Search Results (1,509)

Both experimental and clinical liver fibrosis leave a metabolic footprint that can be uncovered and defined using metabolomic approaches. Metabolomics combines pattern recognition algorithms with analytical chemistry, in particular, ¹H and ¹³C nuclear magnetic resonance spectroscopy (NMR), gas chromatography–mass spectrometry (GC–MS) and various liquid chromatography–mass spectrometry (LC–MS) platforms. The analysis of liver fibrosis by each of these methodologies is reviewed separately. Surprisingly, there was little general agreement between studies within each of these three groups and also between groups. The metabolomic footprint determined by NMR (two or more hits between studies) comprised elevated lactate, acetate, choline, 3-hydroxybutyrate, glucose, histidine, methionine, glutamine, phenylalanine, tyrosine and citrate. For GC–MS, succinate, fumarate, malate, ascorbate, glutamate, glycine, serine and, in agreement with NMR, glutamine, phenylalanine, tyrosine and citrate were delineated. For LC–MS, only β-muricholic acid, tryptophan, acylcarnitine, p-cresol, valine and, in agreement with NMR, phosphocholine were identified. The metabolomic footprint of liver fibrosis was upregulated as regards glutamine, phenylalanine, tyrosine, citrate and phosphocholine. Several investigators employed traditional Chinese medicine (TCM) treatments to reverse experimental liver fibrosis, and a commentary is given on the chemical constituents that may possess fibrolytic activity. It is proposed that molecular docking procedures using these TCM constituents may lead to novel therapies for liver fibrosis affecting at least one-in-twenty persons globally, for which there is currently no pharmaceutical cure. This in-depth review summarizes the relevant literature on metabolomics and its implications in addressing the clinical problem of liver fibrosis, cirrhosis and its sequelae. Full article

In the small intestine, nutrients from ingested food are absorbed and broken down by enterocytes, which constitute over 95% of the intestinal epithelium. Enterocytes demonstrate diet- and segment-dependent metabolic flexibility, enabling them to take up large amounts of glutamine and glucose to meet their energy needs and transfer these nutrients into the bloodstream. During glycolysis, ATP, lactate, and H⁺ ions are produced within the enterocytes. Based on extensive but incomplete glutamine oxidation large amounts of alanine or lactate are produced. Lactate, in turn, promotes hypoxia-inducible factor-1α (Hif-1α) activation and Hif-1α-dependent transcription of various proton channels and exchangers, which extrude cytoplasmic H⁺-ions into the intestinal lumen. In parallel, the vitamin C-dependent and duodenal cytochrome b-mediated conversion of ferric iron into ferrous iron progresses. Finally, the generated electrochemical gradient is utilized by the divalent metal transporter 1 for H⁺-coupled uptake of non-heme Fe²⁺-ions. Iron efflux from enterocytes, subsequent binding to the plasma protein transferrin, and systemic distribution supply a wide range of cells with iron, including erythroid precursors essential for erythropoiesis. In this review, we discuss the impact of vitamin C on the redox capacity of human erythrocytes and connect enterocyte function with iron metabolism, highlighting its effects on erythropoiesis. Full article

Morphine is an important pain reliever employed in pain management, its extended utilize is hindered by the onset of analgesic tolerance and oxidative stress. Long-term morphine administration causes elevated production of reactive oxygen species (ROS), disrupting mitochondrial function and inducing oxidation. Sirtuin 3 (SIRT3), a mitochondrial protein, is essential in modulating ROS levels by regulating mitochondrial antioxidant enzymes as manganese superoxide dismutase (MnSOD). Our investigation focused on the impact of SIRT3 on hyperalgesia and morphine tolerance in mice, as evaluating the antioxidant effect of the polyphenolic fraction of bergamot (BPF). Mice were administered morphine twice daily for four consecutive days (20 mg/kg). On the fifth day, mice received an acute dose of morphine (3 mg/kg), either alone or in conjunction with BPF or Mn (III)tetrakis (4-benzoic acid) porphyrin (MnTBAP). We evaluated levels of malondialdehyde (MDA), nitration, and the activity of SIRT3, MnSOD, glutamine synthetase (GS), and glutamate 1 transporter (GLT1) in the spinal cord. Our findings demonstrate that administering repeated doses of morphine led to the development of antinociceptive tolerance in mice, accompanied by increased superoxide production, nitration, and inactivation of mitochondrial SIRT3, MnSOD, GS, and GLT1. The combined administration of morphine with either BPF or MnTBAP prevented these effects. Full article

Astrocytes are considered to possess a noticeable role in brain metabolism and, as a partners in neuron–glia cooperation, to contribute to the synthesis, bioconversion, and regulation of the flux of substrates for neuronal metabolism. With the aim of investigating to what extent human astrocytes are metabolizing amino acids and by which compounds are they enriching their surroundings, we employed a metabolomics analysis of their culture media by ¹H-NMR. In addition, we compared the composition of media with either 5 mM or 25 mM glucose. The quantitative analysis of culture media by ¹H-NMR revealed that astrocytes readily dispose from their milieu glutamine, branched-chain amino acids, and pyruvate with significantly high rates, while they enrich the culture media with lactate, branched-chain keto acids, citrate, acetate, ketone bodies, and alanine. Hyperglycemia suppressed the capacity of astrocytes to release branched-chain 2-oxo acids, while stimulating the generation of ketone bodies. Our results highlight the active involvement of astrocytes in the metabolism of several amino acids and the regulation of key metabolic intermediates. The observed metabolic activities of astrocytes provide valuable insights into their roles in supporting neuronal function, brain metabolism, and intercellular metabolic interactions within the brain. Understanding the complex metabolic interactions between astrocytes and neurons is essential for elucidating brain homeostasis and the pathophysiology of neurological disorders. The observed metabolic activities of astrocytes provide hints about their putative metabolic roles in brain metabolism. Full article

We identified alterations in the ruminal microbiome, metabolome, and epithelial inflammatory response due to moderate feed restriction (FR). Ruminal digesta and epithelial biopsies from seven ruminally cannulated Angus steers were initially collected during ad libitum access to feed (PRE). After a 10 day recovery, steers underwent a 3-day FR period (FRP) at 25% intake of PRE followed by a 15 day recovery (POST) phase with ad libitum access to feed. At the end of FRP and POST, ruminal digesta and epithelial biopsies were collected again for microbial DNA and tissue RNA extraction. RT-qPCR was applied for relative microbial abundance and RNA extraction. Metabolite profiling of digesta was performed via GC-MS. The abundance of Succinivibrio dextrinosolvens, Streptococcus bovis, and Bifidobacteria spp. (N124) was higher (p < 0.05) during FRP than PRE and POST, while Lactobacillus spp. (C25), Escherichia coli (EC42405), Fibrobacter succinogenes, and Megaspheara elsdenii abundances were lower in FRP than PRE (p < 0.05). The TNF and TLR2 mRNA abundance was greater in FRP than PRE (p < 0.05). Among 15 detected amino acids, glutamine, isoleucine, lysine, phenylalanine, threonine, and valine were lower (p < 0.05) in FRP than PRE. Metabolite pathway analysis revealed alterations in amino acid, fatty acid, vitamin, and energy metabolism during FRP (p < 0.05). The mRNA of the proinflammatory genes TNF and TLR2 in the epithelium peaked (p < 0.05) at FRP and remained higher at POST. Results indicated that a short FR influenced ruminal bacteria, reduced concentrations of most metabolites, and triggered an inflammatory response. Full article

Multidrug resistance (MDR) remains the most difficult problem facing conventional chemotherapy for cancers. Astragalus membranaceus is a historically traditional Chinese medicine. One of its bioactive components, formononetin, exhibits antitumor effects on various cancers. However, the effects of formononetin on MDR cancers have not been evaluated. Therefore, we investigated the defense’s effects of formononetin on MDR. We used rhodamine 123 and doxorubicin efflux assays to analyze the inhibition kinetics of P-glycoprotein (P-gp) mediated-efflux. Cell viability was detected by sulforhodamine B assay, and the synergistic effects of formononetin combined with chemotherapeutic agents were further calculated using CompuSyn software. Molecular docking was performed with iGEMDOCK. We discovered that formononetin considerably induced oxidative stress and the disruption of mitochondrial membrane potential in MDR cancer cells. Furthermore, formononetin inhibits the P-gp efflux function by ATPase stimulation and the uncompetitive inhibition of P-gp-mediated effluxes of rhodamine 123 and doxorubicin. The molecular docking model indicates that formononetin may bind to P-gp by strong hydrogen bonds at Arginine (Arg) 489 and Glutamine (Gln) 912. Formononetin exhibits significant synergistic effects with vincristine and doxorubicin toward MDR cancer cells, and it synergistically suppressed tumor growth in vivo with paclitaxel. These results suggest that formononetin should be seen as a potential candidate for the adjuvant therapy of MDR cancers. Full article

Photorespiration, caused by oxygenation of the enzyme Rubisco, is considered a wasteful process, because it reduces photosynthetic carbon gain, but it also supplies amino acids and is involved in amelioration of stress. Here, we show that a sudden increase in photorespiratory activity not only reduced carbon acquisition and production of sugars and starch, but also affected diurnal dynamics of amino acids not obviously involved in the process. Flux calculations based on diurnal metabolite profiles suggest that export of proline from leaves increases, while aspartate family members accumulate. An immense increase is observed for turnover in the cyclic reaction of glutamine synthetase/glutamine-oxoglutarate aminotransferase (GS/GOGAT), probably because of increased production of ammonium in photorespiration. The hpr1-1 mutant, defective in peroxisomal hydroxypyruvate reductase, shows substantial alterations in flux, leading to a shift from the oxoglutarate to the aspartate family of amino acids. This is coupled to a massive export of asparagine, which may serve in exchange for serine between shoot and root. Full article

The (patho)physiological function of the sphingolipids ceramide-1-phosphate (C1P), sphingosine-1-phosphate (S1P), and sphingosylphosphorylcholine (SPC) in articular joints during osteoarthritis (OA) is largely unknown. Therefore, we investigated the influence of these lipids on protein expression by fibroblast-like synoviocytes (FLSs) from OA knees. Cultured human FLSs (n = 7) were treated with 1 of 3 lipid species—C1P, S1P, or SPC—IL-1β, or with vehicle. The expression of individual proteins was determined by tandem mass tag peptide labeling followed by high-resolution electrospray ionization (ESI) mass spectrometry after liquid chromatographic separation (LC-MS/MS/MS). The mRNA levels of selected proteins were analyzed using RT-PCR. The 3sphingolipids were quantified in the SF of 18 OA patients using LC-MS/MS. A total of 4930 proteins were determined using multiplex MS, of which 136, 9, 1, and 0 were regulated both reproducibly and significantly by IL-1β, C1P, S1P, and SPC, respectively. In the presence of IL-1ß, all 3 sphingolipids exerted ancillary effects. Only low SF levels of C1P and SPC were found. In conclusion, the 3 lipid species regulated proteins that have not been described in OA. Our results indicate that charged multivesicular body protein 1b, metal cation symporter ZIP14, glutamine-fructose-6-P transaminase, metallothionein-1F and -2A, ferritin, and prosaposin are particularly interesting proteins due to their potential to affect inflammatory, anabolic, catabolic, and apoptotic mechanisms. Full article

Boron (B) deficiency has been shown to inhibit root cell growth and division. However, the precise mechanism underlying B deficiency-mediated root tip growth inhibition remains unclear. In this study, we investigated the role of BnaA3.NIP5;1, a gene encoding a boric acid channel, in Brassica napus (B. napus). BnaA3.NIP5;1 is expressed in the lateral root cap and contributes to B acquisition in the root tip. Downregulation of BnaA3.NIP5;1 enhances B sensitivity in B. napus, resulting in reduced shoot biomass and impaired root tip development. Transcriptome analysis was conducted on root tips from wild-type B. napus (QY10) and BnaA3.NIP5;1 RNAi lines to assess the significance of B dynamics in meristematic cells during seedling growth. Differentially expressed genes (DEGs) were significantly enriched in plant circadian rhythm and nitrogen (N) metabolism pathways. Notably, the circadian-rhythm-related gene HY5 exhibited a similar B regulation pattern in Arabidopsis to that observed in B. napus. Furthermore, Arabidopsis mutants with disrupted circadian rhythm (hy5/cor27/toc1) displayed heightened sensitivity to low B compared to the wild type (Col-0). Consistent with expectations, B deficiency significantly disrupted N metabolism in B. napus roots, affecting nitrogen concentration, nitrate reductase enzyme activity, and glutamine synthesis. Interestingly, this disruption was exacerbated in BnaA3NIP5;1 RNAi lines. Overall, our findings highlight the critical role of B dynamics in root tip cells, impacting circadian rhythm and N metabolism, ultimately leading to retarded growth. This study provides novel insights into B regulation in root tip development and overall root growth in B. napus. Full article

Glutaminyl-peptide cyclotransferases (QCs) convert the N-terminal glutamine or glutamate residues of protein and peptide substrates into pyroglutamate (pE) by releasing ammonia or a water molecule. The N-terminal pE modification protects peptides/proteins against proteolytic degradation by amino- or exopeptidases, increasing their stability. Mammalian QC is abundant in the brain and a large amount of evidence indicates that pE peptides are involved in the onset of neural human pathologies such as Alzheimer’s and Huntington’s disease and synucleinopathies. Hence, human QC (hQC) has become an intensively studied target for drug development against these diseases. Soon after its characterization, hQC was identified as a Zn-dependent enzyme, but a partial restoration of the enzyme activity in the presence of the Co(II) ion was also reported, suggesting a possible role of this metal ion in catalysis. The present work aims to investigate the structure of demetallated hQC and of the reconstituted enzyme with Zn(II) and Co(II) and their behavior in the presence of known inhibitors. Furthermore, our structural determinations provide a possible explanation for the presence of the mononuclear metal binding site of hQC, despite the presence of the same conserved metal binding motifs present in distantly related dinuclear aminopeptidase enzymes. Full article

To investigate the metabolomic mechanisms by which changes in cardiorespiratory fitness (CRF) levels affect metabolic syndrome (MetS) risk factors and to provide a theoretical basis for the improvement of body metabolism via CRF in people with MetS risk factors, a comparative blood metabolomics study of individuals with varying levels of CRF and varying degrees of risk factors for MetS was conducted. Methods: Ninety subjects between the ages of 40 and 45 were enrolled, and they were categorized into low-MetS (LM ≤ two items) and high MetS (HM > three items) groups, as well as low- and high-CRF (LC, HC) and LCLM, LCLM, LCHM, and HCHM groups. Plasma was taken from the early morning abdominal venous blood. LC-MS was conducted using untargeted metabolomics technology, and the data were statistically and graphically evaluated using SPSS26.0 and R language. Results: (1) There were eight common differential metabolites in the HC vs. LC group as follows: methionine (↓), γ-aminobutyric acid (↑), 2-oxoglutatic acid (↑), arginine (↑), serine (↑), cis-aconitic acid (↑), glutamine (↓), and valine (↓); the HM vs. LM group are contrast. (2) In the HCHM vs. LCLM group, trends were observed in 2-oxoglutatic acid (↑), arginine (↑), serine (↑), cis-aconitic acid (↑), glutamine (↓), and valine (↓). (3) CRF and MetS risk factors jointly affect biological metabolic pathways such as arginine biosynthesis, TCA cycle, cysteine and methionine metabolism, glycine, serine, and threonine metabolism, arginine and proline metabolism, and alanine, aspartate, and glutamate metabolism. Conclusion: The eight common differential metabolites can serve as potential biomarkers for distinguishing individuals with different CRF levels and varying degrees of MetS risk factors. Increasing CRF levels may potentially mitigate MetS risk factors, as higher CRF levels are associated with reduced MetS risk. Full article

Spinocerebellar ataxia type 3 (SCA3) is the most common type of disease related to poly-glutamine (polyQ) repeats. Its hallmark pathology is related to the abnormal accumulation of ataxin 3 with a longer polyQ tract (polyQ-ATXN3). However, there are other mechanisms related to SCA3 progression that require identifying trait and state biomarkers for a more accurate diagnosis and prognosis. Moreover, the identification of potential pharmacodynamic targets and assessment of therapeutic efficacy necessitates valid biomarker profiles. The aim of this review was to identify potential trait and state biomarkers and their potential value in clinical trials. Our results show that, in SCA3, there are different fluid biomarkers involved in neurodegeneration, oxidative stress, metabolism, miRNA and novel genes. However, neurofilament light chain NfL and polyQ-ATXN3 stand out as the most prevalent in body fluids and SCA3 stages. A heterogeneity analysis of NfL revealed that it may be a valuable state biomarker, particularly when measured in plasma. Nonetheless, since it could be a more beneficial approach to tracking SCA3 progression and clinical trial efficacy, it is more convenient to perform a biomarker profile evaluation than to rely on only one. Full article

Arrow bamboo (Fargesia qinlingensis) is endemic to the Qinling Mountains and has remarkable adaptive resilience to changing climates. However, its complete mitogenome remains unknown. Using the Illumina and PacBio HiFi sequencing platforms, we found that the mitogenome assembly of the F. qinlingensis has a multi-branched skeleton comprising three linear molecules (M1, M2, and M3), with a length of 442,368 bp and a GC content of 44.05%. Thirty-five unique PCGs were identified in the complete mitogenome, including twenty-four core structural genes, eleven noncore structural genes, three rRNAs, and sixteen tRNAs. The GCU for alanine and CAA for glutamine represented the most significant frequency (RSCU = 1.55) in the codon usage preference. A total of 51, 28, and 14 SSRs were determined on M1, M2, and M3, respectively. The mitogenome contained 149 pairs of dispersed repeats with lengths greater than 30 bp, the most abundant of which were 82 forward and 67 palindromic repeats. A long repeat sequence (14,342 bp) was characterized in mediating mitogenome recombination. DNA transfer analyses suggested that 44 MTPTs (30,943 bp, 6.99%) originated from the plastome. Among the 482 potential C-U/T RNA-editing sites predicted in 35 PCGs, ccmFn (38 times) and ccmC (36 times) shoed the highest frequency. Collinearity and phylogenetic trees revealed the close relationship between F. qinlingensis and Bambusa oldhamii. The primary features of the mitogenome of F. qinlingensis will help decipher the functional mitochondrial traits related to growth performance and climate resilience. Moreover, our findings provide insights into the evolution, environmental adaptation, and sustainable use of subalpine bamboo resources in the Qinling Mountains. Full article

Background: Sarcopenia, characterized by degenerative skeletal muscle loss, is increasingly linked to poor surgical outcomes. Glutamine, an immune-modulating formula, may stimulate muscle protein synthesis and inhibit degradation. We used the psoas major muscle area (PMMA) at the third lumbar vertebra, normalized for height (PMMA index), as a skeletal muscle indicator. This study investigates whether perioperative glutamine supplementation mitigates psoas muscle atrophy. Methods: We enrolled gastric adenocarcinoma (GA) patients undergoing gastrectomy. Computed tomography assessed the psoas muscle short axis. Muscle atrophy was estimated by changes between preoperative and three-month post-gastrectomy scans. Perioperative glutamine supplementation (PGS) comprised five-day parenteral plus one-month oral use. Propensity score matching minimized potential bias. A linear regression model predicted the association. Results: Of 516 patients analyzed (2016–2019), 100 (19.4%) received PGS. After propensity score matching, each group contained 97 cases. The PGS group showed a significantly higher median PMMA index change than the non-PGS group (0.3 vs. −0.3 cm²/m², p = 0.004). Multivariate analysis revealed that PGS was significantly associated with increased PMMA index (coefficient = 0.60; 95% CI: 0.19–1.01; p = 0.005). Conclusions: PGS may help restore psoas muscle atrophy in GA patients undergoing gastrectomy. The underlying mechanisms likely relate to glutamine’s role in protein metabolism and immune function. Further studies are needed to elucidate these mechanisms fully. Full article

This paper studies the synthesis, characterization, and application of ZnFe₂O₄ nanoparticles for the removal of rhodamine b dye from aqueous media. Utilizing the combustion procedure, ZnFe₂O₄ nanoparticles were synthesized using two different fuels: glutamine (SG) and L-arginine (SA). In addition, the synthesized ZnFe₂O₄ nanoparticles were characterized through various techniques, including Fourier transform infrared (FTIR), X-ray diffraction (XRD), field emission scanning electron microscope (FE-SEM), energy-dispersive X-ray (EDX), high resolution transmission electron microscope (HR-TEM), and Brunauer-Emmett-Teller (BET) surface area analysis. XRD analysis verified the creation of a ZnFe₂O₄ cubic spinel structure without any contaminants, revealing average crystallite sizes of 43.72 and 29.38 nm for the SG and SA samples, respectively. The FTIR spectra exhibited peaks indicative of metal-oxygen bond stretching, verifying the presence of a spinel formation. Elemental analysis via EDX confirmed the stoichiometric composition typical of zinc ferrite. In addition, FE-SEM imaging displayed that the SG and SA samples are composed of particles with irregular and spherical shapes, measuring average diameters of 135.11 and 59.89 nm, respectively. Furthermore, the BET surface area of the SG and SA samples is 60 and 85 m²/g, respectively. The maximum adsorption capacity of the SA sample (409.84 mg/g) towards rhodamine b dye was higher than that of the SG sample (279.33 mg/g), which was ascribed to its larger surface area and porosity. Kinetic and equilibrium studies revealed that the adsorption process of rhodamine b dye onto the SG and SA samples followed the Langmuir isotherm and pseudo-second-order model. Thermodynamic analysis indicated that the adsorption process was spontaneous, exothermic, and physical. The study concludes that ZnFe₂O₄ nanoparticles synthesized using L-arginine (SA) exhibit enhanced rhodamine b dye removal efficiency due to their smaller size, increased surface area, and higher porosity compared to those synthesized with glutamine (SG). The optimum conditions for the adsorption process of rhodamine b dye were found to be at pH 10, a contact time of 70 min, and a temperature of 298 K. These findings underscore the potential of L-arginine-synthesized ZnFe₂O₄ nanoparticles for effective and sustainable environmental cleanup applications. Full article