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Microbiological Research Jun 2024As the most abundant gram-negative bacterial order in the gastrointestinal tract, Bacteroidales bacteria have been extensively studied for their contribution to various...
As the most abundant gram-negative bacterial order in the gastrointestinal tract, Bacteroidales bacteria have been extensively studied for their contribution to various aspects of gut health. These bacteria are renowned for their involvement in immunomodulation and their remarkable capacity to break down complex carbohydrates and fibers. However, the human gut microbiota is known to produce many metabolites that ultimately mediate important microbe-host and microbe-microbe interactions. To gain further insights into the metabolites produced by the gut commensal strains of this order, we examined the metabolite composition of their bacterial cell cultures in the stationary phase. Based on their abundance in the gastrointestinal tract and their relevance in health and disease, we selected a total of six bacterial strains from the relevant genera Bacteroides, Phocaeicola, Parabacteroides, and Segatella. We grew these strains in modified Gifu anaerobic medium (mGAM) supplemented with mucin, which resembles the gut microbiota's natural environment. Liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based metabolite profiling revealed 179 annotated metabolites that had significantly differential abundances between the studied bacterial strains and the control growth medium. Most of them belonged to classes such as amino acids and derivatives, organic acids, and nucleot(s)ides. Of particular interest, Segatella copri DSM 18205 (previously referred to as Prevotella copri) produced substantial quantities of the bioactive metabolites phenylethylamine, tyramine, tryptamine, and ornithine. Parabacteroides merdae CL03T12C32 stood out due to its ability to produce cadaverine, histamine, acetylputrescine, and deoxycarnitine. In addition, we found that strains of the genera Bacteroides, Phocaeicola, and Parabacteroides accumulated considerable amounts of proline-hydroxyproline, a collagen-derived bioactive dipeptide. Collectively, these findings offer a more detailed comprehension of the metabolic potential of these Bacteroidales strains, contributing to a better understanding of their role within the human gut microbiome in health and disease.
Topics: Humans; Chromatography, Liquid; Liquid Chromatography-Mass Spectrometry; Tandem Mass Spectrometry; Bacteria; Gastrointestinal Microbiome
PubMed: 38518452
DOI: 10.1016/j.micres.2024.127700 -
Heliyon Mar 2024Alterations of nitric oxide (NO) homeostasis have been described in mood disorders. However, the analytical challenges associated with the direct measurement of NO have...
Alterations 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).
PubMed: 38515671
DOI: 10.1016/j.heliyon.2024.e27292 -
Nature Communications Mar 2024Targeting ferroptosis, an iron-dependent form of regulated cell death triggered by the lethal overload of lipid peroxides, in cancer therapy is impeded by our limited...
Targeting ferroptosis, an iron-dependent form of regulated cell death triggered by the lethal overload of lipid peroxides, in cancer therapy is impeded by our limited understanding of the intersection of tumour's metabolic feature and ferroptosis vulnerability. In the present study, arginine is identified as a ferroptotic promoter using a metabolites library. This effect is mainly achieved through arginine's conversion to polyamines, which exerts their potent ferroptosis-promoting property in an HO-dependent manner. Notably, the expression of ornithine decarboxylase 1 (ODC1), the critical enzyme catalysing polyamine synthesis, is significantly activated by the ferroptosis signal--iron overload--through WNT/MYC signalling, as well as the subsequent elevated polyamine synthesis, thus forming a ferroptosis-iron overload-WNT/MYC-ODC1-polyamine-HO positive feedback loop that amplifies ferroptosis. Meanwhile, we notice that ferroptotic cells release enhanced polyamine-containing extracellular vesicles into the microenvironment, thereby further sensitizing neighbouring cells to ferroptosis and accelerating the "spread" of ferroptosis in the tumour region. Besides, polyamine supplementation also sensitizes cancer cells or xenograft tumours to radiotherapy or chemotherapy through inducing ferroptosis. Considering that cancer cells are often characterized by elevated intracellular polyamine pools, our results indicate that polyamine metabolism exposes a targetable vulnerability to ferroptosis and represents an exciting opportunity for therapeutic strategies for cancer.
Topics: Humans; Polyamines; Ferroptosis; Hydrogen Peroxide; Cell Line, Tumor; Arginine; Iron Overload; Neoplasms
PubMed: 38504107
DOI: 10.1038/s41467-024-46776-w -
Frontiers in Immunology 2024Modern fish farming faces challenges in sourcing feed ingredients, most related with their prices, 21 availability, and specifically for plant protein sources,...
INTRODUCTION
Modern fish farming faces challenges in sourcing feed ingredients, most related with their prices, 21 availability, and specifically for plant protein sources, competition for the limited cultivation space for 22 vegetable crops. In that sense, halophytes have the added value of being rich in valuable bioactive compounds and salt tolerant. This study assessed the inclusion of non-food fractions of in European seabass diets.
METHODS
Different levels (2.5%, 5%, and 10%) were incorporated into seabass diets, replacing wheat meal (diets ST2.5, ST5, and ST10) or without inclusion (CTRL). Experimental diets were administered to seabass juveniles (8.62 ± 0.63 g) for 34 and 62 days and subsequent inflammatory responses to a heat-inactivated subsp. () were evaluated in a time-course manner (4, 24, 48, and 72 h after the challenge). At each sampling point, seabass haematological profile, plasma immune parameters, and head-kidney immune-related gene expression were evaluated.
RESULTS
After both feeding periods, most parameters remained unaltered by inclusion; nonetheless, seabass fed ST10 showed an upregulation of macrophage colony-stimulating factor 1 receptor 1 ( and cluster of differentiation 8 ( compared with those fed CTRL after 62 days of feeding. Regarding the inflammatory response, seabass fed ST10 showed lower plasma lysozyme levels than their counterparts fed ST2.5 and ST5 at 24 h following injection, while 4 h after the inflammatory stimulus, seabass fed ST10 presented higher numbers of peritoneal leucocytes than fish fed CTRL. Moreover, at 4 h, fish fed ST2.5, ST5, and ST10 showed a higher expression of interleukin 1β (), while fish fed ST5 showed higher levels of ornithine decarboxylase ( than those fed CTRL. An upregulation of macrophage colony-stimulating factor 1 receptor 1 () and glutathione peroxidase () was also observed at 72 h in fish fed ST10 or ST5 and ST10 compared with CTRL, respectively.
DISCUSSION
In conclusion, incorporating up to 10% of the non-food fraction in feed did not compromise seabass growth or immune status after 62 days, aligning with circular economy principles. However, inclusion improved the leucocyte response and upregulated key immune-related genes in seabass challenged with an inactivated pathogen.
Topics: Animals; Bass; Interleukin-1 Receptor-Like 1 Protein; Macrophage Colony-Stimulating Factor; Diet; Photobacterium
PubMed: 38500885
DOI: 10.3389/fimmu.2024.1342144 -
European Review For Medical and... Mar 2024This study aimed to evaluate clinical, biochemical, and genotypic findings of patients diagnosed with urea cycle mitochondrial transporter disorders.
BACKGROUND
This study aimed to evaluate clinical, biochemical, and genotypic findings of patients diagnosed with urea cycle mitochondrial transporter disorders.
CASE SERIES
In this study, patients followed up with the diagnosis of urea cycle mitochondrial transporter disorders in the pediatric metabolism outpatient clinic of Diyarbakir Children's Hospital were retrospectively examined. Height, weight, head circumference, gender, age at diagnosis, follow-up period, consanguinity history between parents, and treatments of the patients included in the study were evaluated. Eight patients suffering from urea cycle mitochondrial transporter disorders were enrolled in the study. Five patients were found to have biallelic variants of the SLC25A15 gene. Two patients were found to have biallelic variants of the SLC25A13 gene. Two of our patients presented with gait disturbances and were diagnosed with HHH syndrome. One patient presented with liver failure and was diagnosed with HHH syndrome. The other three patients were identified by family screening. Citrin deficiency was detected in two patients with cholestasis and hepatomegaly in the infantile period. Ornithine levels increased in three of our patients with HHH syndrome during the first month of treatment despite a protein-restricted diet and adequate caloric intake.
CONCLUSIONS
Increasing patients' caloric intake with HHH syndrome improves their ornithine levels. Our patients with citrin deficiency recovered clinically and biochemically before seven months.
Topics: Child; Humans; Citrullinemia; Retrospective Studies; Ornithine; Mitochondrial Membrane Transport Proteins; Urea; Hyperammonemia; Urea Cycle Disorders, Inborn
PubMed: 38497870
DOI: 10.26355/eurrev_202403_35601 -
RSC Advances Mar 2024This study delves into the development, characterization, and application of modified mesoporous silica nanoparticles (MSNs) for targeted drug delivery in cancer...
This study delves into the development, characterization, and application of modified mesoporous silica nanoparticles (MSNs) for targeted drug delivery in cancer therapy. MSNs were functionalized with poly(2-(diisopropylamino)ethyl methacrylate) (PDPA) and poly(glycidyl methacrylate) (PGMA), and further modified with cross-linkers DAE and Ornithine. Characterization using FT-IR, SEM, TEM, DLS, and XPS confirmed the successful surface modifications, revealing particle sizes primarily within the 63-94 nm range. The MSNs demonstrated a pH-responsive behavior, crucial for smart drug delivery. Loading and release studies using Doxorubicin (DOX) showed a controlled release, with an 8 μg mg loading capacity. Cytotoxicity assays on Caco2 colon cancer cells revealed that unloaded nano-systems, at concentrations above 45 μM, resulted in approximately 60% cell death, indicating inherent anti-cancer properties. However, variations in cytotoxic effects were observed in drug-loaded MSNs, with some modifications showing reduced anti-cancer activity. These findings highlight the potential of MSNs in drug delivery and cancer treatment, emphasizing the importance of nanoparticle design in therapeutic efficacy.
PubMed: 38495996
DOI: 10.1039/d4ra00282b -
RSC Advances Mar 2024The presence of heavy metal groups can endow compounds with unique structural and chemical attributes beneficial for developing highly potent therapeutic agents and...
The presence of heavy metal groups can endow compounds with unique structural and chemical attributes beneficial for developing highly potent therapeutic agents and effective molecular labels. However, metallocompound binding site specificity is a major challenge that dictates the level of off-site targeting, which is a limiting factor in finding safer and more effective metal-based drugs. Here we designed and tested a family of metallopeptide conjugates based on two different chromatin-tethering viral proteins and a drug being repurposed for cancer, the Au(i) anti-arthritic auranofin. The viral peptides associate with the acidic patch of the nucleosome while the gold moiety can bind allosterically to the H3 H113 imidazole. To achieve synthesis of the conjugates, we also engineered a sulfur-free, nucleosome-binding Kaposi's sarcoma herpesvirus LANA peptide with a methionine-to-ornithine substitution and coupled the peptide to the metal group in a final step using click chemistry. The four conjugates tested are all selectively cytotoxic towards tumor cell lines, but the choice of viral peptide and mode of linkage to the Au(i) group influences metal binding site preference. Our findings suggest that viral peptide-metalloconjugates have potential for use in chromatin delivery of therapeutic warheads and as nucleosome-specific tags.
PubMed: 38495982
DOI: 10.1039/d4ra01617c -
Amino Acids Mar 2024Heart failure (HF) has been recognized as a global epidemic with high rates of morbidity, hospitalization, and mortality. The role of amino acids, which provide the body...
Heart failure (HF) has been recognized as a global epidemic with high rates of morbidity, hospitalization, and mortality. The role of amino acids, which provide the body with energy, in the development of HF is still unclear. The aim of this study was to explore changes in serum amino acids in patients with HF and identify potential biomarkers. First, the serum amino acid metabolism profiles of 44 patients with HF and 30 healthy controls (Con) were quantitatively measured. Then, candidate markers were identified through the utilization of T test, multivariate statistical analysis, and receiver operating characteristic (ROC) curve analysis. The results found that there were 11 amino acid levels that were significantly different between patients with HF and Con. Based on ROC curve analysis, the biomarkers of eight amino acids (Glutamic acid, Taurine, L-aspartic acid, L-ornithine, Ethanolamine, L-Serine, L-Sarcosine, and Cysteine) showed high sensitivity and specificity (AUC > 0.90), and binary logistic regression analysis was used in MetaboAnalyst 5.0. Among the amino acids examined, six exhibited notable alterations in accordance with the severity of HF. In conclusion, this study cannot only provide clinicians with an objective diagnostic approach for the early identification of HF, but also enhances comprehension of the underlying mechanisms involved in the pathogenesis of HF.
Topics: Humans; Metabolomics; Amino Acids; ROC Curve; Biomarkers; Amines; Heart Failure
PubMed: 38483649
DOI: 10.1007/s00726-024-03385-7 -
Frontiers in Drug Delivery May 2023Human African Trypanosomiasis (HAT) is a neglected parasitic disease that continues to persist in sub-Saharan Africa. It is fatal if untreated. The first stage of the...
Human African Trypanosomiasis (HAT) is a neglected parasitic disease that continues to persist in sub-Saharan Africa. It is fatal if untreated. The first stage of the disease is associated with the presence of the parasite in the periphery and the second stage with the presence of the parasites in the CNS. The treatment of CNS stage HAT requires the drugs to cross the blood-brain barrier (BBB). Eflornithine is an amino acid analogue that is used to treat second stage HAT gambiense both alone and in combination with nifurtimox. Recent studies have identified that accumulation of eflornithine into the parasites (trypanosomes) involves the amino acid transporter ( AAT6). In this study we tested the hypothesis that eflornithine uses a cationic amino acid transport system to cross the BBB. We particularly focused on system-y and system-B. To do this we utilized specialist databases to compare the physicochemical characteristics of relevant molecules and an model of the BBB to explore the mechanisms of eflornithine delivery into the CNS. Our results confirmed that eflornithine is related to the endogenous amino acid, ornithine. At pH 7.4, eflornithine is predominately (92.39%) a zwitterionic (dipolar) amino acid and ornithine is predominately (99.08%) a cationic (tripolar) amino acid. In addition, the gross charge distribution at pH 7.4 of eflornithine is much smaller (+0.073) than that of ornithine (+0.99). Further results indicated that eflornithine utilized a saturable transport mechanism(s) to cross the hCMEC/D3 cell membranes and that transport was inhibited by the presence of other amino acids including ornithine. Eflornithine transport was also sodium-independent and sensitive to a y-system inhibitor, but not a B-system inhibitor. Eflornithine transport was also inhibited by pentamidine, suggestive of transport by organic cation transporters (OCT) which are expressed in this cell line. We confirmed expression of the y-system protein, CAT1, and the B-system protein, ATB, in the hCMEC/D3 cells. We conclude that eflornithine uses the cationic amino acid transporter, system y, and OCT to cross the BBB. This research highlights the potential of system-y to deliver drugs, including eflornithine, across the BBB to treat brain diseases.
PubMed: 38482132
DOI: 10.3389/fddev.2023.1113493 -
International Journal of Molecular... Feb 2024Despite the well-known relevance of polyamines to many forms of life, little is known about how polyamines regulate osteogenesis and skeletal homeostasis. Here, we...
Despite the well-known relevance of polyamines to many forms of life, little is known about how polyamines regulate osteogenesis and skeletal homeostasis. Here, we report a series of in vitro studies conducted with human-bone-marrow-derived pluripotent stromal cells (MSCs). First, we show that during osteogenic differentiation, mRNA levels of most polyamine-associated enzymes are relatively constant, except for the catabolic enzyme spermidine/spermine N1-acetyltransferase 1 (SAT1), which is strongly increased at both mRNA and protein levels. As a result, the intracellular spermidine to spermine ratio is significantly reduced during the early stages of osteoblastogenesis. Supplementation of cells with exogenous spermidine or spermine decreases matrix mineralization in a dose-dependent manner. Employing N-cyclohexyl-1,3-propanediamine (CDAP) to chemically inhibit spermine synthase (SMS), the enzyme catalyzing conversion of spermidine into spermine, also suppresses mineralization. Intriguingly, this reduced mineralization is rescued with DFMO, an inhibitor of the upstream polyamine enzyme ornithine decarboxylase (ODC1). Similarly, high concentrations of CDAP cause cytoplasmic vacuolization and alter mitochondrial function, which are also reversible with the addition of DFMO. Altogether, these studies suggest that excess polyamines, especially spermidine, negatively affect hydroxyapatite synthesis of primary MSCs, whereas inhibition of polyamine synthesis with DFMO rescues most, but not all of these defects. These findings are relevant for patients with Snyder-Robinson syndrome (SRS), as the presenting skeletal defects-associated with SMS deficiency-could potentially be ameliorated by treatment with DFMO.
Topics: Humans; Spermidine; Spermine; Spermine Synthase; Ornithine Decarboxylase; Osteogenesis; Polyamines; Mesenchymal Stem Cells; RNA, Messenger
PubMed: 38473716
DOI: 10.3390/ijms25052463