PubMed

Syst Biol Reprod Med. 2024 Dec;70(1):73-90. doi: 10.1080/19396368.2024.2317804. Epub 2024 Mar 22.ABSTRACTMale infertility is a reproductive disorder, accounting for 40-50% of infertility. Currently, in about 70% of infertile men, the cause remains unknown. With the introduction of novel omics and advancement in high-throughput technology, potential biomarkers are emerging. The main purpose of our work was to overview different aspects of omics approaches in association with idiopathic male infertility and highlight potential genes, transcripts, non-coding RNA, proteins, and metabolites worth further exploring. Using the Gene Ontology (GO) analysis, we aimed to compare enriched GO terms from each omics approach and determine their overlapping. A PubMed database screening for the literature published between February 2014 and June 2022 was performed using the keywords: male infertility in association with different omics approaches: genomics, epigenomics, transcriptomics, ncRNAomics, proteomics, and metabolomics. A GO enrichment analysis was performed using the Enrichr tool. We retrieved 281 global studies: 171 genomics (DNA level), 21 epigenomics (19 of methylation and two histone residue modifications), 15 transcriptomics, 31 non-coding RNA, 29 proteomics, two protein posttranslational modification, and 19 metabolomics studies. Gene ontology comparison showed that different omics approaches lead to the identification of different molecular factors and that the corresponding GO terms, obtained from different omics approaches, do not overlap to a larger extent. With the integration of novel omics levels into the research of idiopathic causes of male infertility, using multi-omic systems biology approaches, we will be closer to finding the potential biomarkers and consequently becoming aware of the entire spectrum of male infertility, their cause, prognosis, and potential treatment.PMID:38517373 | DOI:10.1080/19396368.2024.2317804

Aging (Albany NY). 2024 Mar 20;16. doi: 10.18632/aging.205673. Online ahead of print.ABSTRACTBACKGROUND: Modulated by differences in genetic and environmental factors, laboratory mice often show progressive weight gain, eventually leading to obesity and metabolic dyshomeostasis. Since the geroneuroprotector CMS121 has a positive effect on energy metabolism in a mouse model of type 2 diabetes, we investigated the potential of CMS121 to counteract the metabolic changes observed during the ageing process of wild type mice.METHODS: Control or CMS121-containing diets were supplied ad libitum for 6 months, and mice were sacrificed at the age of 7 months. Blood, adipose tissue, and liver were analyzed for glucose, lipids, and protein markers of energy metabolism.RESULTS: The CMS121 diet induced a 40% decrease in body weight gain and improved both glucose and lipid indexes. Lower levels of hepatic caspase 1, caspase 3, and NOX4 were observed with CMS121 indicating a lower liver inflammatory status. Adipose tissue from CMS121-treated mice showed increased levels of the transcription factors Nrf1 and TFAM, as well as markers of mitochondrial electron transport complexes, levels of GLUT4 and a higher resting metabolic rate. Metabolomic analysis revealed elevated plasma concentrations of short chain acylcarnitines and butyrate metabolites in mice treated with CMS121.CONCLUSIONS: The diminished de novo lipogenesis, which is associated with increased acetyl-CoA, acylcarnitine, and butyrate metabolite levels, could contribute to safeguarding not only the peripheral system but also the aging brain. By mimicking the effects of ketogenic diets, CMS121 holds promise for metabolic diseases such as obesity and diabetes, since these diets are hard to follow over the long term.PMID:38517358 | DOI:10.18632/aging.205673

J Immunol. 2024 Mar 22:ji2300783. doi: 10.4049/jimmunol.2300783. Online ahead of print.ABSTRACTSevere SARS-CoV-2 infection is associated with significant immune dysregulation involving different immune cell subsets. In this study, when analyzing critically ill COVID-19 patients versus those with mild disease, we observed a significant reduction in total and memory B cell subsets but an increase in naive B cells. Moreover, B cells from COVID-19 patients displayed impaired effector functions, evidenced by diminished proliferative capacity, reduced cytokine, and Ab production. This functional impairment was accompanied by an increased apoptotic potential upon stimulation in B cells from severely ill COVID-19 patients. Our further studies revealed the expansion of B cells expressing coinhibitory molecules (PD-1, PD-L1, TIM-1, VISTA, CTLA-4, and Gal-9) in intensive care unit (ICU)-admitted patients but not in those with mild disease. The coinhibitory receptor expression was linked to altered IgA and IgG expression and increased the apoptotic capacity of B cells. Also, we found a reduced frequency of CD24hiCD38hi regulatory B cells with impaired IL-10 production. Our mechanistic studies revealed that the upregulation of PD-L1 was linked to elevated plasma IL-6 levels in COVID-19 patients. This implies a connection between the cytokine storm and altered B cell phenotype and function. Finally, our metabolomic analysis showed a significant reduction in tryptophan but elevation of kynurenine in ICU-admitted COVID-19 patients. We found that kynurenine promotes PD-L1 expression in B cells, correlating with increased IL-6R expression and STAT1/STAT3 activation. Our observations provide novel insights into the complex interplay of B cell dysregulation, implicating coinhibitory receptors, IL-6, and kynurenine in impaired B cell effector functions, potentially contributing to the pathogenesis of COVID-19.PMID:38517295 | DOI:10.4049/jimmunol.2300783

Small Methods. 2024 Mar 22:e2301634. doi: 10.1002/smtd.202301634. Online ahead of print.ABSTRACTDeveloping a standardized screening tool for the detection of early and small hepatocellular carcinoma (HCC) through urinary metabolic analysis poses a challenging yet intriguing research endeavor. In this study, a range of intricately interlaced 2D rough nanosheets featuring well-defined sharp edges is fabricated, with the aim of constructing diverse trimetal oxide heterojunctions exhibiting multiscale structures. By carefully engineering synergistic effects in composition and structure, including improved adsorption, diffusion, and other surface-driven processes, the optimized heterojunctions demonstrate a substantial enhancement in signal intensity compared to monometallic or bimetallic oxides, as well as fragmented trimetallic oxides. Additionally, optimal heterojunctions enable the extraction of high-quality urinary metabolic fingerprints using high-throughput mass spectrometry. Leveraging machine learning, discrimination of HCC patients from high-risk and healthy populations achieves impressive performance, with area under the curve values of 0.940 and 0.916 for receiver operating characteristic and precision-recall curves, respectively. Six crucial metabolites are identified, enabling accurate detection of early, small-tumor, alpha-fetoprotein-negative HCC (93.3%-97.3%). A comprehensive screening strategy tailored to clinical reality yields precision metrics (accuracy, precision, recall, and F1 score) exceeding 95.0%. This study advances the application of cutting-edge matrices-based metabolic phenotyping in practical clinical diagnostics.PMID:38517273 | DOI:10.1002/smtd.202301634

Acta Physiol (Oxf). 2024 Mar 22:e14126. doi: 10.1111/apha.14126. Online ahead of print.ABSTRACTAIM: Although of potential biomedical relevance, dipeptide metabolism has hardly been studied. We found the dipeptidase carnosinase-2 (CN2) to be abundant in human proximal tubules, which regulate water and solute homeostasis. We therefore hypothesized, that CN2 has a key metabolic role, impacting proximal tubular transport function.METHODS: A knockout of the CN2 gene (CNDP2-KO) was generated in human proximal tubule cells and characterized by metabolomics, RNA-seq analysis, paracellular permeability analysis and ion transport.RESULTS: CNDP2-KO in human proximal tubule cells resulted in the accumulation of cellular dipeptides, reduction of amino acids and imbalance of related metabolic pathways, and of energy supply. RNA-seq analyses indicated altered protein metabolism and ion transport. Detailed functional studies demonstrated lower CNDP2-KO cell viability and proliferation, and altered ion and macromolecule transport via trans- and paracellular pathways. Regulatory and transport protein abundance was disturbed, either as a consequence of the metabolic imbalance or the resulting functional disequilibrium.CONCLUSION: CN2 function has a major impact on intracellular amino acid and dipeptide metabolism and is essential for key metabolic and regulatory functions of proximal tubular cells. These findings deserve in vivo analysis of the relevance of CN2 for nephron function and regulation of body homeostasis.PMID:38517248 | DOI:10.1111/apha.14126

J Integr Plant Biol. 2024 Mar 22. doi: 10.1111/jipb.13649. Online ahead of print.ABSTRACTCamptothecin is a complex monoterpenoid indole alkaloid with remarkable antitumor activity. Given that two C-10 modified camptothecin derivatives, topotecan and irinotecan, have been approved as potent anticancer agents, there is a critical need for methods to access other aromatic ring-functionalized congeners (e.g., C-9, C-10, etc.). However, contemporary methods for chemical oxidation are generally harsh and low-yielding when applied to the camptothecin scaffold, thereby limiting the development of modified derivatives. Reported herein, we have identified four tailoring enzymes responsible for C-9 modifications of camptothecin from Nothapodytes tomentosa, via metabolomic and transcriptomic analysis. These consist of a cytochrome P450 (NtCPT9H) which catalyzes the regioselective oxidation of camptothecin to 9-hydroxycamptothecin, as well as two methyltransferases (NtOMT1/2, converting 9-hydroxycamptothecin to 9-methoxycamptothecin), and a uridine diphosphate-glycosyltransferase (NtUGT5, decorating 9-hydroxycamptothecin to 9-β-D-glucosyloxycamptothecin). Importantly, the critical residues that contribute to the specific catalytic activity of NtCPT9H have been elucidated through molecular docking and mutagenesis experiments. This work provides a genetic basis for producing camptothecin derivatives through metabolic engineering. This will hasten the discovery of novel C-9 modified camptothecin derivatives, with profound implications for pharmaceutical manufacture.PMID:38517054 | DOI:10.1111/jipb.13649

Plant Biotechnol J. 2024 Mar 22. doi: 10.1111/pbi.14342. Online ahead of print.ABSTRACTThe need for therapeutics to treat a plethora of medical conditions and diseases is on the rise and the demand for alternative approaches to mammalian-based production systems is increasing. Plant-based strategies provide a safe and effective alternative to produce biological drugs but have yet to enter mainstream manufacturing at a competitive level. Limitations associated with batch consistency and target protein production levels are present; however, strategies to overcome these challenges are underway. In this study, we apply state-of-the-art mass spectrometry-based proteomics to define proteome remodelling of the plant following agroinfiltration with bacteria grown under shake flask or bioreactor conditions. We observed distinct signatures of bacterial protein production corresponding to the different growth conditions that directly influence the plant defence responses and target protein production on a temporal axis. Our integration of proteomic profiling with small molecule detection and quantification reveals the fluctuation of secondary metabolite production over time to provide new insight into the complexities of dual system modulation in molecular pharming. Our findings suggest that bioreactor bacterial growth may promote evasion of early plant defence responses towards Agrobacterium tumefaciens (updated nomenclature to Rhizobium radiobacter). Furthermore, we uncover and explore specific targets for genetic manipulation to suppress host defences and increase recombinant protein production in molecular pharming.PMID:38516995 | DOI:10.1111/pbi.14342

Circ Genom Precis Med. 2024 Mar 22:e004312. doi: 10.1161/CIRCGEN.123.004312. Online ahead of print.ABSTRACTBACKGROUND: Heart failure is heterogeneous syndrome with persistently high mortality. Nuclear magnetic resonance spectroscopy enables high-throughput metabolomics, suitable for precision phenotyping. We aimed to use targeted metabolomics to derive a metabolic risk score (MRS) that improved mortality risk stratification in heart failure.METHODS: Nuclear magnetic resonance was used to measure 21 metabolites (lipoprotein subspecies, branched-chain amino acids, alanine, GlycA, ketone bodies, glucose, and citrate) in plasma collected from a heart failure community cohort. The MRS was derived using LASSO penalized Cox regression and temporal validation. The association between the MRS and mortality and whether risk stratification was improved over the Meta-Analysis Global Group in Chronic Heart Failure clinical risk score and NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels were assessed.RESULTS: The study included 1382 patients (median age, 78 years, 52% men, 43% reduced ejection fraction) with a 5-year survival rate of 48% (95% CI, 46%-51%). The MRS included 9 metabolites measured. In the validation data set, a 1 SD increase in the MRS was associated with a large increased rate of death (hazard ratio, 2.2 [95% CI, 1.9-2.5]) that remained after adjustment for Meta-Analysis Global Group in Chronic Heart Failure score and NT-proBNP (hazard ratio, 1.6 [95% CI, 1.3-1.9]). These associations did not differ by ejection fraction. The integrated discrimination and net reclassification indices, and Uno's C statistic, indicated that the addition of the MRS improved discrimination over Meta-Analysis Global Group in Chronic Heart Failure and NT-proBNP.CONCLUSIONS: This MRS developed in a heart failure community cohort was associated with a large excess risk of death and improved risk stratification beyond an established risk score and clinical markers.PMID:38516784 | DOI:10.1161/CIRCGEN.123.004312

Front Plant Sci. 2024 Mar 7;15:1308781. doi: 10.3389/fpls.2024.1308781. eCollection 2024.ABSTRACTBACKGROUND: Brassinosteroids (BRs) are a class of naturally occurring steroidal phytohormones mediating a wide range of pivotal developmental and physiological functions throughout the plant's life cycle. Therefore, it is of great significance to determine the content and the distribution of BRs in plants.Regretfully, although a large number of quantitative methods for BRs by liquid chromatography-tandem mass spectrometry (LC-MS/MS) have been reported, the in planta distribution of BRs is still unclear because of their lower contents in plant tissues and the lack of effective ionizable groups in their chemical structures.METHODS: We stablished a novel analytical method of BRs based on C18 cartridge solid-phase extraction (SPE) purification, 4-(dimethylamino)-phenylboronic acid (DMAPBA) derivatization, and online valve-switching system coupled with ultra-high performance liquid chromatography-electro spray ionization-triple quadrupole mass spectrometry (UHPLC-ESI-MS/MS). This method has been used to quantify three structural types of BRs (epibrassinolide, epicastasterone, and 6-deoxo-24-epicastaster one) in different organs of Brassica napus L. (rapeseed).RESULTS: We obtained the contents of three structural types of BRs in various organ tissues of rapeseed. The contents of three BRs in rapeseed flowers were the highest, followed by tender pods. The levels of three BRs all decreased during the maturation of the organs. We outlined the spatial distribution maps of three BRs in rapeseed based on these results, so as to understand the spatial distribution of BRs at the visual level.CONCLUSIONS: Our results provided useful information for the precise in situ localization of BRs in plants and the metabolomic research of BRs in future work. The in planta spatial distribution of BRs at the visual level has been studied for the first time.PMID:38516662 | PMC:PMC10956354 | DOI:10.3389/fpls.2024.1308781

Front Plant Sci. 2024 Mar 7;15:1326917. doi: 10.3389/fpls.2024.1326917. eCollection 2024.ABSTRACTINTRODUCTION: Endophytes play a significant role in regulating plant root development and facilitating nutrient solubilization and transportation. This association could improve plant growth. The present study has uncovered a distinct phenotype, which we refer to as "white root", arising from the intricate interactions between endophytic fungi and bacteria with the roots in a sugarcane and bamboo fungus (Dictyophora indusiata) intercropping system.METHODS: We investigated the mechanisms underlying the formation of this "white root" phenotype and its impact on sugarcane yield and metabolism by metabarcoding and metabolome analysis.RESULTS AND DISCUSSION: Initial analysis revealed that intercropping with D. indusiata increased sugarcane yield by enhancing the number of viable tillers compared with bagasse and no input control. Metabarcoding based on second-generation and third-generation sequencing indicated that D. indusiate and Bacillus aryabhattai dominates the fungal and bacterial composition in the "white root" phenotype of sugarcane root. The coexistence of D. indusiata and B. aryabhattai as endophytes induced plant growth-promoting metabolites in the sugarcane root system, such as lysoPC 18:1 and dihydrobenzofuran, probably contributing to increased sugarcane yield. Furthermore, the association also enhanced the metabolism of compounds, such as naringenin-7-O-glucoside (Prunin), naringenin-7-O-neohesperidoside (Naringin)*, hesperetin-7-O-neohesperidoside (Neohesperidin), epicatechin, and aromadendrin (Dihydrokaempferol), involved in flavonoid metabolism during the formation of the endophytic phenotype in the sugarcane root system. These observations suggest that the "white root" phenotype promotes sugarcane growth by activating flavonoid metabolism. This study reports an interesting phenomenon where D. indusiata, coordinate with the specific bacteria invade, forms a "white root" phenotype with sugarcane root. The study also provides new insights into using D. indusiata as a soil inoculant for promoting sugarcane growth and proposes a new approach for improve sugarcane cultivation.PMID:38516657 | PMC:PMC10955060 | DOI:10.3389/fpls.2024.1326917

World J Gastroenterol. 2024 Feb 28;30(8):881-900. doi: 10.3748/wjg.v30.i8.881.ABSTRACTBACKGROUND: Immune dysregulation and metabolic derangement have been recognized as key factors that contribute to the progression of hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF). However, the mechanisms underlying immune and metabolic derangement in patients with advanced HBV-ACLF are unclear.AIM: To identify the bioenergetic alterations in the liver of patients with HBV-ACLF causing hepatic immune dysregulation and metabolic disorders.METHODS: Liver samples were collected from 16 healthy donors (HDs) and 17 advanced HBV-ACLF patients who were eligible for liver transplantation. The mitochondrial ultrastructure, metabolic characteristics, and immune microenvironment of the liver were assessed. More focus was given to organic acid metabolism as well as the function and subpopulations of macrophages in patients with HBV-ACLF.RESULTS: Compared with HDs, there was extensive hepatocyte necrosis, immune cell infiltration, and ductular reaction in patients with ACLF. In patients, the liver suffered severe hypoxia, as evidenced by increased expression of hypoxia-inducible factor-1α. Swollen mitochondria and cristae were observed in the liver of patients. The number, length, width, and area of mitochondria were adaptively increased in hepatocytes. Targeted metabolomics analysis revealed that mitochondrial oxidative phosphorylation decreased, while anaerobic glycolysis was enhanced in patients with HBV-ACLF. These findings suggested that, to a greater extent, hepa-tocytes used the extra-mitochondrial glycolytic pathway as an energy source. Patients with HBV-ACLF had elevated levels of chemokine C-C motif ligand 2 in the liver homogenate, which stimulates peripheral monocyte infiltration into the liver. Characterization and functional analysis of macrophage subsets revealed that patients with ACLF had a high abundance of CD68+ HLA-DR+ macrophages and elevated levels of both interleukin-1β and transforming growth factor-β1 in their livers. The abundance of CD206+ CD163+ macrophages and expression of interleukin-10 decreased. The correlation analysis revealed that hepatic organic acid metabolites were closely associated with macrophage-derived cytokines/chemokines.CONCLUSION: The results indicated that bioenergetic alteration driven by hypoxia and mitochondrial dysfunction affects hepatic immune and metabolic remodeling, leading to advanced HBV-ACLF. These findings highlight a new therapeutic target for improving the treatment of HBV-ACLF.PMID:38516248 | PMC:PMC10950637 | DOI:10.3748/wjg.v30.i8.881

Front Mol Biosci. 2024 Mar 7;11:1341950. doi: 10.3389/fmolb.2024.1341950. eCollection 2024.ABSTRACTIntroduction: Parkinson's disease (PD) is the most common motor neurodegenerative disease worldwide. Given the complexity of PD etiology and the different metabolic derangements correlated to the disease, metabolomics profiling of patients is a helpful tool to identify patho-mechanistic pathways for the disease development. Dopamine metabolism has been the target of several previous studies, of which some have reported lower phenylalanine and tyrosine levels in PD patients compared to controls. Methods: In this study, we have collected plasma from 27 PD patients, 18 reference controls, and 8 high-risk controls to perform a metabolomic study using liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS). Results: Our findings revealed higher intensities of trans-cinnamate, a phenylalanine metabolite, in patients compared to reference controls. Thus, we hypothesize that phenylalanine metabolism has been shifted to produce trans-cinnamate via L-phenylalanine ammonia lyase (PAL), instead of producing tyrosine, a dopamine precursor, via phenylalanine hydroxylase (PAH). Discussion: Given that these metabolites are precursors to several other metabolic pathways, the intensities of many metabolites such as dopamine, norepinephrine, and 3-hydroxyanthranilic acid, which connects phenylalanine metabolism to that of tryptophan, have been altered. Consequently, and in respect to Metabolic Control Analysis (MCA) theory, the levels of tryptophan metabolites have also been altered. Some of these metabolites are tryptamine, melatonin, and nicotinamide. Thus, we assume that these alterations could contribute to the dopaminergic, adrenergic, and serotonergic neurodegeneration that happen in the disease.PMID:38516193 | PMC:PMC10955577 | DOI:10.3389/fmolb.2024.1341950

Front Mol Biosci. 2024 Mar 7;11:1332090. doi: 10.3389/fmolb.2024.1332090. eCollection 2024.ABSTRACTBackground: Mycophenolate mofetil (MMF), the morpholinoethyl ester of mycophenolic acid, is widely used for maintenance immunosuppression in transplantation. The gastrointestinal toxicity of MMF has been widely uncovered. However, the comprehensive metabolic analysis of MMF-induced toxicity is lacking. This study is aimed to ascertain the metabolic changes after MMF administration in mice. Methods: A total of 700 mg MMF was dissolved in 7 mL dimethyl sulfoxide (DMSO), and then 0.5 mL of mixture was diluted with 4.5 mL of saline (100 mg/kg). Mice in the treatment group (n = 9) were given MMF (0.1 mL/10 g) each day via intraperitoneal injection lasting for 2 weeks, while those in the control group (n = 9) received the same amount of blank solvent (DMSO: saline = 1:9). Gas chromatography-mass spectrometry was utilized to identify the metabolic profiling in serum samples and multiple organ tissues of mice. The potential metabolites were identified using orthogonal partial least squares discrimination analysis. Meanwhile, we used the MetaboAnalyst 5.0 (http://www.metaboanalyst.ca) and Kyoto Encyclopedia of Genes and Genomes database (http://www.kegg.jp) to depict the metabolic pathways. The percentages of lymphocytes in spleens were assessed by multiparameter flow cytometry analysis. Results: Compared to the control group, we observed that MMF treatment induced differential expression of metabolites in the intestine, hippocampus, lung, liver, kidney, heart, serum, and cortex tissues. Subsequently, we demonstrated that multiple amino acids metabolism and fatty acids biosynthesis were disrupted following MMF treatment. Additionally, MMF challenge dramatically increased CD4+ T cell percentages but had no significant influences on other types of lymphocytes. Conclusion: MMF can affect the metabolism in various organs and serum in mice. These data may provide preliminary judgement for MMF-induced toxicity and understand the metabolic mechanism of MMF more comprehensively.PMID:38516185 | PMC:PMC10955473 | DOI:10.3389/fmolb.2024.1332090

Chem Sci. 2024 Feb 26;15(12):4547-4555. doi: 10.1039/d4sc00839a. eCollection 2024 Mar 20.ABSTRACTSubcellular metabolomics analysis is crucial for understanding intracellular heterogeneity and accurate drug-cell interactions. Unfortunately, the ultra-small size and complex microenvironment inside the cell pose a great challenge to achieving this goal. To address this challenge, we propose an artificial intelligence-assisted subcellular mass spectrometry imaging (AI-SMSI) strategy with in situ image segmentation. Based on the nanometer-resolution MSI technique, the protonated guanine and threonine ions were respectively employed as the nucleus and cytoplasmic markers to complete image segmentation at the subcellular level, avoiding mutual interference of signals from various compartments in the cell. With advanced AI models, the metabolites within the different regions could be further integrated and profiled. Through this method, we decrypted the distinct action mechanism of isomeric drugs, doxorubicin (DOX) and epirubicin (EPI), only with a stereochemical inversion at C-4'. Within the cytoplasmic region, fifteen specific metabolites were discovered as biomarkers for distinguishing the drug action difference between DOX and EPI. Moreover, we identified that the downregulations of glutamate and aspartate in the malate-aspartate shuttle pathway may contribute to the higher paratoxicity of DOX. Our current AI-SMSI approach has promising applications for subcellular metabolomics analysis and thus opens new opportunities to further explore drug-cell specific interactions for the long-term pursuit of precision medicine.PMID:38516065 | PMC:PMC10952063 | DOI:10.1039/d4sc00839a

Front Pharmacol. 2024 Mar 7;15:1335814. doi: 10.3389/fphar.2024.1335814. eCollection 2024.ABSTRACTGentiopicroside (GPS) is a highly water-soluble small-molecule drug and the main bioactive secoiridoid glycoside of Gentiana scabra that has been shown to have hepatoprotective effects against non-alcoholic steatohepatitis (NASH), a form of non-alcoholic fatty liver disease (NAFLD) that can progress to cirrhosis and hepatocellular carcinoma. However, the effects of GPS on NASH and the underlying mechanisms remain obscure. Firstly, a high-fat, high-cholesterol (HFHC) diet and a high-sugar solution containing d-fructose and d-glucose were used to establish a non-alcoholic steatohepatitis (NASH) mice model. Secondly, we confirmed GPS supplementation improve metabolic abnormalities and reduce inflammation in NASH mice induced by HFHC and high-sugar solution. Then we used metabolomics to investigate the mechanisms of GPS in NASH mice. Metabolomics analysis showed GPS may work through the Peroxisome Proliferator-Activated Receptor (PPAR) signaling pathway and glycine, serine, and threonine metabolism. Functional metabolites restored by GPS included serine, glycine, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). Western blot and qRT-PCR analysis confirmed GPS improve NASH by regulating PPARα and Hypoxia-Inducible Factor-1α (HIF-1α) signaling pathways. In vitro, studies further demonstrated EPA and DHA enhance fatty acid oxidation through the PPARα pathway, while serine and glycine inhibit oxidative stress through the HIF-1α pathway in palmitic acid-stimulated HepG2 cells. Our results suggest GPS's anti-inflammatory and anti-steatosis effects in NASH progression are related to the suppression of HIF-1α through the restoration of L-serine and glycine and the activation of PPARα through increased EPA and DHA.PMID:38515850 | PMC:PMC10956515 | DOI:10.3389/fphar.2024.1335814

Heliyon. 2024 Mar 14;10(6):e27292. doi: 10.1016/j.heliyon.2024.e27292. eCollection 2024 Mar 30.ABSTRACTAlterations of nitric oxide (NO) homeostasis have been described in mood disorders. However, the analytical challenges associated with the direct measurement of NO have prompted the search for alternative biomarkers of NO synthesis. We investigated the published evidence of the association between these alternative biomarkers and mood disorders (depressive disorder or bipolar disorder). Electronic databases were searched from inception to the June 30, 2023. In 20 studies, there was a trend towards significantly higher asymmetric dimethylarginine (ADMA) in mood disorders vs. controls (p = 0.072), and non-significant differences in arginine (p = 0.29), citrulline (p = 0.35), symmetric dimethylarginine (SDMA; p = 0.23), and ornithine (p = 0.42). In subgroup analyses, the SMD for ADMA was significant in bipolar disorder (p < 0.001) and European studies (p = 0.02), the SMDs for SDMA (p = 0.001) and citrulline (p = 0.038) in European studies, and the SMD for ornithine in bipolar disorder (p = 0.007), Asian (p = 0.001) and American studies (p = 0.005), and patients treated with antidepressants (p = 0.029). The abnormal concentrations of ADMA, SDMA, citrulline, and ornithine in subgroups of mood disorders, particularly bipolar disorder, warrant further research to unravel their pathophysiological role and identify novel treatments in this group (The protocol was registered in PROSPERO: CRD42023445962).PMID:38515671 | PMC:PMC10955251 | DOI:10.1016/j.heliyon.2024.e27292

Front Bioeng Biotechnol. 2024 Mar 7;12:1365229. doi: 10.3389/fbioe.2024.1365229. eCollection 2024.ABSTRACTContinuous cropping obstacles seriously constrained the sustainable development of the ginseng industry. The allelopathic autotoxicity of ginsenosides is the key "trigger" of continuous cropping obstacles in ginseng. During harvest, the ginseng plants could be broken and remain in the soil. The decomposition of ginseng residue in soil is one of the important release ways of ginsenosides. Therefore, the allelopathic mechanism of ginsenosides through the decomposed release pathway needs an in-depth study. To investigate this allelopathic regulation mechanism, the integrated analysis of transcriptomics and metabolomics was applied. The prototype ginsenosides in ginseng were detected converse to rare ginsenosides during decomposition. The rare ginsenosides caused more serious damage to ginseng hairy root cells and inhibited the growth of ginseng hairy roots more significantly. By high-throughput RNA sequencing gene transcriptomics study, the significantly differential expressed genes (DEGs) were obtained under prototype and rare ginsenoside interventions. These DEGs were mainly enriched in the biosynthesis of secondary metabolites and metabolic pathways, phytohormone signal transduction, and protein processing in endoplasmic reticulum pathways. Based on the functional enrichment of DEGs, the targeted metabolomics analysis based on UPLC-MS/MS determination was applied to screen endogenous differential metabolized phytohormones (DMPs). The influence of prototype and rare ginsenosides on the accumulation of endogenous phytohormones was studied. These were mainly involved in the biosynthesis of diterpenoid, zeatin, and secondary metabolites, phytohormone signal transduction, and metabolic pathways. After integrating the transcriptomics and metabolomics analysis, ginsenosides could regulate the genes in phytohormone signaling pathways to influence the accumulation of JA, ABA, and SA. The conclusion was that the prototype ginsenosides were converted into rare ginsenosides by ginseng decomposition and released into the soil, which aggravated its allelopathic autotoxicity. The allelopathic mechanism was to intervene in the response regulation of genes related to the metabolic accumulation of endogenous phytohormones in ginseng. This result provides a reference for the in-depth study of continuous cropping obstacles of ginseng.PMID:38515624 | PMC:PMC10955472 | DOI:10.3389/fbioe.2024.1365229

Clin Transl Sci. 2024 Mar;17(3):e13773. doi: 10.1111/cts.13773.ABSTRACTOur aim was to evaluate biomarkers for organic anion transporting polypeptide 1B1 (OATP1B1) function using a hypothesis-free metabolomics approach. We analyzed fasting plasma samples from 356 healthy volunteers using non-targeted metabolite profiling by liquid chromatography high-resolution mass spectrometry. Based on SLCO1B1 genotypes, we stratified the volunteers to poor, decreased, normal, increased, and highly increased OATP1B1 function groups. Linear regression analysis, and random forest (RF) and gradient boosted decision tree (GBDT) regressors were used to investigate associations of plasma metabolite features with OATP1B1 function. Of the 9152 molecular features found, 39 associated with OATP1B1 function either in the linear regression analysis (p < 10-5) or the RF or GBDT regressors (Gini impurity decrease > 0.01). Linear regression analysis showed the strongest associations with two features identified as glycodeoxycholate 3-O-glucuronide (GDCA-3G; p = 1.2 × 10-20 for negative and p = 1.7 × 10-19 for positive electrospray ionization) and one identified as glycochenodeoxycholate 3-O-glucuronide (GCDCA-3G; p = 2.7 × 10-16). In both the RF and GBDT models, the GCDCA-3G feature showed the strongest association with OATP1B1 function, with Gini impurity decreases of 0.40 and 0.17. In RF, this was followed by one GDCA-3G feature, an unidentified feature with a molecular weight of 809.3521, and the second GDCA-3G feature. In GBDT, the second and third strongest associations were observed with the GDCA-3G features. Of the other associated features, we identified with confidence two representing lysophosphatidylethanolamine 22:5. In addition, one feature was putatively identified as pregnanolone sulfate and one as pregnenolone sulfate. These results confirm GCDCA-3G and GDCA-3G as robust OATP1B1 biomarkers in human plasma.PMID:38515340 | DOI:10.1111/cts.13773

Twin Res Hum Genet. 2024 Mar 22:1-8. doi: 10.1017/thg.2024.10. Online ahead of print.ABSTRACTFetuses undergo major surgical stress as well as fluid shifts secondary to both twin-twin transfusion (TTTS) as well as the fetoscopic surgery for treatment of TTTS. While the pathophysiology of TTTS is understood, the acute metabolic changes that fetuses experience from fetoscopic surgery are not. We sought to evaluate the changes in recipient metabolomic profile secondary to TTTS surgery. Amniotic fluid was collected at the beginning and end of four TTTS surgical cases performed from 12/2022-2/2023. Samples were immediately processed and evaluated via NMR-based Metabolomics Facility protocol. In univariate analysis, 12 metabolites (glucose, lactate, and 10 key amino acids) showed statistically significant changes between the beginning and end of the surgery. Among these, 11 metabolites decreased at the end, while only lactate increased. Supervised oPLS-DA modeling revealed pyruvate and lactate as the two metabolites most impact on the variance between cases, and that 40% of metabolomic changes could be attributed directly to the timing that the sample was taken (i.e., if pre- or postoperatively). These results indicate significant metabolic changes in the recipient twin during fetoscopic surgery for TTTS. These findings of decreased glucose, increased lactate, and decreased amnio acids would indicate increased catabolism during surgery. This study raises questions regarding optimal maternal and fetal nutrition during surgery and if nutritional status could be optimized to further improve twin survival during fetoscopic surgery.PMID:38515292 | DOI:10.1017/thg.2024.10

Microbiome. 2024 Mar 21;12(1):60. doi: 10.1186/s40168-024-01773-5.ABSTRACTBACKGROUND: The gut microbiota is recognized as a regulator of brain development and behavioral outcomes during childhood. Nonetheless, associations between the gut microbiota and behavior are often inconsistent among studies in humans, perhaps because many host-microbe relationships vary widely between individuals. This study aims to stratify children based on their gut microbiota composition (i.e., clusters) and to identify novel gut microbiome cluster-specific associations between the stool metabolomic pathways and child behavioral outcomes.METHODS: Stool samples were collected from a community sample of 248 typically developing children (3-5 years). The gut microbiota was analyzed using 16S sequencing while LC-MS/MS was used for untargeted metabolomics. Parent-reported behavioral outcomes (i.e., Adaptive Skills, Internalizing, Externalizing, Behavioral Symptoms, Developmental Social Disorders) were assessed using the Behavior Assessment System for Children (BASC-2). Children were grouped based on their gut microbiota composition using the Dirichlet multinomial method, after which differences in the metabolome and behavioral outcomes were investigated.RESULTS: Four different gut microbiota clusters were identified, where the cluster enriched in both Bacteroides and Bifidobacterium (Ba2) had the most distinct stool metabolome. The cluster characterized by high Bifidobacterium abundance (Bif), as well as cluster Ba2, were associated with lower Adaptive Skill scores and its subcomponent Social Skills. Cluster Ba2 also had significantly lower stool histidine to urocanate turnover, which in turn was associated with lower Social Skill scores in a cluster-dependent manner. Finally, cluster Ba2 had increased levels of compounds involved in Galactose metabolism (i.e., stachyose, raffinose, alpha-D-glucose), where alpha-D-glucose was associated with the Adaptive Skill subcomponent Daily Living scores (i.e., ability to perform basic everyday tasks) in a cluster-dependent manner.CONCLUSIONS: These data show novel associations between the gut microbiota, its metabolites, and behavioral outcomes in typically developing preschool-aged children. Our results support the concept that cluster-based groupings could be used to develop more personalized interventions to support child behavioral outcomes. Video Abstract.PMID:38515179 | DOI:10.1186/s40168-024-01773-5