Metabolites最新文献

Background/Objectives: Schizophrenia (SCH) and bipolar disorder (BD) share overlapping symptoms and genetic factors, making differential diagnosis challenging and often leading to misdiagnosis. This study aimed to identify potential lipid biomarkers of serum capable of distinguishing BD from SCH. Methods: Lipid profiles of serum from 30 SCH and 31 BD patients were analyzed in triplicates using liquid chromatography-high-resolution mass spectrometry (LC-HRMS). Chemometric analysis was applied, including class and gender identifiers. Orthogonal partial least squares (OPLS) models with 1000 cross-validations were used to validate feature subsets. Results: The chemometric analysis included the most relevant metabolites in the comparison between all samples of SCH and BD patients, identifying five key biomarkers (LPC 16:0, SM 33:1, SM 32:1, compound C30H58O3, and PC 30:0) with VIP scores > 1 for distinguishing BD from SCH. Gender-specific models revealed five biomarkers in males (SM 32:1, SM 33:1, PC 32:1, PC 30:0, and FA 16:1) and two in females (LPC 16:0 and C30H58O3). These biomarkers primarily belonged to glycerophospholipids (GPs) and sphingophospholipids (SPs). Conclusions: Comparative lipid profiling between SCH and BD, including gender-specific subgroups, enabled identification of potential diagnosis-specific biomarkers. Elevated levels of GPs and SPs in SCH patients suggest lipid metabolism differences that may support improved diagnostic accuracy and personalized treatment strategies.

Background: Distinguishing between osteoarthritis (OA), rheumatoid arthritis (RA), and psoriatic arthritis (PsA) remains challenging despite different underlying mechanisms. Synovial fluid reflects metabolic changes within affected joints, yet comprehensive metabolomic comparisons across these conditions are limited. We aimed to identify disease-specific metabolic signatures in synovial fluid that could improve differential diagnosis and reveal therapeutic targets.

Methods: We collected synovial fluid from 39 patients (20 OA, 5 RA, and 14 PsA) during routine knee arthrocentesis between January 2023 and February 2024. Following metabolite extraction, we performed untargeted metabolomic profiling using quadrupole time-of-flight liquid chromatography-mass spectrometry (Q-TOF LC/MS). Data underwent multivariate statistical analysis, including principal component analysis (PCA) and partial least squares-discriminant analysis (PLS-DA), to identify discriminatory metabolites.

Results: While unsupervised analysis showed overlap between groups, supervised PLS-DA achieved clear metabolic separation. RA samples showed elevated itaconic acid, indicating inflammatory macrophage activation, and increased O-acetylserine, suggesting altered one-carbon metabolism. Hypoxanthine was decreased, which reflected severe metabolic stress. PsA exhibited the unique elevation of 4,4-dimethylcholestane and 2-oxoarginine. These metabolites have previously been unreported in this disease. OA demonstrated increased hippuric acid and indoleacetic acid, which are both gut microbiota products, supporting the gut-joint axis hypothesis.

Conclusions: Each arthritis type displayed distinct metabolic fingerprints in synovial fluid. Candidate discriminatory metabolites, including gut-derived metabolites in OA and specific lipid alterations in PsA, open new diagnostic and therapeutic avenues. Given the limited RA sample size (n = 5), RA-related results should be viewed as exploratory and requiring validation in larger independent cohorts. These metabolites may, after rigorous validation in larger and independent cohorts, contribute to multi-metabolite biomarker panels for earlier diagnosis and to the rational design of targeted therapeutics addressing disease-specific metabolic disruptions.

Background: Colorectal cancer (CRC) is a malignancy that ranks among the top three in terms of both global mortality and incidence. Although numerous studies have demonstrated that gut microbes are implicated in CRC pathogenesis, the precise mechanisms underlying host-microbiota metabolic crosstalk remain poorly understood.

Objective: This study aims to identify and delineate key co-metabolites and their associated metabolic pathways that modulate the biomass of CRC-related gut bacteria within healthy individuals, through the construction of host-gut microbiota co-metabolic network models. We seek to elucidate the underlying mechanisms of metabolic interplay between the host and CRC-related gut microbiota, thereby offering novel perspectives on the microbial involvement in the initiation and progression of CRC.

Methods: We coupled a colon tissue-specific host Genome-Scale Metabolic Model (GEM), which utilized transcriptomic data from healthy human colon tissues, with 12 CRC-associated pro-/anti-carcinogenic gut bacterial GEMs to construct a co-metabolic network. Through a comparative analysis of the network structure and systemic methods (including Flux Sampling and metabolic difference analysis), we simulated scenarios of constrained host co-metabolite supply. Finally, metabolic subsystem enrichment analysis was employed to elucidate the specific molecular mechanisms by which key co-metabolites affect microbial function.

Results: The 17 key co-metabolites identified include chloride ions, zinc ions, and acetate. Among these, thirteen metabolites (e.g., ferric iron, succinate, and acetate) were confirmed by literature to be associated with CRC. All 17 key co-metabolites were found to significantly modulate the biomass of CRC-associated gut bacteria. These regulatory effects primarily influence microbial function through core pathways such as glycerophospholipid metabolism and folate metabolism.

Conclusion: This research provides a systemic perspective for elucidating the mechanisms of host-gut microbiota metabolic interplay in CRC, thereby complementing the existing theoretical framework concerning microbial regulation by the host genetic background.

Metabolomics and lipidomics have emerged as essential tools in systems biology, providing comprehensive insights into small-molecule metabolites and lipids within biological systems [...].

Background/objectives: Mitochondrial dysfunction is a major cause of brain injury in patients with primary mitochondrial disease. New mitochondrial therapeutics and non-invasive tools for efficacy monitoring are urgently needed. To these ends, succinate prodrug NV354 (methyl 3-[(2-acetylaminoethylthio)carbonyl]propionate) and diffuse optical techniques are promising. In this proof-of-concept study, we characterize NV354's effects on microdialysis metrics of cerebral metabolism in a swine model of mitochondrial dysfunction and assess the associations of diffuse optical metrics with mitochondrial dysfunction and metabolic improvement.

Methods: One-month-old swine received a four-hour co-infusion of rotenone with either the succinate prodrug NV354 (n = 5) or placebo (n = 5). Rotenone is a mitochondrial complex I inhibitor. Before and during co-infusion, cerebral metabolism was probed with microdialysis and diffuse optics. Microdialysis acquired interstitial lactate and pyruvate levels invasively, while diffuse optics measured changes in oxygen extraction fraction (OEF) and oxidized cytochrome-c-oxidase concentration (oxCCO).

Results: Interstitial lactate continually increased in the placebo group (p < 0.01), but lactate levels plateaued in the NV354 group (p = 0.90). oxCCO also increased in the placebo group (p = 0.05), but OEF remained constant (p = 0.80). In the NV354 group, oxCCO increased (p < 0.01) while OEF decreased (p < 0.01).

Conclusions: Microdialysis results suggest that NV354 treatment can increase oxygen metabolism in large animals with mitochondrial dysfunction. The optical oxCCO metric was also sensitive to metabolic changes induced by rotenone and NV354 administration.

Background: Uncontrolled diabetes is characterised by a loss of blood glucose control and increased oxidation of fatty acids to produce ATP. Use of metabolic inhibitors to blunt fatty acid oxidation and restore glucose metabolism is a poorly studied intervention for diabetes. Methods: Steptozotocin-induced diabetes was developed in Wistar male rats. A subset was supplemented with mildronate (100 mg/kg-14 days). Exploiting liquid chromatography-mass spectrometry for workflows including ion exchange-, C18-reverse phase- and HILIC-based chromatography methods, metabolite levels were quantified in plasma liver and brain tissue. Using both untargeted and targeted metabolomic analysis changes to the global tissue metabolome and individual metabolic pathways were estimated. Results: We document that an inhibitor of carnitine synthesis, mildronate, decreased plasma (50% p < 0.01) carnitine abundance and decreased plasma glucose concentration by one-third compared to streptozotocin (STZ)-treated rats (p < 0.001). Targeted metabolomic analysis of the liver showed decreased alpha-ketoglutarate abundance (35% p < 0.05) by STZ diabetes that was further decreased following mildronate treatment (50% p < 0.05). For both beta-hydroxybutyrate and succinate levels, STZ diabetes increased hepatic abundance by 50% (p < 0.05 for both), which was restored to control levels by mildronate (p < 0.05 for both). In contrast, brain TCA intermediate abundances were unaffected by either STZ diabetes or mildronate (NS for all). STZ diabetes also decreased abundance of pentose phosphate pathway (PPP) metabolites in the liver (glucose-6-phosphate, 6-phosphogluconolactone, 6-phosphogluconate 50% for all; p < 0.05), which was not restored by mildronate treatment. However, brain PPP metabolite abundance was unchanged by STZ diabetes or mildronate (NS for all). However, mildronate treatment did not affect the increased abundance of brain sorbitol, sorbitol-6-phosphate and glucose-6-phosphate as a result of STZ diabetes. Conclusions: Together, these observations highlight the potential role that metabolic inhibitors, like mildronate, may play in restoring blood glucose for diabetic patients, without a direct effect of tissues that represent obligate consumers of glucose (e.g., brain) whilst manipulating fat oxidation in tissues such as the liver.

Breast cancer is a significant public health concern, with triple-negative breast cancer (TNBC) being the most aggressive subtype characterized by considerable heterogeneity and the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression. Currently, there are no practical alternatives to chemotherapy, which is associated with a poor prognosis. Therefore, developing new treatments for TNBC is an urgent need. Reactive oxygen species (ROS) and redox adaptation play central roles in TNBC biology. Targeting the redox state has emerged as a promising therapeutic approach, as it is vital to the survival of tumors, including TNBC. Although TNBC does not produce high levels of ROS compared to ER- or PR-positive breast cancers, it relies on mitochondria and oxidative phosphorylation (OXPHOS) to sustain ROS production and create an environment conducive to tumor progression. As a result, novel treatments that can modulate redox balance and target organelles essential for redox homeostasis, such as mitochondria, could be promising for TNBC, an area not yet reviewed in the current scientific literature, thus representing a critical gap. This review addresses that gap by synthesizing current evidence on TNBC biology and its connections to redox state and mitochondrial metabolism, with a focus on innovative strategies such as metal-based compounds (e.g., copper, gold), redox nanoparticles that facilitate anticancer drug delivery, mitochondrial-targeted therapies, and immunomodulatory peptides like GK-1. By integrating mechanistic insights into the redox state with emerging therapeutic approaches, I aim to highlight new redox-centered opportunities to improve TNBC treatments. Moreover, this review uniquely integrates mitochondrial metabolism, redox imbalance, and emerging regulated cell-death pathways, including ferroptosis, cuproptosis, and disulfidptosis, within the context of TNBC metabolic heterogeneity, highlighting translational vulnerabilities and subtype-specific therapeutic opportunities.

Background/objectives: Caffeic acid is a hydroxycinnamic acid that has a wide range of applications in the medical field. The synthesis of caffeic acid using microbial fermentation technology is an environmentally friendly method.

Methods: By engaging various enzymes, specifically 4-hydroxyphenylacetate 3-monooxygenase (HpaB), sourced from diverse bacterial strains, we successfully engineered a functional version of this enzyme within Escherichia coli, enabling the production of caffeic acid. In addition to the two common tyrosine ammonia lyases (TAL) and HpaC, different combinations of HpaB demonstrated varying abilities in converting the substrate L-tyrosine into the desired product, caffeic acid.

Results: Under shake-flask culture conditions, the highest yield of caffeic acid was achieved with an enzyme mixture containing HpaB from Escherichia coli, reaching 75.88 mg/L. Enhancing the activity of the rate-limiting enzyme through engineering could potentially increase caffeic acid titer. This study aims to conduct a semi-rational design of HpaB through structure-based approaches to screen for mutants that can enhance the production of caffeic acid. Initially, the predicted three-dimensional structure of HpaB was generated using AlphaFold2, and subsequent analysis was conducted to pinpoint the critical mutation sites within the substrate-binding pocket. Five key amino acid residues (R113, Y117, H155, S210 and Y461) located in the vicinity of the flavin adenine dinucleotide binding domain in HpaB from Escherichia coli could be instrumental in modulating enzyme activity. Subsequently, the mutant S210G/Y117A was obtained by iterative saturation mutagenesis, which increased the titer of caffeic acid by 1.68-fold. The caffeic acid titer was further improved to 2335.48 mg/L in a 5 L fermenter. The findings show that the yield of caffeic acid was significantly enhanced through the integration of semi-rational design and fermentation process optimization.

Cardiovascular diseases (CVDs) have emerged as a common health problem. However, despite their prevalence, little progress has been made in their treatment. In recent years, neurotrophic factors (NTFs) have been discovered to exert cardioprotective functions for CVDs. NTFs can modulate vascular integrity, myocardial remodeling, angiogenesis, and autonomic regulation, playing the roles of maintaining cardiovascular homeostasis and influencing disease progression. Under pathological conditions, the supplement of NTFs can induce substantial adaptations to mitigate adverse cardiac responses. Several NTFs have been investigated in this regard. This review briefly elaborates on present insights into the expression, signaling pathways, and regulatory effects of NTFs on the development of CVDs, and also discusses emerging therapeutic strategies based on NTFs, ranging from exercise to advanced modalities including stem cell therapy, gene transfer, recombinant protein therapy and NTF mimetics, among which the mimetics and exercise interventions emerge as the most promising avenues for clinical translation.