common interstitial lung disease. It progresses with the recruitment of fibroblasts and myofibroblasts that contribute to the accumulation of extracellular matrix (ECM) proteins, leading to the loss of compliance and alveolar integrity, compromising the gas exchange capacity of the lung. Moreover, while there are therapeutics available, they do not offer a cure. Thus, there is a pressing need to identify better therapeutic targets. With the advent of transcriptomics, proteomics, and metabolomics, the cellular mechanisms underlying disease progression are better understood. Metabolic homeostasis is one such factor and its dysregulation has been shown to impact the outcome of IPF. Several metabolic pathways involved in the metabolism of lipids, protein and carbohydrates have been implicated in IPF. While metabolites are crucial for the generation of energy, it is now appreciated that metabolites have several non-metabolic roles in regulating cellular processes such as proliferation, signaling, and death among several other functions. Through this review, we succinctly elucidate the role of several metabolic pathways in IPF. Moreover, we also discuss potential therapeutics which target metabolism or metabolic pathways.PMID:37150402 | DOI:10.1016/j.pharmthera.2023.108436

Environ Pollut. 2023 May 5:121779. doi: 10.1016/j.envpol.2023.121779. Online ahead of print.ABSTRACTAnaerobic digestion (AD) of wastewater is the most promising bioprocess for organic conversion, however, phenol is toxic and resistant to anaerobic degradation. The current study compared the effect of hydrochar and granular activated carbon (GAC) on AD of phenol at four concentrations (100 mg/L, 250 mg/L, 500 mg/L and 1000 mg/L). Results demonstrated that hydrochar significantly improved the methane production rate and reduced the lag phase at all concentrations of phenol. The methane production rate was improved by about 50% at both 100 mg/L and 250 mg/L phenol, while it was raised by >160% at 500 mg/L and 1000 mg/L phenol by hydrochar. The GAC only increased the methane production rate at 500 mg/L and 1000 mg/L due to high adsorption capacity. Further, the adsorption of phenol by hydrochar had no apparent impact on the methane production rate, even though certain amounts of phenol were adsorbed. At 500 mg/L, the amount of methane produced significantly increased, so 16S rRNA transcripts sequencing and metabolomic analysis were conducted. 16S rRNA transcripts sequencing analysis indicated that hydrochar resulted in the enrichment of syntrophic bacteria (e.g., Syntrophorhabdus &Syntrophobacter) and Methanosaeta, which might be related with direct interspecies electron transfer. Further, it was noticed that the growth of Methanobacterium was repressed at 500 mg/L phenol, while hydrochar promoted its growth. Phenol was degraded into L-tyrosine and then followed the benzoate degradation pathway for methane production as revealed by metabolomic analysis. In addition, metabolomic analysis also revealed that hydrochar promoted the degradation of all metabolites and enhanced the phenol degradation into methane.PMID:37150345 | DOI:10.1016/j.envpol.2023.121779

Clin Nutr. 2023 May 2;42(6):1025-1033. doi: 10.1016/j.clnu.2023.04.001. Online ahead of print.ABSTRACTBACKGROUND & AIMS: The beneficial effects of probiotic consumption on age-related decline in cerebral function have been previously reported in the literature; however, the mechanistic link between gut and brain interactions has not yet been fully elucidated. Therefore, this study aimed to identify the role of gut microbiota-derived metabolites in gut-brain interactions via blood metabolomic profiling analysis in clinical trials and in vitro mechanistic studies.METHODS: A randomized, double-blind, placebo-controlled, multicenter clinical trial was conducted in 63 healthy elderly individuals (≥65 years of age). Participants were administered either placebo (placebo group, N = 31) or probiotic capsules (Bifidobacterium bifidum BGN4 and Bifidobacterium longum BORI; probiotics group, N = 32) for 12 weeks. Global and targeted metabolomic profiling analyses of their blood samples were then performed using 1H nuclear magnetic resonance and liquid chromatography-mass spectrometry methods, both at baseline and at the end of the trial. Gut microbial analysis was conducted using the 16S ribosomal ribonucleic acid gene sequencing method. Subsequently, microglial BV2 cells were treated in vitro with indole-3-propionic acid (IPA) following lipopolysaccharide stimulation, and neuronal SH-SY5Y cells were treated with conditioned media from the BV2 cells. Finally, the levels of pro-inflammatory cytokines in BV2 cells and neurotrophins in SH-SY5Y cells were quantified using a real-time polymerase chain reaction or enzyme-linked immunosorbent assay.RESULTS: The metabolomic profiling analyses showed that probiotic consumption significantly altered the levels of metabolites involved in tryptophan metabolism (P < 0.01). Among these metabolites, gut microbiota-produced IPA had a 1.91-fold increase in the probiotics group (P < 0.05) and showed a significant relation to gut bacterial profiles (P < 0.01). Elevated IPA levels were also positively associated with the level of serum brain-derived neurotropic factor (BDNF) in the probiotics group (r = 0.28, P < 0.05), showing an inverse trend compared to the placebo group. In addition, in vitro treatment with IPA (5 μM) significantly reduced the concentration of proinflammatory TNF-α in activated microglia (P < 0.05), and neuronal cells cultured with conditioned media from IPA-treated microglia showed a significant increase in BDNF and nerve growth factor production (P < 0.05).CONCLUSIONS: These results show that gut microbiota-produced IPA plays a role in protecting the microglia from inflammation, thus promoting neuronal function. Therefore, this suggests that IPA is a significant mediator linking the interaction between the gut and the brain in the elderly with probiotic supplementation.PMID:37150125 | DOI:10.1016/j.clnu.2023.04.001

Ecotoxicol Environ Saf. 2023 May 5;258:114979. doi: 10.1016/j.ecoenv.2023.114979. Online ahead of print.ABSTRACTThe widespread usage of 3-tert-butyl-4-hydroxyanisole (3-BHA) as an anthropogenic antioxidant has caused considerable environmental contamination and frequent detection in diverse human-derived samples. 3-BHA can promote adipogenesis and impair hepatic lipid metabolism, while its effects on renal lipid homeostasis remain to be uncertain. Herein, using the human kidney 2 (HK-2) cell experiments, 3-BHA was found to cause a significant reduction in lipid accumulation of the HK-2 cells in both exposure concentration- and duration-dependent manners. Exposure to 3-BHA lowered the transcriptional expressions of sterol regulatory element-binding protein 1 (SREBP1) and acetyl-CoA carboxylase (ACC), as well as ACC activity, indicating the inhibition in the process of de novo lipogenesis in HK-2 cells. On this basis, the mechanism study suggested that the reduced glucose absorption and accelerated glycolysis were concomitantly involved. The antagonism of 3-BHA on the transactivation of androgen receptor (AR) contributed to the lowered de novo lipogenesis and the consequent intracellular lipid reduction. The metabolomics data further confirmed the imbalance of lipid homeostasis and dysregulation of de novo lipogenesis. The new findings on the impaired renal lipid metabolism induced by 3-BHA warranted proper care about the usage of this chemical as a food additive.PMID:37150107 | DOI:10.1016/j.ecoenv.2023.114979

Comput Biol Med. 2023 May 4;160:107007. doi: 10.1016/j.compbiomed.2023.107007. Online ahead of print.ABSTRACTBACKGROUND: The whole herb of Euphorbia helioscopia has been traditionally used for treating pulmonary tuberculosis, malaria, warts, lung cancer and bacillary dysentery for a long time in China. However, E. helioscopia seeds are often discarded and its medicinal value is often ignored, resulting in a waste of resources.METHOD: In this work, widely targeted metabolomics based on UPLC-ESI-QTRAP-MS/MS methods and metware database (MWDB) were firstly used to identify the chemical compositions of EHS. Besides, network pharmacology, molecular docking and molecular dynamics simulation were performed for elucidating the potential compounds and targets of E. helioscopia seeds for the treatment of pulmonary fibrosis via common database (like TCMSP, Genecards, DAVID, STRING) and common software (like Sybyl, Cytoscape, Pymol and Schrödinger).RESULT: The results of widely targeted metabolomics showed 231 compounds including 12 categories were identified. The highest content compositions are lipids (33.89%) followed by amino acids and derivatives (21.78%), nucleotides and derivatives (15.73%), as well as the content of functional ingredients like phenolic acids (7.33%), alkaloids (7.03%) and flavonoids (4.51%) are relatively high. Besides, the results of network pharmacology and molecular docking showed that EHS presented anti-pulmonary fibrosis medicinal value through multi-ingredients, multi-targets and multi-pathways approach. Key ingredients including 9-Hydroxy-12-oxo-15(Z)-octadecenoic acid, Nordihydrocapsiate, 1-O-Salicyl-d-glucose, 9-(Arabinosyl)hypoxanthine, Xanthosine and Galangin-7-O-glucoside. Key targets including SRC, HSP90AA1, AKT1, EGFR, JUN, EP300 and VEGFA, and key signaling pathways mainly related to AGE-RAGE, EGFR tyrosine kinase inhibitor resistance, VEGF and HIF-1 signaling pathway. Molecular dynamics simulation showed that HSP90AA1 and 9-Hydroxy-12-oxo-15(Z)-octadecenoic complex (with the highest docking score) have a stable combination effect.CONCLUSION: In conclusion, this study revealed the chemical compositions of EHS and its anti-pulmonary fibrosis medicinal effect for the first time, it will provide scientific insight for the development of EHS as medicinal resource.PMID:37150086 | DOI:10.1016/j.compbiomed.2023.107007

Plant Physiol Biochem. 2023 Apr 25;199:107722. doi: 10.1016/j.plaphy.2023.107722. Online ahead of print.ABSTRACTGoji berries (Lycium barbarum L.) were rich in flavonoids, showing high nutritional and medicinal value. However, a thorough evaluation and comparison of the flavonoids in goji berries from various regions and the possible biological regulation pathways with differences are scanty. Here, we investigated the flavonoid metabolites and gene expression levels of goji berries from three major production areas in China using transcriptomics sequencing and metabolomics. The total flavonoid content and total polyphenol content of goji berry in Ningxia (57.87 μg/g and 183.41 μg/g, respectively) were higher than in Qinghai (50.77 μg/g and 156.81 μg/g) and Gansu (47.86 μg/g and 111.17 μg/g). We identified the 105 differentially accumulated flavonoids (DAFs) and 1858 differentially expressed genes (DEGs) from the goji berries in three habitats. Interestingly, gossypetin-3-O-rutinoside and isorhamnetin were significantly expressed between Ningxia and Qinghai berries. The chalcone isomerase (CHI), chalcone synthase (CHS), and flavonol synthase (FLS) genes also played key roles in the regulation of flavonoid synthesis. In addition, MYB1 positively regulated the expression of quercetin-3-O-glucoside, quercetin-7-O-glucoside and isohyperoside. As a result, we speculated that CHI, CHS, FLS genes, and related transcription factors jointly controlled the variation of flavone accumulation in goji berries. These findings may provide a new perspective for understanding the accumulation and molecular mechanisms of goji flavonoids.PMID:37150012 | DOI:10.1016/j.plaphy.2023.107722

Plant Physiol Biochem. 2023 Apr 29;199:107727. doi: 10.1016/j.plaphy.2023.107727. Online ahead of print.ABSTRACTCopper (Cu) is one of the essential microelements and widely participates in various pathways in plants, but excess Cu in plant cells could induce oxidative stress and harm plant growth. Rice (Oryza sativa) is a main crop food worldwide. The molecular mechanisms of rice in response to copper toxicity are still not well understood. In this study, two-week-old seedlings of the rice cultivar Nipponbare were treated with 100 μM Cu2+ (CuSO4) in the external solution for 10 days. Physiological analysis showed that excess Cu significantly inhibited the growth and biomass of rice seedlings. After Cu treatment, the contents of Mn and Zn were significantly reduced in the roots and shoots, while the Fe content was significantly increased in the roots. Meanwhile, the activities of antioxidant enzymes including SOD and POD were dramatically enhanced after Cu treatment. Based on metabolomic analysis using liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods, 695 metabolites were identified in rice roots. Among these metabolites, 123 metabolites were up-regulated and 297 were down-regulated, respectively. The differential metabolites (DMs) include carboxylic acids and derivatives, benzene and substituted derivatives, carbonyl compounds, cinnamic acids and derivatives, fatty acyls and organ nitrogen compounds. KEGG analysis showed that these DMs were mainly enriched in TCA cycle, purine metabolism and starch and sucrose metabolism pathways. Many intermediates in the TCA cycle and purine metabolism were down-regulated, indicating a perturbed carbohydrate and nucleic acid metabolism. Taken together, the present study provides new insights into the mechanism of rice roots to Cu toxicity.PMID:37150010 | DOI:10.1016/j.plaphy.2023.107727

Plant Physiol Biochem. 2023 May 2;199:107740. doi: 10.1016/j.plaphy.2023.107740. Online ahead of print.ABSTRACTBlue honeysuckle (Lonicera caerulea L.) is rich in phenolic compounds and has an extremely high nutritional value. Fruit abscission in the ripe period significantly impacts production and economic benefits. However, the mechanism associated with the abscission of blue honeysuckle fruit remains largely unknown. The easy-abscission cultivar 'HSY' and the hard-abscission cultivar 'Berel' were selected as plant materials. Anatomical changes of the 'HSY' fruit abscission zone (FAZ) during the abscission mainly included cell expansion, detachment, and collapse. Active changes in cell wall-degrading enzyme activity between 39 days postanthesis (DPA) and 55 DPA in 'HSY' FAZ, but not in 'Berel', suggest a critical role for cell-wall-degrading enzymes in regulating abscission. Transcriptome and metabolome analyses revealed that the genes and metabolites responding to abscission mainly act on pathways such as plant hormone signal transduction, starch and sucrose metabolism, pentose and glucuronate interconversions, and phenylpropanoid biosynthesis. The regulatory pathways of fruit abscission are mainly summarized into two parts: phytohormone synthesis and signal transduction, FAZ cell wall metabolism. In this study, 46 key genes related to plant hormone response, 45 key genes involved in FAZ cell wall metabolism, and 73 transcription factors were screened. Quantitative real-time PCR (qRT-PCR) assessed the expression pattern of 12 selected candidate genes, demonstrating the accuracy of the transcriptome data and elucidating the expression patterns of key candidate genes during growth and development. This study will provide an essential resource for understanding the molecular regulatory mechanism of fruit abscission in the blue honeysuckle.PMID:37150009 | DOI:10.1016/j.plaphy.2023.107740

J Vet Med Sci. 2023 May 3. doi: 10.1292/jvms.23-0080. Online ahead of print.ABSTRACTL-amino acid oxidase (LAAO) is a metabolic enzyme that converts L-amino acids into ketoacids, ammonia, and hydrogen peroxide (H2O2). The generated H2O2 has previously been shown to have antibacterial and gut microbiota-modulatory properties in LAO1 knock-out (KO) mice. Since most microbial metabolites reach the liver through the portal vein, we examined gut-liver interactions in LAO1 KO mice. We found lower total cholesterol levels, higher glutamic pyruvic transaminase (GPT) levels in the serum, and higher pro-inflammatory cytokine mRNA expression in the liver tissue. In wild-type (WT) mice, LAO1 was expressed in gut tissues (ileum and colon). Microbiome analysis revealed that the abundance of some bacteria was altered in LAO1 KO mice. However, short-chain fatty acid (SCFAs) levels in cecal feces and gut permeability did not change. Fecal microbiota transplantation (FMT) revealed that feces from LAO1 KO mice slightly stimulated pro-inflammatory cytokine expression in the liver. During metabolomic analysis, 5-Aminolevulinic acid (5-ALA) was the only metabolite found to be significantly upregulated in the portal and abdominal veins of the LAO1 KO mice. Intraperitoneal administration of 5-ALA to WT mice significantly increased IL-6 mRNA expression in the liver. These observations suggest that gut LAO1 plays a role in regulating 5-ALA production and that a high level of 5-ALA stimulates the liver to increase pro-inflammatory cytokine expression by disrupting LAO1 in mice.PMID:37150613 | DOI:10.1292/jvms.23-0080

Cell Rep. 2023 May 6;42(5):112485. doi: 10.1016/j.celrep.2023.112485. Online ahead of print.ABSTRACTNeurovascular abnormalities in mouse models of 16p11.2 deletion autism syndrome are reminiscent of alterations reported in murine models of glucose transporter deficiency, including reduced brain angiogenesis and behavioral alterations. Yet, whether cerebrovascular alterations in 16p11.2df/+ mice affect brain metabolism is unknown. Here, we report that anesthetized 16p11.2df/+ mice display elevated brain glucose uptake, a phenomenon recapitulated in mice with endothelial-specific 16p11.2 haplodeficiency. Awake 16p11.2df/+ mice display attenuated relative fluctuations of extracellular brain glucose following systemic glucose administration. Targeted metabolomics on cerebral cortex extracts reveals enhanced metabolic responses to systemic glucose in 16p11.2df/+ mice that also display reduced mitochondria number in brain endothelial cells. This is not associated with changes in mitochondria fusion or fission proteins, but 16p11.2df/+ brain endothelial cells lack the splice variant NT-PGC-1α, suggesting defective mitochondrial biogenesis. We propose that altered brain metabolism in 16p11.2df/+ mice is compensatory to endothelial dysfunction, shedding light on previously unknown adaptative responses.PMID:37149866 | DOI:10.1016/j.celrep.2023.112485

Cell Rep. 2023 May 5;42(5):112474. doi: 10.1016/j.celrep.2023.112474. Online ahead of print.ABSTRACTBacterial vaginosis (BV) is characterized by depletion of Lactobacillus and overgrowth of anaerobic and facultative bacteria, leading to increased mucosal inflammation, epithelial disruption, and poor reproductive health outcomes. However, the molecular mediators contributing to vaginal epithelial dysfunction are poorly understood. Here we utilize proteomic, transcriptomic, and metabolomic analyses to characterize biological features underlying BV in 405 African women and explore functional mechanisms in vitro. We identify five major vaginal microbiome groups: L. crispatus (21%), L. iners (18%), Lactobacillus (9%), Gardnerella (30%), and polymicrobial (22%). Using multi-omics we show that BV-associated epithelial disruption and mucosal inflammation link to the mammalian target of rapamycin (mTOR) pathway and associate with Gardnerella, M. mulieris, and specific metabolites including imidazole propionate. Experiments in vitro confirm that type strain G. vaginalis and M. mulieris supernatants and imidazole propionate directly affect epithelial barrier function and activation of mTOR pathways. These results find that the microbiome-mTOR axis is a central feature of epithelial dysfunction in BV.PMID:37149863 | DOI:10.1016/j.celrep.2023.112474

Sci Rep. 2023 May 6;13(1):7387. doi: 10.1038/s41598-023-34435-x.ABSTRACTCytotrophoblasts fuse to form and renew syncytiotrophoblasts necessary to maintain placental health throughout gestation. During cytotrophoblast to syncytiotrophoblast differentiation, cells undergo regulated metabolic and transcriptional reprogramming. Mitochondria play a critical role in differentiation events in cellular systems, thus we hypothesized that mitochondrial metabolism played a central role in trophoblast differentiation. In this work, we employed static and stable isotope tracing untargeted metabolomics methods along with gene expression and histone acetylation studies in an established BeWo cell culture model of trophoblast differentiation. Differentiation was associated with increased abundance of the TCA cycle intermediates citrate and α-ketoglutarate. Citrate was preferentially exported from mitochondria in the undifferentiated state but was retained to a larger extent within mitochondria upon differentiation. Correspondingly, differentiation was associated with decreased expression of the mitochondrial citrate transporter (CIC). CRISPR/Cas9 disruption of the mitochondrial citrate carrier showed that CIC is required for biochemical differentiation of trophoblasts. Loss of CIC resulted in broad alterations in gene expression and histone acetylation. These gene expression changes were partially rescued through acetate supplementation. Taken together, these results highlight a central role for mitochondrial citrate metabolism in orchestrating histone acetylation and gene expression during trophoblast differentiation.PMID:37149697 | DOI:10.1038/s41598-023-34435-x

BMC Plant Biol. 2023 May 6;23(1):241. doi: 10.1186/s12870-023-04251-6.ABSTRACTBACKGROUND: The biochemical makeup of grape berries at harvest is essential for wine quality and depends on a fine transcriptional regulation occurring during berry development. In this study, we conducted a comprehensive survey of transcriptomic and metabolomic changes occurring in different berry tissues and developmental stages of the ancient grapes Aglianico and Falanghina to establish the patterns of the secondary metabolites contributing to their wine aroma and investigate the underlying transcriptional regulation.RESULTS: Over two hundred genes related to aroma were found, of which 107 were differentially expressed in Aglianico and 99 in Falanghina. Similarly, 68 volatiles and 34 precursors were profiled in the same samples. Our results showed a large extent of transcriptomic and metabolomic changes at the level of isoprenoids (terpenes, norisoprenoids), green leaf volatiles (GLVs), and amino acid pathways, although the terpenoid metabolism was the most distinctive for Aglianico, and GLVs for Falanghina. Co-expression analysis that integrated metabolome and transcriptome data pinpointed 25 hub genes as points of biological interest in defining the metabolic patterns observed. Among them, three hub genes encoding for terpenes synthases (VvTPS26, VvTPS54, VvTPS68) in Aglianico and one for a GDP-L-galactose phosphorylase (VvGFP) in Falanghina were selected as potential active player underlying the aroma typicity of the two grapes.CONCLUSION: Our data improve the understanding of the regulation of aroma-related biosynthetic pathways of Aglianico and Falanghina and provide valuable metabolomic and transcriptomic resources for future studies in these varieties.PMID:37149574 | DOI:10.1186/s12870-023-04251-6

Ann Surg Oncol. 2023 May 6. doi: 10.1245/s10434-023-13587-0. Online ahead of print.ABSTRACTBACKGROUND: There is a paucity of targeted therapies for patients with pseudomyxoma peritonei (PMP) secondary to low-grade appendiceal mucinous neoplasms (LAMNs). Dysregulated metabolism has emerged as a hallmark of cancer, and the relationship of metabolomics and cancer is an area of active scientific exploration. We sought to characterize phenotypic differences found in peritoneal metastases (PM) derived from LAMN versus adenocarcinoma.METHODS: Tumors were washed with phosphate-buffered saline (PBS), microdissected, then dissociated in ice-cold methanol dried and reconstituted in pyridine. Samples were derivatized in tert-butyldimethylsilyl (TBDMS) and subjected to gas chromatography-coupled mass spectrometry. Metabolites were assessed based on a standard library. RNA sequencing was performed, with pathway and network analyses on differentially expressed genes.RESULTS: Eight peritoneal tumor samples were obtained and analyzed: LAMNs (4), and moderate to poorly differentiated adenocarcinoma (colon [1], appendix [3]). Decreases in pyroglutamate, fumarate, and cysteine in PM from LAMNs were found compared with adenocarcinoma. Analyses showed the differential gene expression was dominated by the prevalence of metabolic pathways, particularly lipid metabolism. The gene retinol saturase (RETSAT), downregulated by LAMN, was involved in the multiple metabolic pathways that involve lipids. Using network mapping, we found IL1B signaling to be a potential top-level modulation candidate.CONCLUSIONS: Distinct metabolic signatures may exist for PM from LAMN versus adenocarcinoma. A multitude of genes are differentially regulated, many of which are involved in metabolic pathways. Additional research is needed to identify the significance and applicability of targeting metabolic pathways in the potential development of novel therapeutics for these challenging tumors.PMID:37149550 | DOI:10.1245/s10434-023-13587-0

Plant Sci. 2023 May 4:111726. doi: 10.1016/j.plantsci.2023.111726. Online ahead of print.ABSTRACTCadmium (Cd), one of the most widespread and water-soluble polluting heavy metals, has been widely studied on plants, even if the mechanisms underlying its phytotoxicity remain elusive. Indeed, most experiments are performed using extensive exposure time to the toxicants, not observing the primary targets affected. The present work studied Cd effects on Arabidopsis thaliana (L.) Heynh's root apical meristem (RAM) exposed for short periods (24h and 48h) to acute phytotoxic concentrations (100 and 150µM). The effects were studied through integrated morpho-histological, molecular, pharmacological and metabolomic analyses, highlighting that Cd inhibited primary root elongation by affecting the meristem zone via altering cell expansion. Moreover, Cd altered Auxin accumulation in RAM and affected PINs polar transporters particularly PIN2. In addition, we observed that high Cd concentration induced accumulation of reactive oxygen species (ROS) in roots, which resulted in an altered organization of cortical microtubules and the starch and sucrose metabolism, altering the statolith formation and, consequently, the gravitropic root response. Our results demonstrated that short Cd exposition (24h) affected cell expansion preferentially, altering auxin distribution and inducing ROS accumulation, which resulted in an alteration of gravitropic response and microtubules orientation pattern.PMID:37149227 | DOI:10.1016/j.plantsci.2023.111726

Chemosphere. 2023 May 4:138856. doi: 10.1016/j.chemosphere.2023.138856. Online ahead of print.ABSTRACTAlthough the previous research confirmed that triclosan (TCS) affects the female proportion at the early stage of zebrafish (Danio rerio) and has an estrogen effect, the mechanism by which TCS affects the sex differentiation of zebrafish is not entirely clear. In this study, zebrafish embryos were exposed to different concentrations of TCS (0, 2, 10, and 50 μg/L) for 50 consecutive days. The expression of sex differentiation related genes and metabolites were then determined in larvae using reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Liquid Chromatography-Mass Spectrometer (LC-MS), respectively. TCS upregulated the expression of the sox9a, dmrt1a and amh genes, down-regulating the expression of wnt4a, cyp19a1b, cyp19a1a, and vtg2 gene. The overlapped classification of Significant Differential Metabolites (SDMs) between the control group and three TCS treated groups related to gonadal differentiation was Steroids and steroid derivatives, including 24 down-regulated SDMs. The enriched pathways related to gonadal differentiation were Steroid hormone biosynthesis, Retinol metabolism, Metabolism of xenobiotics by cytochrome P450, and Cortisol synthesis and secretion. Moreover, SDMs were significantly enriched in Steroid hormone biosynthesis in the 2 μg/L TCS group, which included Dihydrotestosterone, Cortisol, 11beta-hydroxyandrost-4-ene-3, 17-dione, 21-Hydroxypregnenolone, Androsterone, Androsterone glucuronide, Estriol, Estradiol, 19-Hydroxytestosterone, Cholesterol, Testosterone, and Cortisone acetate. Results showed that TCS affects the female proportion mainly through Steroid hormone biosynthesis, in which aromatase plays a key role in zebrafish. Retinol metabolism, metabolism of xenobiotics by cytochrome P450, and cortisol synthesis and secretion may also participate in TCS-mediated sex differentiation. These findings reveal the molecular mechanisms of TCS-induced sex differentiation, and provide theoretical guidance for the maintenance of water ecological balance.PMID:37149099 | DOI:10.1016/j.chemosphere.2023.138856

Behav Brain Res. 2023 May 4:114476. doi: 10.1016/j.bbr.2023.114476. Online ahead of print.ABSTRACTThe prevalence of mental disorders such as depression and anxiety is high and often comorbid with other diseases. Chronic stress is a common risk factor for these disorders, but the mechanisms behind their development are not yet fully understood. Metabolomics has revealed a close association between purine and pyrimidine metabolism and depression and anxiety, with increased levels of serum xanthine observed in both humans and mice. Xanthine is known as purine metabolism, and this compound shows several biological activities, but the impact of xanthine on our brain function is still unclear. The hippocampus, which plays a crucial role in memory and learning, is also implicated in the pathophysiology of depression and anxiety. Here, we investigated the effects of xanthine intraperitoneal administration on spatial memory and anxiety-like behavior in mice. The findings indicated that xanthine administration induced a deficit of hippocampus-dependent spatial memory and a tendency to anxiety-like behavior in mice. RNA-seq analysis showed that xanthine administration upregulated hemoglobin (Hb) genes involved in oxygen transport in the hippocampus. The upregulated Hb genes occurred in the neuronal cells, and in vitro experiments revealed that both Hba-a1 derived from mice and HBA2 derived from humans were upregulated by xanthine treatment. These observations suggest that the xanthine-induced Hb in the hippocampus could be related to spatial memory deficit and anxiety. This study sheds light on the direct effects of xanthine on the brain and its potential role in the development of depression and anxiety symptoms caused by chronic stress.PMID:37148916 | DOI:10.1016/j.bbr.2023.114476

Int Immunopharmacol. 2023 May 4;119:110236. doi: 10.1016/j.intimp.2023.110236. Online ahead of print.ABSTRACTColorectal cancer (CRC) is currently recognized as the third most prevalent cancer worldwide. Vinpocetine is a synthetic derivative of the vinca alkaloid vincamine. It has been found effective in ameliorating the growth and progression of cancerous cells. However, its pharmacological effect on colon damage remains elusive. Hence, in this study, we have shown the role of vinpocetine in DMH-induced colon carcinogenesis. At first, male albino Wistar rats were administered with DMH consistently for four weeks to induce pre-neoplastic colon damage. Afterward, animals were treated with vinpocetine (4.2 and 8.4 mg/kg/day p.o.) for 15 days. Serum samples were collected to assess the physiological parameters, including ELISA and NMR metabolomics. Colon from all the groups was collected and processed separately for histopathology and western blot analysis. Vinpocetine attenuated the altered plasma parameters; lipid profile and showed anti-proliferative action as evidenced by suppressed COX-2 stimulation and decreased levels of IL-1β, IL-2, IL-6, and IL-10. Vinpocetine is significantly effective in preventing CRC which may be associated with its anti-inflammatory and antioxidant potential. Accordingly, vinpocetine could serve as a potential anticancer agent for CRC treatment and thus be considered for future clinical and therapeutic research.PMID:37148772 | DOI:10.1016/j.intimp.2023.110236