PubMed

Food Chem. 2023 Sep 12;434:137410. doi: 10.1016/j.foodchem.2023.137410. Online ahead of print.ABSTRACTMetabolomics is widely established in the field of food authenticity to address demanding issues, such as adulteration cases. Trapped ion mobility spectrometry (TIMS) coupled to liquid chromatography (LC) and high-resolution mass spectrometry (HRMS) provides an additional analytical dimension, introducing mobility-enhanced metabolomics in four dimensions (4D). In the present work, the potential of LC-TIMS-HRMS as a reliable analytical platform for authenticity studies is being explored, applied in extra virgin olive oil (EVOO) adulteration study. An integrated untargeted 4D-metabolomics approach is being implemented to investigate adulteration, with refined olive oils (ROOs) and olive pomace oils (OPOs) set as adulterants. Robust prediction models are built, successfully discriminating authentic EVOOs from adulterated ones and highlighting markers in each group. Noteworthy outcomes are retrieved regarding TIMS added value in LC-HRMS workflows, resulting in a significant increase of metabolic coverage, while, thanks to platform's enhanced sensitivity, detection of adulteration is being achieved down to 1%.PMID:37708573 | DOI:10.1016/j.foodchem.2023.137410

J Am Soc Mass Spectrom. 2023 Sep 14. doi: 10.1021/jasms.3c00158. Online ahead of print.ABSTRACTMeningiomas are among the most common brain tumors that arise from the leptomeningeal cover of the brain and spinal cord and account for around 37% of all central nervous system tumors. According to the World Health Organization, meningiomas are classified into three histological subtypes: benign, atypical, and anaplastic. Sometimes, meningiomas with a histological diagnosis of benign tumors show clinical characteristics and behavior of aggressive tumors. In this study, we examined the metabolomic and lipidomic profiles of meningioma tumors, focusing on comparing low-grade and high-grade tumors and identifying potential markers that can discriminate between benign and malignant tumors. High-resolution mass spectrometry coupled to liquid chromatography was used for untargeted metabolomics and lipidomics analyses of 85 tumor biopsy samples with different meningioma grades. We then applied feature selection and machine learning techniques to find the features with the highest information to aid in the diagnosis of meningioma grades. Three biomarkers were identified to differentiate low- and high-grade meningioma brain tumors. The use of mass-spectrometry-based metabolomics and lipidomics combined with machine learning analyses to prospect and characterize biomarkers associated with meningioma grades may pave the way for elucidating potential therapeutic and prognostic targets.PMID:37708056 | DOI:10.1021/jasms.3c00158

Cell Rep. 2023 Sep 13;42(9):113131. doi: 10.1016/j.celrep.2023.113131. Online ahead of print.ABSTRACTCold-induced brown adipose tissue (BAT) activation is considered to improve metabolic health. In murine BAT, cold increases the fundamental molecule for mitochondrial function, nicotinamide adenine dinucleotide (NAD+), but limited knowledge of NAD+ metabolism during cold in human BAT metabolism exists. We show that cold increases the serum metabolites of the NAD+ salvage pathway (nicotinamide and 1-methylnicotinamide) in humans. Additionally, individuals with cold-stimulated BAT activation have decreased levels of metabolites from the de novo NAD+ biosynthesis pathway (tryptophan, kynurenine). Serum nicotinamide correlates positively with cold-stimulated BAT activation, whereas tryptophan and kynurenine correlate negatively. Furthermore, the expression of genes involved in NAD+ biosynthesis in BAT is related to markers of metabolic health. Our data indicate that cold increases serum tryptophan conversion to nicotinamide to be further utilized by BAT. We conclude that NAD+ metabolism is activated upon cold in humans and is probably regulated in a coordinated fashion by several tissues.PMID:37708023 | DOI:10.1016/j.celrep.2023.113131

JCI Insight. 2023 Sep 14:e169208. doi: 10.1172/jci.insight.169208. Online ahead of print.ABSTRACTModulation of the immune response to initiate and halt the inflammatory process occurs both at the site of injury as well as systemically. Due to the evolving role of cellular metabolism in regulating cell fate and function, tendon injuries which undergo normal and aberrant repair were evaluated by metabolic profiling to determine its impact on healing outcomes. Metabolomics revealed an increasing abundance of the immunomodulatory metabolite itaconate with the injury site. Subsequent single-cell RNA sequencing, molecular and metabolomic validation identified a highly mature neutrophil subtype, not macrophages, as the primary producers of itaconate following trauma. These mature itaconate-producing neutrophils were highly inflammatory, producing cytokines that promote local injury fibrosis before cycling back to the bone marrow. In the bone marrow, itaconate was shown to alter hematopoiesis, skewing progenitor cells down myeloid lineages, thereby regulating systemic inflammation. Therapeutically, exogenous itaconate was found to reduce injury site inflammation, promoting tenogenic differentiation and impairing aberrant vascularization with disease ameliorating effects. These results present an intriguing role for cycling neutrophils as a sensor of inflammation induced by injury, potentially regulating immune cell production in the bone marrow, through delivery of endogenously produced itaconate and demonstrate a therapeutic potential for exogenous itaconate following tendon injury.PMID:37707952 | DOI:10.1172/jci.insight.169208

Med Sci Sports Exerc. 2023 Sep 13. doi: 10.1249/MSS.0000000000003291. Online ahead of print.ABSTRACTPURPOSE: To determine if time-efficient, high-resistance inspiratory muscle strength training (IMST), comprising 30 inhalation-resisted breaths per day, improves cardiorespiratory fitness, exercise tolerance, physical function and/or regional body composition in healthy midlife and older adults.METHODS: We performed a double-blind, randomized, sham-controlled clinical trial (NCT03266510) testing 6 weeks of IMST (30 breaths/day, 6 days/week, 55%-75% maximal inspiratory pressure) versus low-resistance sham training (15% maximal inspiratory pressure) in healthy men and women aged 50-79 years. Subjects performed a graded treadmill exercise test to exhaustion, physical performance battery (e.g., handgrip strength, leg press), and body composition testing (dual x-ray absorptiometry) at baseline and after 6 weeks of training.RESULTS: Thirty-five participants (17 women, 18 men) completed high-resistance IMST (n = 17) or sham training (n = 18). Cardiorespiratory fitness (V̇O2peak) was unchanged, but exercise tolerance, measured as treadmill exercise time during a graded exercise treadmill test, increased with IMST (baseline: 539 ± 42 s, end-intervention: 606 ± 42 s; p = 0.01) but not sham training (baseline: 562 ± 39 s, end-intervention: 553 ± 38 s; p = 0.69). IMST increased peak respiratory exchange ratio (baseline: 1.09 ± 0.02, end-intervention: 1.13 ± 0.02; p = 0.012), peak ventilatory efficiency (baseline: 25.2 ± 0.8, end-intervention: 24.6 ± 0.8; p = 0.036) and improved submaximal exercise economy (baseline: 23.5 ± 1.1 ml/kg/min, end-intervention: 22.1 ± 1.1 ml/kg/min; p < 0.001); none of these factors were altered by sham training (all p > 0.05). Changes in plasma acylcarnitines (targeted metabolomics analysis) were consistently positively correlated with changes in exercise tolerance following IMST but not sham training. IMST was associated with regional increases in thorax lean mass (+4.4%; p = 0.06) and reductions in trunk fat mass (-4.8%; p = 0.04); however, peripheral muscle strength, muscle power, dexterity and mobility were unchanged.CONCLUSIONS: These data suggest that high-resistance IMST is an effective, time-efficient lifestyle intervention for improving exercise tolerance in healthy midlife and older adults.PMID:37707508 | DOI:10.1249/MSS.0000000000003291

Cardiovasc Res. 2023 Sep 14:cvad147. doi: 10.1093/cvr/cvad147. Online ahead of print.ABSTRACTAIMS: Myocardial infarction (MI) is a major cause of death and disability worldwide. Most metabolomics studies investigating metabolites predicting MI are limited by the participant number and/or the demographic diversity. We sought to identify biomarkers of incident MI in the Consortium of Metabolomics Studies (COMETS).METHODS AND RESULTS: We included 7,897 individuals aged on average 66 years from six intercontinental cohorts with blood metabolomic profiling (n = 1,428 metabolites, of which 168 were present in at least 3 cohorts with over 80% prevalence) and MI information (1,373 cases). We performed a two-stage Individual Patients Data meta-analysis. We first assessed the associations between circulating metabolites and incident MI for each cohort adjusting for traditional risk factors, and then performed a fixed effect inverse-variance meta-analysis to pull the results together. Finally, we conducted a pathway enrichment analysis to identify potential pathways linked to MI.On meta-analysis, 56 metabolites including 21 lipids and 17 amino acids were associated with incident MI after adjusting for multiple testing (false discovery rate, FDR < 0.05), and 10 were novel. The largest increased risk was observed for the carbohydrate mannitol/sorbitol (HR [95% CI] = 1.40[1.26-1.56], p-value < 0.001), whereas the largest decrease in risk was found for glutamine (HR [95% CI] = 0.74[0.67-0.82], p-value < 0.001). Moreover, the identified metabolites were significantly enriched (corrected p-value < 0.05) in pathways previously linked with cardiovascular diseases, including aminoacyl-tRNA biosynthesis.CONCLUSIONS: In the most comprehensive metabolomics study of incident MI to date, 10 novel metabolites were associated with MI. Metabolite profiles might help to identify high-risk individuals before disease onset. Further research is needed to fully understand the mechanisms of action and elaborate pathway findings.TRANSLATIONAL PERSPECTIVE: In the largest meta-analyses covering six international cohorts, we identify 10 novel and 46 known metabolites associated with incident MI, that can be used to identify at-risk individuals before disease onset. Our results improve our understanding of the molecular changes that take place in MI development and provide potential novel targets for clinical prediction and a deeper understanding of causal mechanisms.PMID:37706562 | DOI:10.1093/cvr/cvad147

Oncologist. 2023 Sep 14:oyad261. doi: 10.1093/oncolo/oyad261. Online ahead of print.ABSTRACTBACKGROUND: To date, no study has systematically explored the potential role of serum metabolites and lipids in the diagnosis of small cell lung cancer (SCLC). Therefore, we aimed to conduct a case-cohort study that included 191 cases of SCLC, 91 patients with lung adenocarcinoma, 82 patients with squamous cell carcinoma, and 97 healthy controls.METHODS: Metabolomics and lipidomics were applied to analyze different metabolites and lipids in the serum of these patients. The SCLC diagnosis model (d-model) was constructed using an integrated machine learning technology and a training cohort (n = 323) and was validated in a testing cohort (n=138).RESULTS: Eight metabolites, including 1-mristoyl-sn-glycero-3-phosphocholine, 16b-hydroxyestradiol, 3-phosphoserine, cholesteryl sulfate, D-lyxose, dioctyl phthalate, DL-lactate and Leu-Phe, were successfully selected to distinguish SCLC from controls. The d-model was constructed based on these 8 metabolites and showed improved diagnostic performance for SCLC, with the area under curve (AUC) of 0.933 in the training cohort and 0.922 in the testing cohort. Importantly, the d-model still had an excellent diagnostic performance after adjusting the stage and related clinical variables and, combined with the progastrin-releasing peptide (ProGRP), showed the best diagnostic performance with 0.975 of AUC for limited-stage patients.CONCLUSION: This study is the first to analyze the difference between metabolomics and lipidomics and to construct a d-model to detect SCLC using integrated machine learning. This study may be of great significance for the screening and early diagnosis of SCLC patients.PMID:37706531 | DOI:10.1093/oncolo/oyad261

Curr Opin Organ Transplant. 2023 Sep 13. doi: 10.1097/MOT.0000000000001100. Online ahead of print.ABSTRACTPURPOSE OF REVIEW: Molecular omics data is increasingly ubiquitous throughout medicine. In organ transplantation, recent large-scale research efforts are generating the 'transplant-ome' - the entire set of molecular omics data, including the genome, transcriptome, proteome, and metabolome. Importantly, early studies in anesthesiology have demonstrated how perioperative interventions alter molecular profiles in various patient populations. The next step for anesthesiologists and intensivists will be to tailor perioperative care to the transplant-ome of individual liver transplant patients.RECENT FINDINGS: In liver transplant patients, elements of the transplant-ome predict complications and point to novel interventions. Importantly, molecular profiles of both the donor organ and recipient contribute to this risk, and interventions like normothermic machine perfusion influence these profiles. As we can now measure various omics molecules simultaneously, we can begin to understand how these molecules interact to form molecular networks and emerging technologies offer noninvasive and continuous ways to measure these networks throughout the perioperative period. Molecules that regulate these networks are likely mediators of complications and actionable clinical targets throughout the perioperative period.SUMMARY: The transplant-ome can be used to tailor perioperative care to the individual liver transplant patient. Monitoring molecular networks continuously and noninvasively would provide new opportunities to optimize perioperative management.PMID:37706301 | DOI:10.1097/MOT.0000000000001100

Cancer Sci. 2023 Sep 14. doi: 10.1111/cas.15960. Online ahead of print.ABSTRACTPTEN and PIK3CA mutations are the most prevalent PI3K pathway alterations in prostate, breast, colorectal, and endometrial cancers. p110β becomes the prominent PI3K isoform upon PTEN loss. In this study, we aimed to understand the molecular mechanisms of PI3K dependence in the absence of PTEN. Using online bioinformatical tools, we examined two publicly available microarray datasets with aberrant PI3K activation. We found that the rate-limiting enzyme of cholesterol biogenesis, SQLE, was significantly upregulated in p110β-hyperactivated or PTEN-deficient mouse prostate tumors. Concomitantly, the expression of cholesterol biosynthesis pathway enzymes was directly correlated with PI3K activation status in microarray datasets and diminished upon PTEN re-expression in PTEN-null prostate cancer cells. Particularly, PTEN re-expression decreased SQLE protein levels in PTEN-deficient prostate cancer cells. We performed targeted metabolomics and detected reduced levels of cholesteryl esters as well as free cholesterol upon PTEN re-expression. Notably, PTEN-null prostate and breast cancer cell lines were more sensitive to pharmacological intervention with the cholesterol pathway than PTEN-replete cancer cells. Since steroid hormones use sterols as structural precursors, we studied whether cholesterol biosynthesis may be a metabolic vulnerability that enhances antihormone therapy in PTEN-null castration-resistant prostate cancer cells. Coinhibition of cholesterol biosynthesis and the androgen receptor enhanced their sensitivity. Moreover, PTEN suppression in endocrine therapy-resistant luminal-A breast cancer cells leads to an increase in SQLE expression and a corresponding sensitization to the inhibition of cholesterol synthesis. According to our data, targeting cholesterol biosynthesis in combination with the hormone receptor signaling axis can potentially treat hormone-resistant prostate and breast cancers.PMID:37706278 | DOI:10.1111/cas.15960

J Am Soc Mass Spectrom. 2023 Sep 14. doi: 10.1021/jasms.3c00103. Online ahead of print.ABSTRACTImatinib (IM) resistance is considered to be a significant challenge in the management of chronic myeloid leukemia (CML). Previous studies have reported that hsa-miR-145-5p and hsa-miR-203a-5p can overcome IM resistance and hsa-miR-203a-5p can alter glutathione metabolism in IM-resistant cells. The purpose of this study was to examine whether hsa-miR-145-5p or hsa-miR-203a-5p counters IM resistance by targeting the overall metabolic profile of IM-resistant K562 cells. The metablic profiling of cell lysates obtained from IM-sensitive, IM-resistant, and miR-transfected IM-resistant K562 cells was carried out using the GC-MS technique. Overall, 75 major metabolites were detected, of which 32 were present in all samples. The pathway analysis of MetaboAnalyst 5.0 revealed that the majorly enriched pathways included glucose metabolism, fatty acid biosynthesis, lipogenesis, and nucleotide metabolism. Eleven of identified metabolites, l-glutamine, l-glutamic acid, l-lactic acid, phosphoric acid, 9,12-octadecadienoic acid, 9-octadecenoic acid, myristic acid, palmitic acid, cholesterol, and β-alanine, appeared in enriched pathways. IM-resistant cells had comparatively higher concentrations of all of these metabolites. Notably, the introduction of hsa-miR-145-5p or hsa-miR-203a-5p into resistant cells resulted in a decrease in levels of these metabolites. The efficacy of miR-203a-5p was particularly remarkable in comparison with miR-145-5p, as evidenced by partial least-squares-discriminant analysis (PLS-DA), which showed a high level of similarity in metabolic profile between IM-sensitive K562 cells and IM-resistant cells transfected with hsa-miR-203a-5p. The results indicate that GC-MS-based metabolic profiling has the potential to distinguish between drug-resistant and -sensitive cells. This approach can also be used to routinely monitor therapeutic response in drug-resistant patients, thus, enabling personalized therapy.PMID:37706267 | DOI:10.1021/jasms.3c00103

Plant Cell Physiol. 2023 Sep 14:pcad110. doi: 10.1093/pcp/pcad110. Online ahead of print.ABSTRACTDesiccation-tolerant (DT) plants can survive extreme dehydration and tolerate the loss of up to 95% of their water content, making them ideal systems to determine the mechanism behind extreme drought stress and identify potential approaches for developing drought-tolerant crops. The desert moss Syntrichia caninervis is an emerging model for extreme desiccation tolerance that has benefited from high-throughput sequencing analyses, allowing identification of stress-tolerant genes; however, its metabolic response to desiccation is unknown. A liquid chromatography-mass spectrometry analysis of S. caninervis at six dehydration-rehydration stages revealed 912 differentially abundant compounds, belonging to 93 metabolic classes. Many (256) metabolites accumulated during rehydration in S. caninervis, whereas only 71 accumulated during the dehydration period, in contrast to the pattern observed in vascular DT plants. During dehydration, nitrogenous amino acids (L-glutamic acid and cysteinylglycine), alkaloids (vinleurosine), and steroids (physalin D) accumulated, whereas glucose 6-phosphate decreased. During rehydration, γ-aminobutyric acid, glucose 6-phosphate, and flavonoids (karanjin and aromadendrin) accumulated, as did the plant hormones 12-OPDA and trans-zeatin riboside. The contents of L-arginine, maltose, turanose, lactulose, and sucrose remained high throughout dehydration-rehydration. S. caninervis thus accumulates antioxidants to scavenge reactive oxygen species, accumulating nitrogenous amino acids and cytoprotective metabolites and decreasing energy metabolism to enter a protective state from dehydration-induced damage. During subsequent rehydration, many metabolites rapidly accumulated to prevent oxidative stress and restore physiological activities while repairing cells, representing a more elaborate rehydration repair mechanism than vascular DT plants, with a faster and greater accumulation of metabolites. This metabolic kinetics analysis in S. caninervis deepens our understanding of its dehydration mechanisms and provides new insights into the different strategies of plant responses to dehydration and rehydration.PMID:37706231 | DOI:10.1093/pcp/pcad110

Plant Direct. 2023 Sep 12;7(9):e531. doi: 10.1002/pld3.531. eCollection 2023 Sep.ABSTRACTInfection of Arabidopsis with avirulent Pseudomonas syringae and exposure to nitrogen dioxide (NO2) both trigger hypersensitive cell death (HCD) that is characterized by the emission of bright blue-green (BG) autofluorescence under UV illumination. The aim of our current work was to identify the BG fluorescent molecules and scrutinize their biosynthesis, localization, and functions during the HCD. Compared with wild-type (WT) plants, the phenylpropanoid-deficient mutant fah1 developed normal HCD except for the absence of BG fluorescence. Ultrahigh resolution metabolomics combined with mass difference network analysis revealed that WT but not fah1 plants rapidly accumulate dehydrodimers of sinapic acid, sinapoylmalate, 5-hydroxyferulic acid, and 5-hydroxyferuloylmalate during the HCD. FAH1-dependent BG fluorescence appeared exclusively within dying cells of the upper epidermis as detected by microscopy. Saponification released dehydrodimers from cell wall polymers of WT but not fah1 plants. Collectively, our data suggest that HCD induction leads to the formation of free BG fluorescent dehydrodimers from monomeric sinapates and 5-hydroxyferulates. The formed dehydrodimers move from upper epidermis cells into the apoplast where they esterify cell wall polymers. Possible functions of phenylpropanoid dehydrodimers are discussed.PMID:37705693 | PMC:PMC10496137 | DOI:10.1002/pld3.531

Front Pharmacol. 2023 Aug 29;14:1220780. doi: 10.3389/fphar.2023.1220780. eCollection 2023.ABSTRACTIntroduction: Inflammation is a defensive response of the body and the pathological basis of many diseases. However, excessive inflammation and chronic inflammation impair the homeostasis of the organism. Arachidonic acid (AA) has a close relationship with inflammation and is the main mediator of the pro-inflammatory response. Based on the prodrug principle, the new pharmaceutical compound aspirin eugenol ester (AEE) was designed and synthesized. However, the effects of AEE on key enzymes, metabolites and inflammatory signaling pathways in the AA metabolic network have not been reported. Methods: In this study, the anti-inflammation effects of AEE were first investigated in mice and RAW264.7 cells in LPS induced inflammation model. Then, the changes of the key enzymes and AA metabolites were explored by RT-PCR and targeted metabolomics. Moreover, the regulatory effects on NF-kB and MAPKS signaling pathways were explored by Western Blotting. Results: Results indicated that AEE significantly reduced the number of leukocyte and increased the lymphocyte percentage. AEE decreased the expression levels of IL-1β, IL-6, IL-8 and TNF-α both in vivo and in vitro. In the liver of mice, AEE downregulated the levels of AA, prostaglandin D2 (PGD2) and upregulated 12- hydroxyeicosatetraenoic acid (12-HETE). However, the changes of PGE2, PGF2α, 6-keto-prostaglandin F1α (6-KETO-PGF1α), 9-hydroxy-octadecenoic acid (9- HODE), 13-HODE, 15-HETE, docosahexaenoic acid (DHA) and thromboxane B2 (TXB2) were not significant. Additionally, it was found that AEE decreased the relative mRNA expression levels of p65 and p38 and the ratio of p-p65/p65. Discussion: It was concluded that AEE might inhibit the LPS-induced inflammatory response through the regulation of AA metabolism. This study provides the theoretical foundation for the development of AEE as a medicinal anti-inflammatory drug.PMID:37705535 | PMC:PMC10495573 | DOI:10.3389/fphar.2023.1220780

Acta Biochim Biophys Sin (Shanghai). 2023 Sep 14. doi: 10.3724/abbs.2023151. Online ahead of print.ABSTRACTCancer cachexia (CAC) is a debilitating condition that often arises from noncachexia cancer (NCAC), with distinct metabolic characteristics and medical treatments. However, the metabolic changes and underlying molecular mechanisms during cachexia progression remain poorly understood. Understanding the progression of CAC is crucial for developing diagnostic approaches to distinguish between CAC and NCAC stages, facilitating appropriate treatment for cancer patients. In this study, we establish a mouse model of colon CAC and categorize the mice into three groups: CAC, NCAC and normal control (NOR). By performing nuclear magnetic resonance (NMR)-based metabolomic profiling on mouse sera, we elucidate the metabolic properties of these groups. Our findings unveil significant differences in the metabolic profiles among the CAC, NCAC and NOR groups, highlighting significant impairments in energy metabolism and amino acid metabolism during cachexia progression. Additionally, we observe the elevated serum levels of lysine and acetate during the transition from the NCAC to CAC stages. Using multivariate ROC analysis, we identify lysine and acetate as potential biomarkers for distinguishing between CAC and NCAC stages. These biomarkers hold promise for the diagnosis of CAC from noncachexia cancer. Our study provides novel insights into the metabolic mechanisms underlying cachexia progression and offers valuable avenues for the diagnosis and treatment of CAC in clinical settings.PMID:37705348 | DOI:10.3724/abbs.2023151

Biomed Chromatogr. 2023 Sep 13:e5733. doi: 10.1002/bmc.5733. Online ahead of print.ABSTRACTWhile clinical surveys have frequently reported that patients with traumatic brain injuries (TBIs) and comorbidities experience faster healing, the underlying mechanisms have been investigated but remain unclear. As a comprehensive comparison and analysis of the metabolic characteristics of these two pathologies have not been undertaken, we developed a rat model of fracture and TBI and collected serum samples for metabolomic analysis using ultra-high performance liquid chromatography-quadrupole time-of-flight MS (UHPLC-Q-TOF/MS). In total, we identified 40 differential metabolites and uncovered related pathways and potential mechanisms, including aminoacyl-transfer RNA biosynthesis; differential amino acids such as leucine, cholylhistidine, aspartyl-lysine; and related lipid metabolism, and discussed their impacts on bone formation in detail. This study highlights that the UHPLC-Q-TOF/MS-based metabolomics approach offers a better understanding of the metabolic links between TBI and accelerated bone recovery.PMID:37705144 | DOI:10.1002/bmc.5733

Pediatr Clin North Am. 2023 Oct;70(5):929-936. doi: 10.1016/j.pcl.2023.05.006. Epub 2023 Jul 6.ABSTRACTAs the availability of advanced molecular testing like whole exome and genome sequencing expands, it comes with the added complication of interpreting inconclusive results, including determining the relevance of variants of uncertain significance or failing to find a variant in an otherwise suspected specific genetic disorder. This complication necessitates the use of alternative testing methods to gather more information in support of, or against, a particular genetic diagnosis. Therefore, new genome-wide approaches, including DNA epigenetic testing, RNA sequencing, and metabolomics, are increasingly being used to increase the diagnostic yield when used in conjunction with more conventional genetic tests.PMID:37704351 | DOI:10.1016/j.pcl.2023.05.006

Adv Cancer Res. 2023;160:253-315. doi: 10.1016/bs.acr.2023.03.005. Epub 2023 Apr 20.ABSTRACTCurrent treatment of solid tumors with standard of care chemotherapies, radiation therapy and/or immunotherapies are often limited by severe adverse toxic effects, resulting in a narrow therapeutic index. Cancer gene therapy represents a targeted approach that in principle could significantly reduce undesirable side effects in normal tissues while significantly inhibiting tumor growth and progression. To be effective, this strategy requires a clear understanding of the molecular biology of cancer development and evolution and developing biological vectors that can serve as vehicles to target cancer cells. The advent and fine tuning of omics technologies that permit the collective and spatial recognition of genes (genomics), mRNAs (transcriptomics), proteins (proteomics), metabolites (metabolomics), epiomics (epigenomics, epitranscriptomics, and epiproteomics), and their interactomics in defined complex biological samples provide a roadmap for identifying crucial targets of relevance to the cancer paradigm. Combining these strategies with identified genetic elements that control target gene expression uncovers significant opportunities for developing guided gene-based therapeutics for cancer. The purpose of this review is to overview the current state and potential limitations in developing gene promoter-directed targeted expression of key genes and highlights their potential applications in cancer gene therapy.PMID:37704290 | DOI:10.1016/bs.acr.2023.03.005

Sci Total Environ. 2023 Sep 11:167011. doi: 10.1016/j.scitotenv.2023.167011. Online ahead of print.ABSTRACTPlenty of emerging bisphenol A (BPA) substitutes rise to wait for assessment of bioconcentration and metabolism disruption. Computational methods are useful to fill the data gap in chemical risk assessment, such as automated quantitative structure-activity relationship (AutoQSAR). It is not clear how AutoQSAR performs in predicting the bioconcentration factor (BCF) in adult zebrafish. Herein, AutoQSAR was used to predict the logBCFs of BPA, bisphenol AF (BPAF), bisphenol B, bisphenol F and bisphenol S (BPS). For the test set, a linear relationship was shown between the observed and predicted logBCFs with a slope of 0.97. The predicted logBCFs of these five bisphenols were quite close to their experimental data with a slope of 0.94, suggesting better performance than directed message passing neural networks and EPI Suite with a slope of 0.69 and 0.61, respectively. Thus, AutoQSAR is powerful in modeling logBCFs in fish with minimal time and expertise. To link bioconcentration with metabolic effects, female zebrafish were exposed to BPA, BPAF and BPS for metabolomics analysis. BPA caused a significant disturbance in amino acid metabolism, while BPAF and BPS significantly altered another three metabolic pathways, showing chemical-specific responses. BPAF with the highest logBCF elicited the strongest metabolomic responses reflected by the metabolic effect level index, followed by BPA and BPS. Thus, BPAF and BPS elicited higher or similar metabolism disruption compared with BPA in female zebrafish, respectively, reflecting consequences of bioconcentration.PMID:37704156 | DOI:10.1016/j.scitotenv.2023.167011

Food Chem Toxicol. 2023 Sep 11:114034. doi: 10.1016/j.fct.2023.114034. Online ahead of print.ABSTRACTPhthalate esters (PAEs), widely used as plasticizers, may pose a potential environmental and human hazard. The aim of this study was to compare the cytotoxicity of di(2-ethylhexyl) phthalates (DEHP) and dibutyl phthalate (DBP)) after their exposure to HepG2 cells alone or in combination. HepG2 cells treated with individual/combined DEHP and DBP at a dose of 10-2 M for 24 h were selected for metabolome and transcriptome analysis. The results demonstrated that exposure to the mixtures of DEHP and DBP caused enhanced or reduced toxic effects regarding 8 pathways with 1065 downregulated genes and 643 upregulated genes, in comparison with those of single chemicals. The combined toxicity of mixture revealed both synergistic and antagonistic interactions between DEHP and DBP. Besides, combined exposure to DEHP and DBP promoted TCA cycle, pyrimidine, and purine metabolism, while an antagonistic effect on fatty acid derangement should require further investigation. To summarize, our results suggest that DEHP exposed alone or combined with DBP caused a variety of metabolic disorders, and the type of combination effects varied among metabolic pathways.PMID:37703926 | DOI:10.1016/j.fct.2023.114034

Redox Biol. 2023 Sep 7;67:102878. doi: 10.1016/j.redox.2023.102878. Online ahead of print.ABSTRACTCruciferous-rich diets, particularly broccoli, have been associated with reduced risk of developing cancers of various sites, cardiovascular disease and type-2 diabetes. Sulforaphane (SF), a sulfur-containing broccoli-derived metabolite, has been identified as the major bioactive compound mediating these health benefits. Sulforaphane is a potent dietary activator of the transcription factor Nuclear factor erythroid-like 2 (NRF2), the master regulator of antioxidant cell capacity responsible for inducing cytoprotective genes, but its role in glucose homeostasis remains unclear. In this study, we set to test the hypothesis that SF regulates glucose metabolism and ameliorates glucose overload and its resulting oxidative stress by inducing NRF2 in human hepatoma HepG2 cells. HepG2 cells were exposed to varying glucose concentrations: basal (5.5 mM) and high glucose (25 mM), in the presence of physiological concentrations of SF (10 μM). SF upregulated the expression of glutathione (GSH) biosynthetic genes and significantly increased levels of reduced GSH. Labelled glucose and glutamine experiments to measure metabolic fluxes identified that SF increased intracellular utilisation of glycine and glutamate by redirecting the latter away from the TCA cycle and increased the import of cysteine from the media, likely to support glutathione synthesis. Furthermore, SF altered pathways generating NADPH, the necessary cofactor for oxidoreductase reactions, namely pentose phosphate pathway and 1C-metabolism, leading to the redirection of glucose away from glycolysis and towards PPP and of methionine towards methylation substrates. Finally, transcriptomic and targeted metabolomics LC-MS analysis of NRF2-KD HepG2 cells generated using CRISPR-Cas9 genome editing revealed that the above metabolic effects are mediated through NRF2. These results suggest that the antioxidant properties of cruciferous diets are intricately connected to their metabolic benefits.PMID:37703668 | DOI:10.1016/j.redox.2023.102878