PubMed

Food Funct. 2024 May 22. doi: 10.1039/d4fo00961d. Online ahead of print.ABSTRACTBackground: The escalating prevalence of hyperuricemia is emerging as a significant public health concern. The association between dietary lignans and hyperuricemia is yet to be fully elucidated. Our study aims to evaluate the relationships between dietary lignan intake and hyperuricemia among middle-aged and elderly Chinese individuals, with an additional focus on investigating the underlying mechanisms. Methods: Dietary lignan intake was measured using a validated Food Frequency Questionnaire in 3801 participants at the baseline. Among them, 2552 participants were included in the longitudinal study with a median follow-up of 10.5 years. The gut microbiota was analyzed by shotgun metagenome sequencing in 1789 participants, and the targeted fecal metabolome was determined in 987 participants using UPLC-MS/MS at the midpoint of follow-up. Results: The multivariable-adjusted HRs (95% CIs) for hyperuricemia incidence in the highest quartile (vs. the lowest quartile) of dietary intake of total lignans, matairesinol, pinoresinol, and secoisolariciresinol were 0.93 (0.78-1.10), 0.77 (0.66-0.90), 0.83 (0.70-0.97), and 0.85 (0.73-1.00), respectively. The gut microbial and fecal metabolic compositions were significantly different across the dietary lignan groups and the hyperuricemia groups. The beneficial associations between dietary lignans and hyperuricemia might be mediated by several gut microbes (e.g., Fusobacterium mortiferum and Blautia sp. CAG-257) and the downstream bile acid products (e.g., NorCA, glycochenodeoxycholic acid, and glycoursodeoxycholic acid). Conclusion: We found that dietary lignans were inversely associated with hyperuricemia incidence, and the gut microbiota-bile acid axis might mediate this association. Our findings provide new perspectives on precise therapeutic targets and underlying mechanisms for conditions associated with elevated uric acid.PMID:38775706 | DOI:10.1039/d4fo00961d

Mem Inst Oswaldo Cruz. 2024 May 20;119:e230243. doi: 10.1590/0074-02760230243. eCollection 2024.ABSTRACTBACKGROUND: Leishmania tarentolae is a non-pathogenic species found in lizards representing an important model for Leishmania biology. However, several aspects of this Sauroleishmania remain unknown to explain its low level of virulence.OBJECTIVES: We reported several aspects of L. tarentolae biology including glycoconjugates, proteolytic activities and metabolome composition in comparison to pathogenic species (Leishmania amazonensis, Leishmania braziliensis, Leishmania infantum and Leishmania major).METHODS: Parasites were cultured for extraction and purification of lipophosphoglycan (LPG), immunofluorescence probing with anti-gp63 and resistance against complement. Parasite extracts were also tested for proteases activity and metabolome composition.FINDINGS: Leishmania tarentolae does not express LPG on its surface. It expresses gp63 at lower levels compared to pathogenic species and, is highly sensitive to complement-mediated lysis. This species also lacks intracellular/extracellular activities of proteolytic enzymes. It has metabolic differences with pathogenic species, exhibiting a lower abundance of metabolites including ABC transporters, biosynthesis of unsaturated fatty acids and steroids, TCA cycle, glycine/serine/threonine metabolism, glyoxylate/dicarboxylate metabolism and pentose-phosphate pathways.MAIN CONCLUSIONS: The non-pathogenic phenotype of L. tarentolae is associated with alterations in several biochemical and molecular features. This reinforces the need of comparative studies between pathogenic and non-pathogenic species to elucidate the molecular mechanisms of virulence during host-parasite interactions.PMID:38775551 | DOI:10.1590/0074-02760230243

Electrophoresis. 2024 May 22. doi: 10.1002/elps.202300223. Online ahead of print.ABSTRACTGenetic factors, diet, lifestyle, and other factors lead to various complications in the body, such as obesity and other chronic diseases. The inflammatory state caused by excessive accumulation of body fat affects the pathways related to the control of glycemic homeostasis, leading to a high demand for insulin, to subsequent failure of stressed β cells, and development of type 2 diabetes mellitus (T2DM). The study of new endocrine signalers, such as bile acids (BAs), becomes necessary as it allows the development of alternatives for T2DM treatment. In this work, a methodology was developed to quantify tauroursodeoxycholic BA (TUDCA) in liver cells of the HepG2 strain treated in hyperlipidic medium. This BA helps to improve insulin clearance by increasing the expression of the insulin-degrading enzyme, restoring sensitivity to this hormone, and making it viable for treating T2DM. Herein, a targeted metabolomic method for TUDCA determination in extracellular medium of hepatocyte matrices by micellar electrokinetic chromatography-UV was optimized, validated, and applied. The optimized background electrolyte was composed of 40 mmol/L sodium cholate and 30 mmol/L sodium tetraborate at pH 9.0. The following figures of merit were evaluated: linearity, limit of quantification, limit of detection, accuracy, and precision. Data obtained with the validated electrophoretic method showed a self-stimulation of TUDCA production in media supplemented only with BA. On the other hand, TUDCA concentration was reduced in the hyperlipidic medium. This suggests that, in these media, the effect of TUDCA is reduced, such as self-stimulated production and consequent regulation of glycemic homeostasis. Therefore, the results reinforce the need for investigating TUDCA as a potential T2DM biomarker as well as its use to treat several comorbidities, such as obesity and diabetes mellitus.PMID:38775263 | DOI:10.1002/elps.202300223

J Cell Physiol. 2024 May 22. doi: 10.1002/jcp.31317. Online ahead of print.ABSTRACTMitochondrial dysfunction has long been implicated in the development of insulin resistance, which is a hallmark of type 2 diabetes. However, recent studies reveal ethnicity-related differences in mitochondrial processes, underscoring the need for nuance in studying mitochondrial dysfunction and insulin sensitivity. Furthermore, the higher prevalence of type 2 diabetes among African Americans and individuals of African descent has brought attention to the role of ethnicity in disease susceptibility. In this review, which covers existing literature, genetic studies, and clinical data, we aim to elucidate the complex relationship between mitochondrial alterations and insulin stimulation by considering how mitochondrial dynamics, contact sites, pathways, and metabolomics may be differentially regulated across ethnicities, through mechanisms such as single nucleotide polymorphisms (SNPs). In addition to achieving a better understanding of insulin stimulation, future studies identifying novel regulators of mitochondrial structure and function could provide valuable insights into ethnicity-dependent insulin signaling and personalized care.PMID:38775168 | DOI:10.1002/jcp.31317

Physiol Plant. 2024 May-Jun;176(3):e14357. doi: 10.1111/ppl.14357.ABSTRACTThe application of protein hydrolysates (PH) biostimulants is considered a promising approach to promote crop growth and resilience against abiotic stresses. Nevertheless, PHs bioactivity depends on both the raw material used for their preparation and the molecular fraction applied. The present research aimed at investigating the molecular mechanisms triggered by applying a PH and its fractions on plants subjected to nitrogen limitations. To this objective, an integrated transcriptomic-metabolomic approach was used to assess lettuce plants grown under different nitrogen levels and treated with either the commercial PH Vegamin® or its molecular fractions PH1(>10 kDa), PH2 (1-10 kDa) and PH3 (<1 kDa). Regardless of nitrogen provision, biostimulant application enhanced lettuce biomass, likely through a hormone-like activity. This was confirmed by the modulation of genes involved in auxin and cytokinin synthesis, mirrored by an increase in the metabolic levels of these hormones. Consistently, PH and PH3 upregulated genes involved in cell wall growth and plasticity. Furthermore, the accumulation of specific metabolites suggested the activation of a multifaceted antioxidant machinery. Notwithstanding, the modulation of stress-response transcription factors and genes involved in detoxification processes was observed. The coordinated action of these molecular entities might underpin the increased resilience of lettuce plants against nitrogen-limiting conditions. In conclusion, integrating omics techniques allowed the elucidation of mechanistic aspects underlying PH bioactivity in crops. Most importantly, the comparison of PH with its fraction PH3 showed that, except for a few peculiarities, the effects induced were equivalent, suggesting that the highest bioactivity was ascribable to the lightest molecular fraction.PMID:38775128 | DOI:10.1111/ppl.14357

Acta Biochim Biophys Sin (Shanghai). 2024 May 22. doi: 10.3724/abbs.2024065. Online ahead of print.ABSTRACTAutophagy dysregulation and Ca 2+-induced mitochondrial dysfunction in trophoblast cells are proposed to contribute to preeclampsia (PE) development. FAM134B is identified as a receptor associated with endoplasmic reticulum autophagy (ER-phagy). In this study, the placentas of normal pregnant women and PE patients are collected and analyzed by immunohistochemistry, quantitative real-time PCR, and western blot analysis. The effects of ER-phagy are investigated in HTR8/SVneo cells. Significantly increased levels of FAM134B, inositol-1,4,5-triphosphate receptor type 1 (IP3R), calnexin, cleaved caspase 3 and cytochrome C are detected in the PE placenta and sodium nitroprusside (SNP)-treated HTR-8/SVneo cells. Overexpression of FAM134B in HTR-8/SVneo cells results in increased apoptosis, impaired invasion capacity, and diminished mitochondrial function, while an autophagy inhibitor improves mitochondrial performance. Excessive ER-phagy is also associated with an increased concentration of gamma linolenic acid. Our findings suggest that FAM134B contributes to trophoblast apoptosis by mediating ER-mitochondria Ca 2+ transfer through mitochondria-associated endoplasmic reticulum membranes (MAMs) and subsequent mitochondrial function, further enhancing our understanding of PE etiology.PMID:38774969 | DOI:10.3724/abbs.2024065

Arch Rheumatol. 2024 Feb 12;39(1):1-9. doi: 10.46497/ArchRheumatol.2024.10664. eCollection 2024 Mar.ABSTRACTIntelligence is the ability of humans to learn from experiences to ascribe conscious weights and unconscious biases to modulate their outputs from given inputs. Transferring this ability to computers is artificial intelligence (AI). The ability of computers to understand data in an intelligent manner is machine learning. When such learning is with images and videos, which involves deeper layers of artificial neural networks, it is described as deep learning. Large language models are the latest development in AI which incorporate self-learning into deep learning through transformers. AI in Rheumatology has immense potential to revolutionize healthcare and research. Machine learning could aid clinical diagnosis and decision-making, and deep learning could extend this to analyze images of radiology or positron emission tomography scans or histopathology images to aid a clinician's diagnosis. Analysis of routinely obtained patient data or continuously collected information from wearables could predict disease flares. Analysis of high-volume genomics, transcriptomics, proteomics, or metabolomics data from patients could help identify novel markers of disease prognosis. AI might identify newer therapeutic targets based on in-silico modelling of omics data. AI could help automate medical administrative work such as inputting information into electronic health records or transcribing clinic notes. AI could help automate patient education and counselling. Beyond the clinic, AI has the potential to aid medical education. The ever-expanding capabilities of AI models bring along with them considerable ethical challenges, particularly related to risks of misuse. Nevertheless, the widespread use of AI in Rheumatology is inevitable and a progress with great potential.PMID:38774703 | PMC:PMC11104749 | DOI:10.46497/ArchRheumatol.2024.10664

Front Cell Infect Microbiol. 2024 May 7;14:1394038. doi: 10.3389/fcimb.2024.1394038. eCollection 2024.ABSTRACTINTRODUCTION: Recent years, microbiota-associated aspects have been analysed in multiple disorders regarding cancers. Existing evidence pints that gut microorganisms might take part in tumour origin and therapy efficacy. Nevertheless, to date, data on faecal metabolomics in cancer patients is still strongly limited. Therefore, we aimed to analyse gut untargeted metabolome in gastrointestinal cancer patients (i.e., gastric and colorectal cancer).PATIENTS AND METHODS: There were 12 patients with either gastric (n=4) or colorectal cancer (n=8) enrolled and 8 analysed (n=4 each). Stool samples were collected prior to anti-cancer treatments. Untargeted metabolomics analyses were conducted by means of mass spectrometry.RESULTS: A plethora of metabolites in cancer patients we analysed were noted, with higher homogenity in case of gastric cancer patients. We found that the level of Deoxyguanosine,m/z 266.091,[M-H]-, Uridine,m/z 245.075,[M+H]+, Deoxyguanosine,m/z 268.104,[M]+, 3-Indoleacetic acid,m/z 176.07,[M+H]+, Indoxyl,m/z 132.031,[M-H]-, L-Phenylalanine,m/z 164.073,[M-H]-, L-Methionine,m/z 150.058,[M+NH4]+, was significantly higher in colorectal cancer patients and Ethyl hydrogen malonate,m/z 133.031,[M+H]+ in gastric cancer.CONCLUSION: The overall insights into untargeted metabolomics showed that most often higher levels of analysed metabolites were detected in colorectal cancer patients compared to gastric cancer patients. The link between gut metabolome and both local and distal metastasis might exist, however it requires confirmation in further multi-centre studies regarding larger sample size.PMID:38774628 | PMC:PMC11106370 | DOI:10.3389/fcimb.2024.1394038

Curr Res Food Sci. 2024 May 8;8:100767. doi: 10.1016/j.crfs.2024.100767. eCollection 2024.ABSTRACTMaillard reaction readily takes place in dairy products because of the association between thermal treatments, extended storage and the matrix composition. Along with the impairment of protein digestion, the formation of glycation and α-dicarbonyl compounds is a concern for quality attributes of whey proteins when used as ingredients. In this paper, we outline the capacity of brewer's spent grain melanoidins in reducing the accumulation of α-dicarbonyl compounds, thus controlling the formation of dietary advanced glycation end-products in accelerated shelf life at 35 °C. Results revealed that brewer's spent grain melanoidins targeted methylglyoxal and glyoxal reactivity leading to the reduction of N-ε-carboxymethyllysine and methylglyoxal-hydroimidazolone up to 27 and 60%, respectively. We here describe that the presence of melanoidins is instrumental in limiting the undesired effects of α-dicarbonyl compounds on whey proteins.PMID:38774268 | PMC:PMC11107219 | DOI:10.1016/j.crfs.2024.100767

Curr Res Food Sci. 2024 May 9;8:100761. doi: 10.1016/j.crfs.2024.100761. eCollection 2024.ABSTRACTNata de coco, an edible bacterial cellulose (BC) product, is a traditional dessert fermented in coconut water. Production of Nata de coco by Komagataeibacter nataicola is enhanced by pre-fermented coconut water, but its instability is a challenge. Here, BC production by K. nataicola Y19 was significantly improved by Saccharomyces cerevisiae 84-3 through shaping the metabolite profile of the coconut water. Different fermentation time with S. cerevisiae 84-3 resulted in distinct metabolite profiles and different promoting effect on BC yield. Compared to unfermented coconut water, coconut water fermented by S. cerevisiae 84-3 for 1d and 7d enhanced BC yield by 14.1-fold and 5.63-fold, respectively. Analysis between unfermented coconut water and 1d-fermented coconut water showed 129 significantly different metabolites, including organic acids, amino acids, nucleotides, and their derivatives. Prolonged fermentation for 7d changed levels of 155 metabolites belongs to organic acids, amino acids, nucleotides and their derivatives. Spearman correlation analysis further revealed that 17 metabolites were positively correlated with BC yield and 21 metabolites were negatively correlated with BC yield. These metabolites may affect energy metabolism, cell signaling, membrane integrity, and BC production by K. nataicola Y19. The further verification experiment gave the view that BC yield was not only closely related to the types of metabolites but also the concentration of metabolites. This study provides a novel theoretical framework for a highly efficient BC fermentation system utilizing stable fermented coconut water mediums.PMID:38774267 | PMC:PMC11107218 | DOI:10.1016/j.crfs.2024.100761

Front Endocrinol (Lausanne). 2024 May 7;15:1331282. doi: 10.3389/fendo.2024.1331282. eCollection 2024.ABSTRACTINTRODUCTION: Polycystic ovary syndrome (PCOS) is a common multifactorial and polygenic disorder of the endocrine system, affecting up to 20% of women in reproductive age with a still unknown etiology. Follicular fluid (FF) represents an environment for the normal development of follicles rich in metabolites, hormones and neurotransmitters, but in some instances of PCOS the composition can be different. Vasoactive intestinal peptide (VIP) is an endogenous autonomic neuropeptide involved in follicular atresia, granulosa cell physiology and steroidogenesis.METHODS: ELISA assays were performed to measure VIP and estradiol levels in human follicular fluids, while AMH, FSH, LH, estradiol and progesterone in the plasma were quantified by chemiluminescence. UHPLC/QTOF was used to perform the untargeted metabolomic analysis.RESULTS: Our ELISA and metabolomic results show: i) an increased concentration of VIP in follicular fluid of PCOS patients (n=9) of about 30% with respect to control group (n=10) (132 ± 28 pg/ml versus 103 ± 26 pg/ml, p=0,03) in women undergoing in vitro fertilization (IVF), ii) a linear positive correlation (p=0.05, r=0.45) between VIP concentration and serum Anti-Müllerian Hormone (AMH) concentration and iii) a linear negative correlation between VIP and noradrenaline metabolism. No correlation between VIP and estradiol (E2) concentration in follicular fluid was found. A negative correlation was found between VIP and noradrenaline metabolite 3,4-dihydroxyphenylglycolaldehyde (DOPGAL) in follicular fluids.CONCLUSION: VIP concentration in follicular fluids was increased in PCOS patients and a correlation was found with noradrenaline metabolism indicating a possible dysregulation of the sympathetic reflex in the ovarian follicles. The functional role of VIP as noradrenergic modulator in ovarian physiology and PCOS pathophysiology was discussed.PMID:38774232 | PMC:PMC11106456 | DOI:10.3389/fendo.2024.1331282

Front Plant Sci. 2024 May 7;15:1383018. doi: 10.3389/fpls.2024.1383018. eCollection 2024.ABSTRACTPinus sibirica is primarily distributed in Siberia. Owing to its excellent cold resistance and development potential, it has become an important introduced tree species in the Greater Xing'an area of China. Pine wilt disease, triggered by the pine wood nematode (PWN, Bursaphelenchus xylophilus), constitutes a profoundly critical affliction within forest ecosystems. Its incidence has extended to the northeastern region of China in recent years. To explore the potential host status of P. sibirica in the Greater Xing'an area for PWN and to elucidate the responses following inoculation, artificial inoculation, transcriptomics, and metabolomics methods were used. In the artificial inoculation experiments, quantitative analysis of nematode populations within the trees demonstrated that PWN exhibited normal growth and reproductive capabilities within P. sibirica. Subsequently, transcriptome and metabolome sequencing were conducted at four time points before disease onset (3-, 5-, 7-, and 9-days post inoculation). Gene trend analysis and differentially expressed gene screening were employed and the results indicated that genes associated with the flavonoid biosynthesis pathway exhibited predominant enrichment among the up-regulated genes. Metabolome analysis showed that the abundance of flavonoid-related metabolites in P. sibirica increased after inoculation with PWN. Integrated analysis of transcriptome and metabolome revealed that after PWN inoculation in P. sibirica, two chalcone synthase (chs) genes and a chalcone isomerase (chi) gene were significantly upregulated, and the upregulation should accumulate naringenin, pinocembrin, and apigenin to help P. sibirica resist infection of PWN. The results suggested that flavonoid biosynthesis pathway continued to respond after P. sibirica was infected with PWN and played an important role in the interaction between P. sibirica and PWN.PMID:38774221 | PMC:PMC11106439 | DOI:10.3389/fpls.2024.1383018

Front Pharmacol. 2024 May 7;15:1357381. doi: 10.3389/fphar.2024.1357381. eCollection 2024.ABSTRACTIntroduction: Agarwood is a traditional aromatic southern medicine. It has a long history of being used in traditional Chinese aromatherapy to treat insomnia, anxiety and depression. Due to the scarcity of wild resources, people have planted trees successfully and begun to explore various agarwood-inducing techniques. This study comparative analysis of volatile metabolites in agarwood produced by various inducing techniques and its potential sleep-promoting, anti-anxiety and anti-depressant network pharmacological activities. Methods: A total of 23 batches of two types of agarwood were collected, one of which was produced by artificial techniques, including 6 batches of TongTi (TT) agarwood produced by "Agar-Wit" and 6 batches of HuoLao (HL) agarwood produced by "burning, chisel and drilling", while the other was collected from the wild, including 6 batches of BanTou (BT) agarwood with trunks broken due to natural or man-made factors and 5 batches of ChongLou (CL) agarwood with trunks damaged by moth worms. The study employed metabolomics combined with network analysis to compare the differences in volatile metabolites of agarwood produced by four commonly used inducing techniques, and explored their potential roles and possible action targets in promoting sleep, reducing anxiety, and alleviating depression. Results: A total of 147 volatile metabolites were detected in agarwood samples, mainly including small aromatic hydrocarbons, sesquiterpenes and 2-(2-phenylethyl) chromone and their pyrolysis products. The results showed composition of metabolites was minimally influenced by the agarwood induction method. However, their concentrations exhibited significant variations, with 17 metabolites showing major differences. The two most distinct metabolites were 6-methoxy-2-(2-phenylethyl) chromone and 6,7-dimethoxy-2-(2-phenylethyl) chromone. Among the volatile metabolites, 142 showed promising potential in treating insomnia, anxiety, and depression, implicating various biological and signaling pathways, predominantly ALB and TNF targets. The top three active metabolites identified were 2-(2-phenylethyl) chromone, 1,5-diphenylpent-1-en-3-one, and 6-methoxy-2-[2-(4'-methoxyphenyl) ethyl] chromone, with their relative content in the four types of agarwood being TT>HL>CL>BT. Conclusion: The differences in the content of 2-(2-phenylethyl) chromones suggest that they may be responsible for the varying therapeutic activities observed in different types of agarwood aromatherapy. This study offers theoretical support for the selection of agarwood in aromatherapy practices.PMID:38774207 | PMC:PMC11107428 | DOI:10.3389/fphar.2024.1357381

Osteoarthr Cartil Open. 2024 May 4;6(3):100479. doi: 10.1016/j.ocarto.2024.100479. eCollection 2024 Sep.ABSTRACTOBJECTIVE: Obesity is a leading risk factor for both the incidence and progression of osteoarthritis (OA). Omic technologies, including transcriptomics and metabolomics are capable of identifying RNA and metabolite profiles in tissues and biofluids of OA patients. The objective of this review is to highlight studies using transcriptomics and metabolomics that contribute to our understanding of OA pathology in relation to obesity.DESIGN: We conducted a targeted search of PUBMED for articles, and GEO for datasets, published up to February 13, 2024, screening for those using high-throughput transcriptomic and metabolomic techniques to study human or pre-clinical animal model tissues or biofluids related to obesity-associated OA. We describe relevant studies and discuss challenges studying obesity as a disease-related factor in OA.RESULTS: Of the 107 publications identified by our search criteria, only 15 specifically used transcriptomics or metabolomics to study joint tissues or biofluids in obesity-related OA. Specific transcriptomic and metabolomic signatures associated with obesity-related OA have been defined in select local joint tissues, biofluids and other biological material. However, considerable challenges exist in understanding contributions of obesity-associated modifications of transcriptomes and metabolomes related to OA, including sociodemographic, anthropometric, dietary and molecular redundancy-related factors.CONCLUSIONS: A number of additional transcriptomic and metabolomic studies are needed to comprehensively understand how obesity affects OA incidence, progression and outcomes. Integration of transcriptome and metabolome signatures from multiple tissues and biofluids, using network-based approaches will likely help to better define putative therapeutic targets that could enable precision medicine approaches to obese OA patients.PMID:38774038 | PMC:PMC11103424 | DOI:10.1016/j.ocarto.2024.100479

Theranostics. 2024 Apr 29;14(7):2856-2880. doi: 10.7150/thno.88223. eCollection 2024.ABSTRACTCell metabolism reprogramming to sustain energy production, while reducing oxygen and energy consuming processes is crucially important for the adaptation to hypoxia/ischemia. Adaptive metabolic rewiring is controlled by hypoxia-inducible factors (HIFs). Accumulating experimental evidence indicates that timely activation of HIF in brain-resident cells improves the outcome from acute ischemic stroke. However, the underlying molecular mechanisms are still incompletely understood. Thus, we investigated whether HIF-dependent metabolic reprogramming affects the vulnerability of brain-resident cells towards ischemic stress. Methods: We used genetic and pharmacological approaches to activate HIF in the murine brain in vivo and in primary neurons and astrocytes in vitro. Numerous metabolomic approaches and molecular biological techniques were applied to elucidate potential HIF-dependent effects on the central carbon metabolism of brain cells. In animal and cell models of ischemic stroke, we analysed whether HIF-dependent metabolic reprogramming influences the susceptibility to ischemic injury. Results: Neuron-specific gene ablation of prolyl-4-hydroxylase domain 2 (PHD2) protein, negatively regulating the protein stability of HIF-α in an oxygen dependent manner, reduced brain injury and functional impairment of mice after acute stroke in a HIF-dependent manner. Accordingly, PHD2 deficient neurons showed an improved tolerance towards ischemic stress in vitro, which was accompanied by enhanced HIF-1-mediated glycolytic lactate production through pyruvate dehydrogenase kinase-mediated inhibition of the pyruvate dehydrogenase. Systemic treatment of mice with roxadustat, a low-molecular weight pan-PHD inhibitor, not only increased the abundance of numerous metabolites of the central carbon and amino acid metabolism in murine brain, but also ameliorated cerebral tissue damage and sensorimotor dysfunction after acute ischemic stroke. In neurons and astrocytes roxadustat provoked a HIF-1-dependent glucose metabolism reprogramming including elevation of glucose uptake, glycogen synthesis, glycolytic capacity, lactate production and lactate release, which enhanced the ischemic tolerance of astrocytes, but not neurons. We found that strong activation of HIF-1 in neurons by non-selective inhibition of all PHD isoenzymes caused a HIF-1-dependent upregulation of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 redirecting glucose-6-phosphate from pentose phosphate pathway (PPP) to the glycolysis pathway. This was accompanied by a reduction of NADPH production in the PPP, which further decreased the low intrinsic antioxidant reserve of neurons, making them more susceptible to ischemic stress. Nonetheless, in organotypic hippocampal cultures with preserved neuronal-glial interactions roxadustat decreased the neuronal susceptibility to ischemic stress, which was largely prevented by restricting glycolytic energy production through lactate transport blockade. Conclusion: Collectively, our results indicate that HIF-1-mediated metabolic reprogramming alleviates the intrinsic vulnerability of brain-resident cells to ischemic stress.PMID:38773968 | PMC:PMC11103502 | DOI:10.7150/thno.88223

Anal Chim Acta. 2024 Jun 22;1309:342689. doi: 10.1016/j.aca.2024.342689. Epub 2024 May 4.ABSTRACTBACKGROUND: Metabolomics plays a critical role in deciphering metabolic alterations within individuals, demanding the use of sophisticated analytical methodologies to navigate its intricate complexity. While many studies focus on single biofluid types, simultaneous analysis of multiple matrices enhances understanding of complex biological mechanisms. Consequently, the development of data fusion methods enabling multiblock analysis becomes essential for comprehensive insights into metabolic dynamics.RESULTS: This study introduces a novel guideline for jointly analyzing diverse metabolomic datasets (serum, urine, metadata) with a focus on metabolic differences between groups within a healthy cohort. The guideline presents two fusion strategies, 'Low-Level data fusion' (LLDF) and 'Mid-Level data fusion' (MLDF), employing a sequential application of Multivariate Curve Resolution with Alternating Least Squares (MCR-ALS), linking the outcomes of successive analyses. MCR-ALS is a versatile method for analyzing mixed data, adaptable at various stages of data processing-encompassing resonance integration, data compression, and exploratory analysis. The LLDF and MLDF strategies were applied to 1H NMR spectral data extracted from urine and serum samples, coupled with biochemical metadata sourced from 145 healthy volunteers.SIGNIFICANCE: Both methodologies effectively integrated and analysed multiblock datasets, unveiling the inherent data structure and variables associated with discernible factors among healthy cohorts. While both approaches successfully detected sex-related differences, the MLDF strategy uniquely revealed components linked to age. By applying this analysis, we aim to enhance the interpretation of intricate biological mechanisms and uncover variations that may not be easily discernible through individual data analysis.PMID:38772669 | DOI:10.1016/j.aca.2024.342689

Appl Spectrosc. 2024 May 21:37028241254403. doi: 10.1177/00037028241254403. Online ahead of print.ABSTRACTAcute myeloid leukemia (AML) is a malignant hematological tumor disease. Chromosomal abnormality is an independent prognostic factor in AML. AML with t(8:21) (q22; q22)/AML1-ETO (AE) is an independent disease group. In this research, a new method based on Raman spectroscopy is reported for label-free single-cell identification and analysis of AE fusion genes in clinical AML patients. Raman spectroscopy reflects the intrinsic vibration information of molecules in a label-free and non-destructive manner, and the fingerprint Raman spectrum of cells characterizes intracellular molecular types and relative concentration information, so as to realize the identification and molecular metabolism analysis of different kinds of cells. We collected the Raman spectra of bone marrow cells from clinically diagnosed AML M2 patients with and without the AE fusion gene. Through comparison of the average spectra and identification analysis based on multivariate statistical methods such as principal component analysis and linear discriminant analysis, the distinction between AE positive and negative sample cells in M2 AML patients was successfully achieved, and the single-cell identification accuracy was more than 90%. At the same time, the Raman spectra of the two types of cells were analyzed by the multivariate curve resolution alternating least squares decomposition method. It was found that the presence of the AE fusion gene may lead to the metabolic changes of lipid and nucleic acid in AML cells, which was consistent with the results of genomic and metabolomic multi-omics studies. The above results indicate that single-cell Raman spectroscopy has the potential for early identification of AE-positive AML.PMID:38772561 | DOI:10.1177/00037028241254403

World J Mens Health. 2024 May 17. doi: 10.5534/wjmh.230337. Online ahead of print.ABSTRACTPURPOSE: Erectile dysfunction (ED) is a common male sexual dysfunction. Gut microbiota plays an important role in various diseases. To investigate the effects and mechanisms of intestinal flora dysregulation induced by high-fat diet (HFD) on erectile function.MATERIALS AND METHODS: Male Sprague-Dawley rats aged 8 weeks were randomly divided into the normal diet (ND) and HFD groups. After 24 weeks, a measurement of erectile function was performed. We performed 16S rRNA sequencing of stool samples. Then, we established fecal microbiota transplantation (FMT) rat models by transplanting fecal microbiota from rats of ND group and HFD group to two new groups of rats respectively. After 24 weeks, erectile function of the rats was evaluated and 16S rRNA sequencing was performed, and serum samples were collected for the untargeted metabolomics detection.RESULTS: The erectile function of rats and the species diversity of intestinal microbiota in the HFD group was significantly lower, and the characteristics of the intestinal microbiota community structure were also significantly different between the two groups. The erectile function of rats in the HFD-FMT group was significantly lower than that of rats in the ND-FMT group. The characteristics of the intestinal microbiota community structure were significantly different. In the HFD-FMT group, 27 metabolites were significantly different and they were mainly involved in the several inflammation-related pathways.CONCLUSIONS: Intestinal microbiota disorders induced by HFD can damage the intestinal barrier of rats, change the serum metabolic profile, induce low-grade inflammation and apoptosis in the corpus cavernosum of the penis, and lead to ED.PMID:38772541 | DOI:10.5534/wjmh.230337

Clin Chim Acta. 2024 May 19:119735. doi: 10.1016/j.cca.2024.119735. Online ahead of print.ABSTRACTBACKGROUND AND AIMS: Obesity-induced chronic inflammation and metabolic abnormalities are highly relevant to the functional dysregulation of macrophages, especially under obese conditions. Hyperglycemia and hyperlipidemia, central to obesity, directly alter macrophage activity. However, the impacts of different nutritional cues on the intricate metabolic networks in macrophages remain unclear.MATERIALS AND METHODS: In this study, we employed metabolomic approaches to examine the metabolic responses of macrophages to high glucose, high fat and their coexistence, aiming to delineate the molecular mechanisms of nutritional factors on macrophage activation and obesity-related diseases from a metabolic perspective.RESULTS: Our findings revealed that different nutritional conditions could reprogram key metabolism in macrophages. Additionally, we identified a metabolite derived from macrophages, Long-Chain Phosphatidylcholine (LPC), which exerts beneficial effects on obese mice. It ameliorates the obesity phenotype and improves glucose metabolism profiles. This discovery suggests that LPC has a significant therapeutic potential in the context of obesity-induced metabolic dysfunctions. Our study unveils the metabolic phenotype of macrophages in high-fat and high-sugar environments and uncovers a macrophage-derived metabolite that significantly ameliorates the obesity phenotype.CONCLUSION: This finding reveals a potential dialogue mechanism between macrophages and adipocytes, shedding light on the complex interplay of immune and metabolic systems in obesity. This discovery not only enhances our understanding of obesity's underlying mechanisms but also opens up new avenues for therapeutic interventions targeting macrophage-adipocyte interactions.PMID:38772523 | DOI:10.1016/j.cca.2024.119735

Clin Chim Acta. 2024 May 19:119732. doi: 10.1016/j.cca.2024.119732. Online ahead of print.ABSTRACTAIM: Our study focuses on the microbial and metabolomic profile changes during the adenoma stage, as adenomas can be considered potential precursors to colorectal cancer through the adenoma-carcinoma sequence. Identifying possible intervention targets at this stage may aid in preventing the progression of colorectal adenoma (CRA) to malignant lesions. Furthermore, we evaluate the efficacy of combined microbial and metabolite biomarkers in detecting CRA.METHODS: Fecal metagenomic and serum metabolomic analyses were performed for the discovery of alterations of gut microbiome and metabolites in CRA patients (n = 26), Colorectal cancer (CRC) patients (n = 19), Familial Adenomatous Polyposis (FAP) patients (n = 10), and healthy controls (n = 20). Finally, analyzing the associations between gut microbes and metabolites was performed by a Receiver Operating Characteristic (ROC) curve.RESULTS: Our analysis present that CRA patients differ significantly in gut microflora and serum metabolites compared with healthy controls, especially for Lachnospiraceae and Parasutterella. Its main metabolite, butyric acid, concentrations were raised in CRA patients compared with the healthy controls, indicating its role as a promoter of colorectal tumorigenesis. α-Linolenic acid and lysophosphatidylcholine represented the other healthy metabolite for CRA. Combining five microbial and five metabolite biomarkers, we differentiated CRA from CRC with an Area Under the Curve (AUC) of 0.85 out of this performance vastly superior to the specificity recorded by traditional markers CEA and CA199 in such differentiation of these conditions.CONCLUSIONS: The study underlines significant microbial and metabolic alterations in CRA with a novel insight into screening and early intervention of its tumorigenesis.PMID:38772522 | DOI:10.1016/j.cca.2024.119732