PubMed

Kardiologiia. 2023 Mar 31;63(3):3-12. doi: 10.18087/cardio.2023.3.n2376.ABSTRACTRelevant aspects of the pathogenesis, diagnosis, And treatment of heart failure with preserved LV EFThis review analyzes results of studies of the recent decade that focus on epidemiology, mechanisms of development, diagnostic methods, and treatments of heart failure with preserved ejection fraction (HFpEF). As expected, the prevalence of HFpEF continues to increase due to the growing contribution of comorbidities to the structure of causes for chronic heart failure (CHF), such as arterial hypertension with left ventricular hypertrophy, obesity, chronic kidney disease, as well as due to ageing of the population and decreased contributions of ischemic heart disease and myocardial infarction. Concomitant diseases are a source of low-intensity microvascular inflammation, which is currently assigned a role of a trigger mechanism eventually provoking energy deficiency, disorders of cardiomyocyte relaxation, and diffuse myocardial fibrosis. Both these processes lead to increased heart muscle rigidity and abnormally high left ventricular filling pressure (LVFP). High LVFP is associated with the development of pulmonary venous congestion and impairment of alveolar blood oxygenation, which form the clinical picture of HFpEF. Detecting high LVEF with tissue Doppler echocardiography by the E / e' value became the instrumental basis for the HFpEF diagnostics. Recognition of inflammation and fibrosis as the key pathogenetic factors marked the main vector of modern therapy for HFpEF (anti-inflammatory and antifibrotic). The best implementation of this vector became possible with the advent of drugs from the class of angiotensin receptor and neprilysin inhibitors (ARNI), sodium-glucose cotransporter type 2 (SGLT2) inhibitors, and aldosterone antagonists. However, the efficacy of such treatments is evident only with the LV EF <60-65% while at higher values, the efficacy substantially decreases. This limitation may result from the heterogenous nature of the disease and requires more advanced methods for verification of HFpEF clinical phenotypes. Among such methods, transcriptomic, metabolomic, and proteomic approaches are considered. With the use of capabilities of the "machine learning" and the artificial intelligence, these approaches can become a new frontier in research to represent an important step towards personalized medicine for patients with HFpEF.PMID:37061855 | DOI:10.18087/cardio.2023.3.n2376

Bioorg Chem. 2023 Apr 15;136:106545. doi: 10.1016/j.bioorg.2023.106545. Online ahead of print.ABSTRACTTetracyclic oxindole alkaloids (TOAs), main active ingredients of Uncaria rhynchophylla (UR), has inspired the interest of pharmacologists and chemists because of its great potential in the treatment of the diseases of the nervous system and cardiovascular system and its special spirooxindole scaffold, but the biosynthetic pathway of this compounds is still unknown. In this work, the metabolomics and transcriptomics of hook, leaf and stem of UR were analyzed, and 31 alkaloids and 47,423 unigenes were identified, as well as the relative contents of these alkaloids were evaluated. Based on the above results and literatures, a proposal biosynthetic pathway for TOAs was devised. Furthermore, three unigenes were suggested mediating the biosynthesis of TOAs through the integrated analysis of metabolomics and transcriptomics, and three enzymes, tryptophan decarboxylase, strictosidine synthase and strictosidine-β-d-glucosidase, were identified as important catalytic enzymes for the synthesis of tryptamine, strictosidine (7) and 4,21-dehydrogeissochizine, respectively, which are considered as the important precursors of TOAs.PMID:37087849 | DOI:10.1016/j.bioorg.2023.106545

Proteome Sci. 2023 Apr 15;21(1):5. doi: 10.1186/s12953-023-00204-x.ABSTRACTOBJECTIVE: This study aims to explore the effect of an extract of Atractylodes lancea (A. lancea) on antibiotics-induced intestinal tract disorder and the probable therapeutic mechanisms employed by this extract to ameliorate these disorders.METHODS: Three days after acclimatization, nine male and nine female specific-pathogen-free (SPF) mice were randomly assigned into three groups: Group C (normal saline), Group M (antibiotic: cefradine + gentamicin), and Group T (antibiotic + A. lancea extract). Each mouse in Groups M and T received intragastric (i.g.) gavage antibiotics containing cefradine and gentamicin sulfate (0.02 ml/g-1/D-1) for 7 days. A. lancea extract (0.02 ml/g-1/D-1) was administered by i.g. gavage to Group T mice for 7 days following the cessation of antibiotic therapy. Group M received an equivalent volume of normal saline for 7 days, while Group C received an equivalent volume of normal saline for 14 days. Afterwards, we collected mouse feces to assess changes in intestinal microbiota by 16S ribosomal ribonucleic acid (rRNA) sequencing and metabolomics. In addition, serum samples were gathered and analyzed using liquid chromatography-mass spectrometry (LS-MS). Finally, we performed a correlation analysis between intestinal microbiota and metabolites.RESULTS: After treatment with antibiotic, the richness and diversity of the flora, numbers of wall-breaking bacteria and Bacteroidetes, and the numbers of beneficial bacteria decreased, while the numbers of harmful bacteria increased. After i.g. administration of A. lancea extract, the imbalance of microbial flora began to recover. Antibiotics primarily influence the metabolism of lipids, steroids, peptides, organic acids, and carbohydrates, with lipid compounds ranking first. Arachidonic acid (AA), arginine, and proline have relatively strong effects on the metabolisms of antibiotic-stressed mice. Our findings revealed that A. lancea extract might restore the metabolism of AA and L-methionine. The content of differential metabolites detected in the serum of Group T mice was comparable to that in the serum of Group C mice, but significantly different from that of Group M mice. Compared to putative biomarkers in the Kyoto Encyclopedia of Genes and Genomes (KEGG) database, it was found that altered metabolites, such as amino acids, glycerol, and phospholipids, were primarily associated with the metabolism.CONCLUSIONS: The effective mechanisms of A. lancea extract in regulating the disorder of intestinal flora in mice are related to the mechanisms of A. lancea. It could relate to lipid metabolism, bile acid metabolism, and amino acid metabolism. These results will provide a basis for further explaining the mechanism by which A. lancea regulats intestinal flora.PMID:37061727 | DOI:10.1186/s12953-023-00204-x

Lipids Health Dis. 2023 Apr 15;22(1):51. doi: 10.1186/s12944-023-01810-6.ABSTRACTBACKGROUND: The long-term excessive intake of exogenous cholesterol can lead to abnormally elevated blood lipid levels and induce cardiovascular and cerebrovascular diseases. However, the influence and relevance of exogenous cholesterol on plasma cholesterol components were still unclear, and the influence on intestinal lipid metabolism targets needs to be further explored.METHODS: In vivo, the C57BL/6 + NF group and ApoE-/- + NF group mice were fed a normal specific pathogen-free (SPF) diet; the ApoE-/- + HF group mice were fed a high-cholesterol SPF diet. The plasma and jejunum tissue homogenate were obtained for non-targeted lipid metabolomics. The lipid droplets in tissues were observed by transmission electron microscope and oil red O staining. Jejunum tissue morphology was observed by HE staining. The kits were used to detect lipid content in plasma, tissues, intestinal contents, and cells. Western blot, RT-PCR, immunohistochemistry (IHC), and immunofluorescence (IF) were used to observe the key target of lipid metabolism. In vitro, the final concentration of cholesterol was 100 μmol/L in Caco-cells. Oil red O staining, western blot, RT-PCR and immunofluorescence (IF) were used to observe the changes of lipid metabolism. Finally, the influence of liver X receptor alpha (LXRα) on intestinal cholesterol metabolism was clarified by applying the LXRα inhibitor GSK2033 and siRNA targeting LXRα.RESULTS: The aortic arch and intestinal villi of the two groups of ApoE-/- mice showed apparent lesions and lipid accumulation, and there were significant changes in a variety of lipids in the plasma and jejunum. Additionally, jejunum LXRα was markedly activated. High cholesterol can significantly activate LXRα in Caco-2 cells. After LXRα was inhibited, the protein level of ATP-binding cassette transporter A1/G5/G8 (ABCA1/G5/G8) decreased, and the quantity and volume of intracellular lipids soared.CONCLUSION: In a high-cholesterol environment, the intestine promotes the excretion of cholesterol from the cell through the LXRα-ABCA1/G5/G8 pathway, reduces the intestinal intake of a variety of exogenous cholesterol, and reduces the risk of AS.PMID:37061692 | DOI:10.1186/s12944-023-01810-6

Sci Rep. 2023 Apr 15;13(1):6161. doi: 10.1038/s41598-023-33377-8.ABSTRACTChronic kidney disease (CKD) is a serious public health problem characterized by progressive kidney function loss leading to end-stage renal disease (ESRD) that demands dialysis or kidney transplantation. Early detection can prevent or delay progression to ESRD. The study aimed to gain new insights into the perturbed biochemical reactions and to identify novel distinct biomarkers between ESRD and CKD. Serum samples of 32 patients with ESRD (n = 13) and CKD (n = 19) were analyzed using chemical isotope labeling liquid chromatography-mass spectrometry metabolomics approach. A total of 193 metabolites were significantly altered in ESRD compared to CKD and were mainly involved in aminoacyl-tRNA biosynthesis, branched-chain amino acid (BCAA) biosynthesis, taurine metabolism, and tryptophan metabolism. Three kynurenine derivatives, namely, 2-aminobenzoic acid, xanthurenic acid, and hydroxypicolinic acid were upregulated in ESRD compared to CKD due to the significant decrease in glomerular filtration rate with the progression of CKD to ESRD. N-Hydroxy-isoleucine, 2-aminobenzoic acid, and picolinic acid yielded AUC > 0.99 when analyzed using Receiver Operating Characteristic (ROC) analysis. Our findings suggest that inhibiting the kynurenine pathway might be a promising target to delay CKD progression and that metabolites with high discriminative ability might serve as potential prognostic biomarkers to monitor the progression of CKD to ESRD or used in combination with current markers to indicate the status of kidney damage better.PMID:37061630 | DOI:10.1038/s41598-023-33377-8

ISME J. 2023 Apr 15. doi: 10.1038/s41396-023-01410-3. Online ahead of print.ABSTRACTWhile the field of microbial biogeography has largely focused on the contributions of abiotic factors to community patterns, the potential influence of biotic interactions in structuring microbial communities, such as those mediated by the production of specialized metabolites, remains largely unknown. Here, we examined the relationship between microbial community structure and specialized metabolism at local spatial scales in marine sediment samples collected from the Long-Term Ecological Research (LTER) site in Moorea, French Polynesia. By employing a multi-omic approach to characterize the taxonomic, functional, and specialized metabolite composition within sediment communities, we find that biogeographic patterns were driven by local scale processes (e.g., biotic interactions) and largely independent of dispersal limitation. Specifically, we observed high variation in biosynthetic potential (based on Bray-Curtis dissimilarity) between samples, even within 1 m2 plots, that reflected uncharacterized chemical space associated with site-specific metabolomes. Ultimately, connecting biosynthetic potential to community metabolomes facilitated the in situ detection of natural products and revealed new insights into the complex metabolic dynamics associated with sediment microbial communities. Our study demonstrates the potential to integrate biosynthetic genes and metabolite production into assessments of microbial community dynamics.PMID:37061583 | DOI:10.1038/s41396-023-01410-3

NPJ Breast Cancer. 2023 Apr 15;9(1):26. doi: 10.1038/s41523-023-00531-4.ABSTRACTDespite the high prevalence of mammographic calcifications, our understanding remains limited regarding the clinical and molecular features of calcifications within triple-negative breast cancer (TNBC). To investigate the clinical relevance and biological basis of TNBC with calcifications of high suspicion for malignancy, we established a study cohort (N = 312) by integrating mammographic records with clinical data and genomic, transcriptomic, and metabolomic profiling. Despite similar clinicopathological features, patients with highly suspicious calcifications exhibited a worse overall survival than those without. In addition, TNBC with highly suspicious calcifications was characterized by a higher frequency of PIK3CA mutation, lower infiltration of immune cells, and increased abnormality of lipid metabolism. Overall, our study systematically revealed clinical and molecular heterogeneity between TNBC with or without calcifications of high suspicion for malignancy. These data might help to understand the clinical relevance and biological basis of mammographic calcifications.PMID:37061514 | DOI:10.1038/s41523-023-00531-4

Aquat Toxicol. 2023 Apr 5:106521. doi: 10.1016/j.aquatox.2023.106521. Online ahead of print.ABSTRACTChemical pollutants, such as herbicides, released into the aquatic environment adversely affect the phytoplankton community structure. While majority of herbicides are specifically designed to target photosynthetic processes, they also can be toxic to phytoplankton; however, despite the photosynthetic toxicity, some herbicides can target multiple physiological processes. Therefore, a full picture of toxicity pathway of herbicide to phytoplankton is necessary. In the present study, the cyanobacterium Microcystis aeruginosa was exposed to two levels (17 μg L-1 (EC10) and 65 μg L-1 (EC50)) of paraquat for 72 h. The physiological and metabolic responses were analyzed to elucidate the toxicity pathway and establish the adverse outcome pathway of paraquat to M. aeruginosa. The results revealed that enhanced glycolysis (upregulation of pyruvic acid level) and tricarboxylic acid cycle (upregulation of the levels of malic acid, isocitric acid and citric acid) exposed to EC10 level of paraquat, which probably acted as a temporary strategy to maintain a healthy energy status in M. aeruginosa cells. Meanwhile, the expressions of glutathione and benzoic acid were enhanced to scavenge the excessive reactive oxygen species (ROS). Additionally, the accumulation of pigments (chlorophyll a and carotenoid) might play a supplementary role in the acclimation to EC10 level paraquat treatment. In cells exposed to paraquat by EC50 level, the levels of SOD, CAT, glutathione and benzoic acid increased significantly; however, the ROS exceeded the tolerance level of antioxidant system in M. aeruginosa. The adverse effects were revealed by inhibition of chlorophyll a fluorescence, the decreases in several carbohydrates (e.g., glucose 1-phosphate, fructose and galactose) and total protein content. Consequently, paraquat-induced oxidative stress caused the growth inhibition of M. aeruginosa. These findings provide new insights into the mode of action of paraquat in M. aeruginosa.PMID:37061422 | DOI:10.1016/j.aquatox.2023.106521

Aquat Toxicol. 2023 Apr 13:106520. doi: 10.1016/j.aquatox.2023.106520. Online ahead of print.ABSTRACTExcessive copper can induce many adverse effects although it's an essential trace element in organisms. The effects of copper on the lipid metabolism have aroused increasing attention. This study investigated the liver lipid metabolism in swamp eel (Monopterus albus, M. albus) chronically exposed to 0, 10, 50, and 100 μg/L Cu2+ for 56 days. The results showed that copper increased the contents of triglyceride (TG), total cholesterol (T-CHO), non-esterified fatty acids (NEFA), and lipid droplets. Transcriptomic analysis found 1901 differentially expressed genes (DEGs) and 140 differential alternative splicing (DAS) genes in the 50 μg/L Cu2+ group, and 1787 DEGs and 184 DAS genes in the 100 μg/L Cu2+ group, respectively, which were enriched in peroxisome proliferator-activated receptor (PPAR), adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK), and other signaling pathways. The expression levels of key genes related to PPAR and AMPK signaling pathways were significantly down-regulated after chronic exposure to Cu2+. Meanwhile, metabolomics analysis showed that 52 and 110 differentially expressed metabolites (DEMs) were identified, which were mainly enriched in glycerophospholipids metabolism and steroid synthesis. Moreover, combined analysis of transcriptome and metabolome showed that glycerophospholipid metabolism co-enriched 19 down-regulated DEGs and 4 down-regulated DEMs. Taken together, our results suggested that chronic waterborne copper exposure promoted lipid synthesis, disrupted the metabolic homeostasis of glycerophospholipid, and led to excessive hepatic lipid deposition in M. albus. The combined omics approach enhanced our understanding of copper pollution to lipid metabolism.PMID:37061419 | DOI:10.1016/j.aquatox.2023.106520

J Hepatol. 2023 Apr 13:S0168-8278(23)00217-9. doi: 10.1016/j.jhep.2023.03.041. Online ahead of print.ABSTRACTBACKGROUND & AIMS: Nonalcoholic steatohepatitis (NASH)-driven hepatocellular carcinoma (HCC) is rapidly rising and lacks effective therapies, yet the underlying mechanisms remain unclear. This study aims to determine the role of hypoxia-inducible lipid droplet associated protein (HILPDA), a selective inhibitor of intracellular lipolysis, in NASH-HCC.METHODS: Clinical significance of HILPDA was assessed in human NASH-HCC specimens by immunohistochemistry and transcriptomics analyses. The oncogenic effect of HILPDA was assessed in human HCC cells and in 3D epithelial spheroids upon exposure to free fatty acids and either normoxia or hypoxia. Lipidomics profiling of WT and HILPDA knockout HCC cells was assessed via shotgun and targeted approaches. WT (HILPDAfl/fl) and HILPDA hepatocyte-specific knockout (HILPDAΔHep) mice were fed a western diet and high sugar in drinking water while receiving carbon tetrachloride to induce NASH-driven HCC.RESULTS: In patients with NASH-driven HCC, upregulated HILPDA expression is strongly associated with poor survival. In oxygen-deprived and lipid-loaded culture conditions, HILPDA promotes viability of human hepatoma cells and growth of 3D epithelial spheroids. Lack of HILPDA triggered flux of polyunsaturated fatty acids to membrane phospholipids and of saturated fatty acids to ceramide synthesis, exacerbating lipid peroxidation and apoptosis in hypoxia. The apoptosis induced by HILPDA deficiency was reversed by pharmacological inhibition of ceramide synthesis. In our experimental mouse model of NASH-driven HCC, HILPDAΔHep reduced hepatic steatosis and tumorigenesis while increasing oxidative stress in the liver. Single cell analysis supports a dual role of hepatic HILPDA in protecting HCC cells and facilitating the establishment of a pro-tumorigenic immune microenvironment in NASH.CONCLUSIONS: Hepatic HILPDA is a pivotal oncometabolic factor in the NASH liver microenvironment and represents a novel potential therapeutic target.IMPACT AND IMPLICATIONS: Nonalcoholic steatohepatitis (NASH, chronic metabolic liver disease caused by buildup of fat, inflammation and damage in the liver) is emerging as the leading risk factor and the fastest growing cause of hepatocellular carcinoma (HCC), the most common form of liver cancer. While curative therapeutic options exist for HCC, it frequently presents at a late stage when such options are no longer effective and only systemic therapies are available. However, systemic therapies are still associated with poor efficacy and some side effects. In addition, no approved drugs are available for NASH. Therefore, understaing the underlying metabolic alterations occurring during NASH-HCC is key to identify new cancer treatments that target the unique metabolic needs of cancer cells.PMID:37061197 | DOI:10.1016/j.jhep.2023.03.041

Pharmacol Res. 2023 Apr 13:106766. doi: 10.1016/j.phrs.2023.106766. Online ahead of print.ABSTRACTDigestive tract diseases are presently the hotspot of clinical diagnosis and treatment, and the incidence of digestive tract tumor is increasing annually. Surgery remains the main therapeutic schedule for digestive tract tumor. Though benefits were brought by neoadjuvant chemotherapy, a part of patients lose the chance of surgery because of late detection or inappropriate intervention. Therefore, the treatment of inoperable patients has become an urgent need. At the same time, tumor metabolism is an extremely complex and diverse process. Natural products are confirmed effective to inhibit the development of tumors in vitro and in vitro. There are many kinds of natural products and their functions remain not clear. However, some natural products such as polyphenols have been proven to have definite anti-cancer effects, and some terpenoids have definite anti-inflammatory, anti-ulcer, anti-tumor, and other effects. Therefore, the anti-tumor characteristics of natural products should arouse our high attention. Although there are many obstacles to study the activities of natural products in tumor, including the difficulty in detection or distinguishing each component due to their low levels in tumor tissue, etc., the emergence of highly sensitive and locatable spatial metabolomics make the research and application of natural products a big step forward. In this review, natural products such as phenols, terpenoids and biotinoids were summarized to further discuss the development and therapeutic properties of natural metabolites on digestive tract tumors.PMID:37061144 | DOI:10.1016/j.phrs.2023.106766

J Invest Dermatol. 2023 Apr 13:S0022-202X(23)01975-9. doi: 10.1016/j.jid.2023.02.039. Online ahead of print.ABSTRACTImpaired skin wound healing is a significant global health issue, especially among the elderly. Wound healing is a well-orchestrated process involving the sequential phases of inflammation, proliferation and tissue remodeling. Whilst wound healing is a highly dynamic and energy-requiring process, the role of metabolism remains largely unexplored. By combined transcriptomics and metabolomics of human skin biopsy samples, we mapped the core bioenergetic metabolic changes in normal acute as well as chronic wounds in elderly subjects. We found upregulation of glycolysis, tricarboxylic acid (TCA) cycle, glutaminolysis, and β-oxidation in later stages of acute wound healing and in chronic wounds. To ascertain the role of these metabolic pathways on wound healing, we targeted each pathway in a wound healing assay as well as in a human skin explant model using metabolic inhibitors and stimulants. Enhancement or inhibition of glycolysis and to a lesser extent glutaminolysis had a far greater impact on wound healing than similar manipulations of oxidative phosphorylation (OXPHOS) and fatty acid β-oxidation. These findings increase the understanding of wound metabolism and identifies glycolysis and glutaminolysis as potential targets for therapeutic intervention.PMID:37061123 | DOI:10.1016/j.jid.2023.02.039

Prog Neuropsychopharmacol Biol Psychiatry. 2023 Apr 13:110768. doi: 10.1016/j.pnpbp.2023.110768. Online ahead of print.ABSTRACTNeuroticism is one of the most robust risk factors for addictive behaviors including food addiction (a key contributor to obesity), although the associated mechanisms are not well understood. A transdiagnostic approach was used to identify the neuroticism-related neuropsychological and gut metabolomic patterns associated with food addiction. Predictive modeling of neuroticism was implemented using multimodal features (23 clinical, 13,531 resting-state functional connectivity (rsFC), 336 gut metabolites) in 114 high body mass index (BMI ≥25 kg/m2) (cross-sectional) participants. Gradient boosting machine and logistic regression models were used to evaluate classification performance for food addiction. Neuroticism was significantly associated with food addiction (P < 0.001). Neuroticism-related features predicted food addiction with high performance (89% accuracy). Multimodal models performed better than single-modal models in predicting food addiction. Transdiagnostic alterations corresponded to rsFC involved in the emotion regulation, reward, and cognitive control and self-monitoring networks, and the metabolite 3-(4-hydroxyphenyl) propionate, as well as anxiety symptoms. Neuroticism moderated the relationship between BMI and food addiction. Neuroticism drives neuropsychological and gut microbial signatures implicated in dopamine synthesis and inflammation, anxiety, and food addiction. Such transdiagnostic models are essential in identifying mechanisms underlying food addiction in obesity, as it can help develop multiprong interventions to improve symptoms.PMID:37061021 | DOI:10.1016/j.pnpbp.2023.110768

J Biol Chem. 2023 Apr 13:104715. doi: 10.1016/j.jbc.2023.104715. Online ahead of print.ABSTRACTTrypanosomatids are a diverse group of uniflagellate protozoan parasites that include globally relevant pathogens such asTrypanosoma cruzi, the causative agent of Chagas disease. Trypanosomes lack the fatty acid synthase (FAS)-I system typically used for de novo fatty acid (FA) synthesis in other eukaryotes. Instead, these microbes have evolved a modular fatty acid elongase (ELO) system comprised of individual ELO enzymes (ELO1-4) that can operate processively to generate long chain- and very long chain-fatty acids. The importance of ELO's for maintaining lipid homeostasis in trypanosomatids is currently unclear, given their ability to take up and utilize exogenous fatty acids for lipid synthesis. To assess ELO function in T. cruzi, we generated individual knockout lines, Δelo1, Δelo2 and Δelo3, in which the genes encoding ELO1-3 were functionally disrupted in the parasite insect stage (epimastigote). Using unbiased lipidomic and metabolomic analyses, in combination with metabolic tracing and biochemical approaches, we demonstrate that ELO2 and ELO3 are required for global lipid homeostasis, whereas ELO1 is dispensable for this function. Instead, ELO1 activity is needed to sustain mitochondrial activity and normal growth in T. cruziepimastigotes. The cross-talk between microsomal ELO1 and the mitochondrion is a novel finding that, we propose, merits further examination of the trypanosomatid ELO pathway as critical for central metabolism.PMID:37061002 | DOI:10.1016/j.jbc.2023.104715

NanoImpact. 2023 Apr 13:100463. doi: 10.1016/j.impact.2023.100463. Online ahead of print.ABSTRACTGraphene oxide (GO) nanomaterials have unique physicochemical properties that make them highly promising for biomedical, environmental, and agricultural applications. There is growing interest in the use of GO and extensive in vitro and in vivo studies have been conducted to assess its nanotoxicity. Although it is known that GO can alter the composition of the gut microbiota in mice and zebrafish, studies on the potential impacts of GO on the human gut microbiome are largely lacking. This study addresses an important knowledge gap by investigating the impact of GO exposure- at low (25 mg/L) and high (250 mg/L) doses under both fed (nutrient rich) and fasted (nutrient deplete) conditions- on the gut microbial communitys' structure and function, using an in vitro model. This model includes simulated oral, gastric, small intestinal phase digestion of GO followed by incubation in a colon bioreactor. 16S rRNA amplicon sequencing revealed that GO exposure resulted in a restructuring of community composition. 25 mg/L GO induced a marked decrease in the Bacteroidota phylum and increased the ratio of Firmicutes to Bacteroidota (F/B). Untargeted metabolomics on the supernatants indicated that 25 mg/L GO impaired microbial utilization and metabolism of substrates (amino acids, carbohydrate metabolites) and reduced production of beneficial microbial metabolites such as 5-hydroxyindole-3-acetic acid and GABA. Exposure to 250 mg/L GO resulted in community composition and metabolome profiles that were very similar to the controls that lacked both GO and digestive enzymes. Differential abundance analyses revealed that 3 genera from the phylum Bacteroidota (Bacteroides, Dysgonomonas, and Parabacteroides) were more abundant after 250 mg/L GO exposure, irrespective of feed state. Integrative correlation network analysis indicated that the phylum Bacteroidota showed strong positive correlations to multiple microbial metabolites including GABA and 3-indoleacetic acid, are much larger number of correlations compared to other phyla. These results show that GO exposure has a significant impact on gut microbial community composition and metabolism at both low and high GO concentrations.PMID:37060994 | DOI:10.1016/j.impact.2023.100463

Biochem Pharmacol. 2023 Apr 13:115550. doi: 10.1016/j.bcp.2023.115550. Online ahead of print.ABSTRACTCancer stem cells (CSCs) are a subset of cancer cells with self-renewal ability and tumor initiating properties. Unlike the other non-stem cancer cells, CSCs resist traditional therapy and remain a major cause of disease relapse. With the recent advances in metabolomics, various studies have demonstrated that CSCs have distinct metabolic properties. Metabolic reprogramming in CSCs contributes to self-renewal and maintenance of stemness. Accumulating evidence suggests that rewiring of energy metabolism is a key player that enables to meet energy demands, maintains stemness, and sustains cancer growth and invasion. CSCs use various mechanisms such as increased glycolysis, redox signaling and autophagy modulation to overcome nutritional deficiency and sustain cell survival. The alterations in lipid metabolism acquired by the CSCs support biomass production through increased dependence on fatty acid synthesis and β-oxidation and contribute to oncogenic signaling pathways. This review summarizes our current understanding of lipid metabolism in CSCs and how pharmacological regulation of autophagy and lipid metabolism influences CSC phenotype. Increased dependence on lipid metabolism appears as an attractive strategy to eliminate CSCs using therapeutic agents that specifically target CSCs based on their modulation of lipid metabolism.PMID:37060962 | DOI:10.1016/j.bcp.2023.115550

J Steroid Biochem Mol Biol. 2023 Apr 13:106311. doi: 10.1016/j.jsbmb.2023.106311. Online ahead of print.ABSTRACTSteroid hormone level is a crucial factor affecting the outcomes of in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI). The purpose of this study was to evaluate serum steroid metabolome on the day of oocyte retrieval in women with polycystic ovarian syndrome (PCOS) and explore whether specific steroids can be potential indicators to improve the prediction of pregnancy outcomes in PCOS patients undergoing IVF/ICSI. In this study, the serum levels of 21 steroids in 89 women with PCOS and 73 control women without PCOS on the day of oocyte retrieval of the first IVF/ICSI treatment cycle were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). All patients subsequently received good-quality embryo transfer, and the correlation between their steroid profiles and pregnancy outcomes of the first embryo transfer (ET) was retrospectively analyzed. We found PCOS patients had aberrant levels of 11 out of 21 steroid hormones compared to control individuals, with androgen steroid hormones being considerably enhanced. Enzyme activity evaluation indicated that PCOS women might have abnormal activity of CYP17A1, CYP21A2, CYP11B2, CYP19A1, HSD3B, HSD11B, and HSD17B. Additionally, the level of 18-hydroxycorticosterone (p = 0.014), corticosterone (p = 0.035), and 17-hydroxypregnenolone (p = 0.005) were markedly higher in live birth group than in non- live birth group for PCOS women following frozen embryo transfer (FET). Multiple logistic regressions indicated that 18-hydrocorticosterone and 17-hydroxypregnenolone were independently associated with live birth outcomes of PCOS women following FET. Receiver operating characteristic (ROC) curve analysis revealed that 0.595ng/mL for 18-hydrocorticosterone level (AUC: 0.6936, p = 0.014).and 2.829ng/mL for 17-hydroxypregnenolone level (AUC: 0.7215, p = 0.005) were the best cutoff values to predict live birth outcomes of PCOS. In conclusion, the blood steroid metabolome was closely related to the IVF/ICSI outcomes of PCOS patients. 18-hydroxycorticosterone and 17-hydroxypregnenolone might be potential indicators to predict pregnancy outcomes of PCOS undergoing IVF/ICSI treatment. AVAILABILITY OF DATA AND MATERIALS: The data used in the current study are available from the database of Women's Hospital, School of Medicine, Zhejiang University on reasonable request.PMID:37060931 | DOI:10.1016/j.jsbmb.2023.106311

Aquat Toxicol. 2023 Apr 8;259:106537. doi: 10.1016/j.aquatox.2023.106537. Online ahead of print.ABSTRACTNon-steroidal anti-inflammatory drugs (NSAID) are recently monitored in the aquatic environment. Naproxen (NPX), paracetamol (PCT) and their transformation products can influence the biochemical and physiological processes at the sub-cellular and cellular levels taking part in the growth and development of plants. This study aimed to compare the effects of NPX and PCT, drugs with different physico-chemical properties, on the growth and photosynthetic processes in Lemna minor during a short-term (7 days) exposure. Although duckweed took up more than five times higher amount of PCT as compared to NPX (275.88 µg/g dry weight to 43.22 µg/g when treated with 10 mg/L), only NPX limited the number of new plants by 9% and 26% under 1 and 10 mg/L, respectively, and increased their dry weight (by 18% under 10 mg/L) and leaf area per plant. A considerable (by 30%) drop in the content of photosynthetic pigments under 10 mg/L treatment by both drugs did not significantly affect the efficiency of the primary processes of photosynthesis. Values of induced chlorophyll fluorescence parameters (F0, FV/FM, ΦII, and NPQ) showed just a mild stimulation by PCT and a negative effect by NPX (by up to 10%), especially on the function of photosystem II and electron transport in both intact duckweed plants and isolated chloroplasts. Lowered efficiency of Hill reaction activity (by more than 10% under 0.1 - 10 mg/L treatments) in isolated chloroplasts suspension proved the only inhibition effect of PCT to primary photosynthetic processes. In intact plants, higher treatments (0.5 - 10 mg/L) by both NPX and PCT induced an increase in RuBisCO content. The results prove that the potential effect of various drugs on plants is hard to generalise.PMID:37060818 | DOI:10.1016/j.aquatox.2023.106537

J Chromatogr B Analyt Technol Biomed Life Sci. 2023 Apr 11;1222:123719. doi: 10.1016/j.jchromb.2023.123719. Online ahead of print.ABSTRACTCarboxylic acids participate in many metabolic pathways including tricarboxylic acid (TCA) cycle. Therefore, there have been ongoing attempts to develop sensitive liquid chromatography-mass spectrometry methods over the last decades. Derivatization of the carboxylic acids with 3-nitrophenylhydrazine presents a well-established methodology, and yet the derivatized species of polycarboxylic acids and their fragmentation in collision-induced dissociation have not been fully studied before. In our study, we elucidated how annotation of most abundant 3-nitrophenylhydrazine derivatives and optimization of their fragmentation in multiple reaction monitoring can boost the sensitivity, especially for polycarboxylic acids. Finally, the optimized liquid chromatography-tandem mass spectrometry method allowed for low detection limits ranging from 10 pM for 2-oxoglutaric acid to 800 pM for pyruvic acid. All TCA carboxylates were quantified in 20 µL of human plasma and the targeted method was validated in the same matrix. The same methodology with a modified gradient elution was also applied to untargeted screening of fatty acids by using high-resolution mass spectrometry enabling identification of 29 medium- to long-chain fatty acids in human plasma. The TCA carboxylates were also quantified in 105 of C2C12 mouse myuotube cells grown under different treatments to proof applicability of the methodology to biological studies in a wider sense. However, unfortunately all the TCA carboxylates were also found in the derivatized blanks in substantial amounts, which prevents from using the methodology for quantification of the carboxylates in less than 105 cells.PMID:37060816 | DOI:10.1016/j.jchromb.2023.123719

Ecotoxicol Environ Saf. 2023 Apr 13;256:114905. doi: 10.1016/j.ecoenv.2023.114905. Online ahead of print.ABSTRACTThe aquatic plant Elodea canadensis is considered a good candidate for ecotoxicological investigations. Cadmium (Cd) is a widespread contaminant in aquatic systems. In this study, to better elucidate the underlying tolerance mechanism and molecular impact of environmentally relevant Cd concentration in aquatic plants, subcellular distribution, chemical forms, and gas chromatography-mass spectrometry-based non-targeted metabolomics profiles were comprehensively analyzed in E. canadensis subjected to 0 and 10 µM Cd treatment for 5 d. Subcellular fractionation analysis of Cd-containing leaves showed that 67% of Cd was compartmentalized in cell wall followed by the soluble fraction (24 %) and organelles (9 %). The majority of Cd (90 %) was found in the extraction using 1 M NaCl. Metabolomic analysis using unsupervised principal component analyses and a supervised partial least squares discriminant analysis revealed clear differences in metabolic profiles between the two groups, demonstrating the metabolic effects of Cd. The 155 identified compounds altered by Cd were mainly from primary metabolism, including sugars, amino acids, organic acids, and their derivatives. Secondary metabolites such as polyphenols and phenolamides were also detected. The massive up-regulation of metabolites, including trehalose, proline, sarcosine, nicotianamine, putrescine, α-ketoglutaric acid, citric acid, and phytol might represent a detoxification mechanism. These findings highlighted the mechanistic strategies that E. canadensis employs to defend against Cd toxicity.PMID:37060802 | DOI:10.1016/j.ecoenv.2023.114905