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Frontiers in Bioscience (Landmark... Oct 2023Inhibition of fatty acid synthase (FAS) plays a crucial protective role in pulmonary hypertension (PH). Our aim was to identify novel metabolites in mice with...
BACKGROUND
Inhibition of fatty acid synthase (FAS) plays a crucial protective role in pulmonary hypertension (PH). Our aim was to identify novel metabolites in mice with hypoxia-induced PH after treatment with C75 (FAS inhibitor) and to confirm the presence of these metabolites in paediatric patients with PH.
METHODS
The PH mouse model was built by chronic hypoxia and ovalbumin (OVA) assistance. Untargeted metabolomics was used to analyse mouse serum. Six children with PH and six relative controls (patients without lung and heart disease) were selected in Shanghai Children's Hospital and they all performed blood tandem mass spectrometry during hospitalization.
RESULTS
First, a total of 29 differential metabolites, including lipid metabolites, polyamine, and glutamine were identified as differential metabolites in the hypoxia group compared with the control group. After C75 treatment, symptoms were partially relieved in the PH mouse, and 15 differential metabolites, including lipid metabolites, polyamine, and glutamine were identified in the hypoxia + C75 group compared with the hypoxia group. These differential metabolites were enriched in arginine and glycerolipid metabolism through metabolite set enrichment analyses and were involved in excessive cell proliferation, which was a characteristic of PH. Second, glutamine and caproyl carnitine levels were increased in paediatric patients with PH.
CONCLUSIONS
FAS may be a potential PH therapeutic target. Lipid metabolites, polyamine, and glutamine, are closely related to PH. Putrescine and glutamine might be biomarkers for PH.
Topics: Humans; Mice; Animals; Child; Hypertension, Pulmonary; Glutamine; China; Hypoxia; Polyamines; Lipids
PubMed: 37919066
DOI: 10.31083/j.fbl2810251 -
Science Advances Oct 2023Spermidine, a ubiquitous polyamine, is known to be required for critical physiological functions in bacteria. Two principal pathways are known for spermidine...
Spermidine, a ubiquitous polyamine, is known to be required for critical physiological functions in bacteria. Two principal pathways are known for spermidine biosynthesis, both of which involve aminopropylation of putrescine. Here, we identified a spermidine biosynthetic pathway via a previously unknown metabolite, carboxyaminopropylagmatine (CAPA), in a model cyanobacterium sp. PCC 6803 through an approach combining C and N tracers, metabolomics, and genetic and biochemical characterization. The CAPA pathway starts with reductive condensation of agmatine and l-aspartate-β-semialdehyde into CAPA by a previously unknown CAPA dehydrogenase, followed by decarboxylation of CAPA to form aminopropylagmatine, and ends with conversion of aminopropylagmatine to spermidine by an aminopropylagmatine ureohydrolase. Thus, the pathway does not involve putrescine and depends on l-aspartate-β-semialdehyde as the aminopropyl group donor. Genomic, biochemical, and metagenomic analyses showed that the CAPA-pathway genes are widespread in 15 different phyla of bacteria distributed in marine, freshwater, and other ecosystems.
Topics: Spermidine; Putrescine; Biosynthetic Pathways; Aspartic Acid; Ecosystem; Cyanobacteria
PubMed: 37878710
DOI: 10.1126/sciadv.adj9075 -
Nature Structural & Molecular Biology Oct 2023Synaptic complexes of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (AMPARs) with auxiliary subunits mediate most excitatory neurotransmission...
Synaptic complexes of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (AMPARs) with auxiliary subunits mediate most excitatory neurotransmission and can be targeted to treat neuropsychiatric and neurological disorders, including epilepsy. Here we present cryogenic-electron microscopy structures of rat GluA2 AMPAR complexes with inhibitory mouse γ5 and potentiating human cornichon-2 (CNIH2) auxiliary subunits. CNIH2 appears to destabilize the desensitized state of the complex by reducing the separation of the upper lobes in ligand-binding domain dimers. At the same time, CNIH2 stabilizes binding of polyamine spermidine to the selectivity filter of the closed ion channel. Nevertheless, CNIH2, and to a lesser extent γ5, attenuate polyamine block of the open channel and reduce the potency of the antiepileptic drug perampanel that inhibits the synaptic complex allosterically by binding to sites in the ion channel extracellular collar. These findings illustrate the fine-tuning of synaptic complex structure and function in an auxiliary subunit-dependent manner, which is critical for the study of brain region-specific neurotransmission and design of therapeutics for disease treatment.
Topics: Rats; Mice; Animals; Humans; Polyamines; Anticonvulsants; Receptors, AMPA; Nitriles
PubMed: 37653241
DOI: 10.1038/s41594-023-01080-x -
Biomolecules Aug 2023The widespread incidence of antimicrobial resistance necessitates the discovery of new classes of antimicrobials as well as adjuvant molecules that can restore the...
The widespread incidence of antimicrobial resistance necessitates the discovery of new classes of antimicrobials as well as adjuvant molecules that can restore the action of ineffective antibiotics. Herein, we report the synthesis of a new class of indole-3-acetamido-polyamine conjugates that were evaluated for antimicrobial activities against a panel of bacteria and two fungi, and for the ability to enhance the action of doxycycline against and erythromycin against . Compounds , , , , , , , , and exhibited strong growth inhibition of methicillin-resistant (MRSA) and , with minimum inhibitory concentrations (MIC) typically less than 0.2 µM. Four analogues, including a 5-bromo and three 5-methoxyls - also exhibited intrinsic activity towards . Antibiotic kill curve analysis of identified it to be a bactericide. While only one derivative was found to (weakly) enhance the action of erythromycin against , three examples, including , were found to be strong enhancers of the antibiotic action of doxycycline against . Collectively, these results highlight the promising potential of α,ω-disubstituted indole-3-acetamido polyamine conjugates as antimicrobials and antibiotic adjuvants.
Topics: Anti-Bacterial Agents; Doxycycline; Escherichia coli; Methicillin-Resistant Staphylococcus aureus; Anti-Infective Agents; Adjuvants, Immunologic; Adjuvants, Pharmaceutic; Erythromycin; Fatty Acids, Omega-3; Indoles; Polyamines; Pseudomonas aeruginosa
PubMed: 37627291
DOI: 10.3390/biom13081226 -
International Journal of Molecular... Jun 2024Polyamines are ubiquitous in almost all biological entities and involved in various crucial physiological processes. They are also closely associated with the onset and... (Review)
Review
Polyamines are ubiquitous in almost all biological entities and involved in various crucial physiological processes. They are also closely associated with the onset and progression of many diseases. Polyaminopathies are a group of rare genetic disorders caused by alterations in the function of proteins within the polyamine metabolism network. Although the identified polyaminopathies are all rare diseases at present, they are genetically heritable, rendering high risks not only to the carriers but also to their descendants. Meanwhile, more polyaminopathic patients might be discovered with the increasing accessibility of gene sequencing. This review aims to provide a comprehensive overview of the structural variations of mutated proteins in current polyaminopathies, in addition to their causative genes, types of mutations, clinical symptoms, and therapeutic approaches. We focus on analyzing how alterations in protein structure lead to protein dysfunction, thereby facilitating the onset of diseases. We hope this review will offer valuable insights and references for the future clinical diagnosis and precision treatment of polyaminopathies.
Topics: Humans; Polyamines; Mutation; Animals
PubMed: 38928047
DOI: 10.3390/ijms25126340 -
Science Advances Mar 2024Much is known about molecular mechanisms by which animals detect pathogenic microbes, but how animals sense beneficial microbes remains poorly understood. The roundworm...
Much is known about molecular mechanisms by which animals detect pathogenic microbes, but how animals sense beneficial microbes remains poorly understood. The roundworm is a microbivore that must distinguish nutritive microbes from pathogens. We characterized a neural circuit used by to rapidly discriminate between nutritive bacteria and pathogens. Distinct sensory neuron populations responded to chemical cues from nutritive and pathogenic , and these neural signals are decoded by downstream AIB interneurons. The polyamine metabolites cadaverine, putrescine, and spermidine produced by activate this neural circuit and elicit positive chemotaxis. Our study shows how polyamine odorants can be sensed by animals as proxies for microbe identity and suggests that, hence, polyamines might have widespread roles brokering host-microbe interactions.
Topics: Animals; Polyamines; Caenorhabditis elegans; Escherichia coli; Spermidine; Putrescine
PubMed: 38517971
DOI: 10.1126/sciadv.adj4387 -
EMBO Molecular Medicine Nov 2023Snyder-Robinson syndrome (SRS) is a rare genetic disorder characterized by intellectual disability and delayed development beginning early in childhood. It was first...
Snyder-Robinson syndrome (SRS) is a rare genetic disorder characterized by intellectual disability and delayed development beginning early in childhood. It was first described in a single family in 1969 as a sex-linked disorder (Snyder & Robinson, 1969) and has since been only identified in less than 100 individuals worldwide. Inherited in an X-linked recessive pattern, SRS has only been identified in males thus far. Snyder-Robinson syndrome primarily affects the nervous system and skeletal tissues and is caused by loss-of-function mutations in the gene encoding spermine synthase (SMS), a polyamine biosynthesis enzyme. Affected males display a collection of clinical features including intellectual disability ranging from mild to profound, speech and vision impairment, osteoporosis, hypotonia, and increasing loss of muscle tissue with age, kyphoscoliosis, seizures, and distinctive facial features including a prominent lower lip and facial asymmetry. Currently, there is no cure or treatment for this debilitating disorder aside from symptom management.
Topics: Male; Humans; Polyamines; Intellectual Disability; Mental Retardation, X-Linked; Mutation; Sulfadiazine
PubMed: 37712293
DOI: 10.15252/emmm.202318506 -
Biosensors Sep 2023The screening procedure for antibodies is considered the most tedious among the three pretransfusion operations, i.e., ABO and Rhesus (Rh) typing, irregular antibody...
The screening procedure for antibodies is considered the most tedious among the three pretransfusion operations, i.e., ABO and Rhesus (Rh) typing, irregular antibody screening/identification, and crossmatching tests. The commonly used screening method for irregular antibodies in clinics at present is a manual polybrene test (MP). The MP test involves numerous reagent replacement and centrifuge procedures, and the sample volume is expected to be relatively less. Herein, screening red blood cells (RBCs) and serum irregular antibodies are encapsulated in microdroplets with a diameter of ~300 μm for a hemagglutination reaction. Owing to the advantage of spatial limitation in microdroplets, screening RBCs and irregular antibodies can be directly agglutinated, thereby eliminating the need for centrifugation and the addition of reagents to promote agglutination, as required by the MP method. Furthermore, the results for a large number of repeated tests can be concurrently obtained, further simplifying the steps of irregular antibody screening and increasing accuracy. Eight irregular antibodies are screened using the proposed platform, and the results are consistent with the MP method. Moreover, the volume of blood samples and antibodies can be reduced to 10 μL and 5 μL, respectively, which is ten times less than that using the MP method.
Topics: Antibodies; Erythrocytes; Hexadimethrine Bromide; Immunologic Tests
PubMed: 37754103
DOI: 10.3390/bios13090869 -
Biochimica Et Biophysica Acta.... Feb 2024Intracellular Ca signals play a vital role in a broad range of cell biological and physiological processes in all eukaryotic cell types. Dysregulation of Ca signaling... (Review)
Review
Intracellular Ca signals play a vital role in a broad range of cell biological and physiological processes in all eukaryotic cell types. Dysregulation of Ca signaling has been implicated in numerous human diseases. Over the past four decades, the understanding of how cells use Ca as a messenger has flourished, largely because of the development of reporters that enable visualization of Ca signals in different cellular compartments, and tools that can modulate cellular Ca signaling. One such tool that is frequently used is BAPTA; a fast, high-affinity Ca-chelating molecule. By making use of a cell-permeable acetoxymethyl ester (AM) variant, BAPTA can be readily loaded into the cytosol of cells (referred to as BAPTAi), where it is trapped and able to buffer changes in cytosolic Ca. Due to the ease of loading of the AM version of BAPTA, this reagent has been used in hundreds of studies to probe the role of Ca signaling in specific processes. As such, for decades, researchers have almost universally attributed changes in biological processes caused by BAPTAi to the involvement of Ca signaling. However, BAPTAi has often been used without any form of control, and in many cases has neither been shown to be retained in cells for the duration of experiments nor to buffer any Ca signals. Moreover, increasing evidence points to off-target cellular effects of BAPTA that are clearly not related to Ca chelation. Here, we briefly introduce Ca signaling and the history of Ca chelators and fluorescent Ca indicators. We highlight Ca-independent effects of BAPTAi on a broad range of molecular targets and describe some of BAPTAi's impacts on cell functions that occur independently of its Ca-chelating properties. Finally, we propose strategies for determining whether Ca chelation, the binding of other metal ions, or off-target interactions with cell components are responsible for BAPTAi's effect on a particular process and suggest some future research directions.
Topics: Humans; Egtazic Acid; Chelating Agents; Cytosol
PubMed: 37739271
DOI: 10.1016/j.bbamcr.2023.119589 -
Environmental Science & Technology Sep 2023The rubber antioxidant 6PPD has gained significant attention due to its highly toxic transformation product, 6PPD-quinone (6PPDQ). Despite their detection in urines of...
The rubber antioxidant 6PPD has gained significant attention due to its highly toxic transformation product, 6PPD-quinone (6PPDQ). Despite their detection in urines of pregnant women, the placental transfer and developmental toxicity of 6PPD and 6PPDQ are unknown. Here, we treated C57Bl/6 mice with 4 mg/kg 6PPD or 6PPDQ to investigate their urine excretion and placental transfer. Female and male mice exhibited sex difference in excretion profiles of 6PPD and 6PPDQ. Urine concentrations of 6PPDQ were one order of magnitude lower than those of 6PPD, suggesting lower excretion and higher bioaccumulation of 6PPDQ. In pregnant mice treated with 6PPD or 6PPDQ from embryonic day 11.5 to 15.5, 6PPDQ showed ∼1.5-8 times higher concentrations than 6PPD in placenta, embryo body, and embryo brain, suggesting higher placental transfer of 6PPDQ. Using in vitro dual-luciferase reporter assays, we revealed that 6PPDQ activated the human retinoic acid receptor α (RARα) and retinoid X receptor α (RXRα) at concentrations as low as 0.3 μM, which was ∼10-fold higher than the concentrations detected in human urines. 6PPD activated the RXRα at concentrations as low as 1.2 μM. These results demonstrate the exposure risks of 6PPD and 6PPDQ during pregnancy and emphasize the need for further toxicological and epidemiological investigations.
Topics: Animals; Female; Humans; Male; Mice; Pregnancy; Benzoquinones; Placenta; Phenylenediamines; Mice, Inbred C57BL; Tissue Distribution; Sex Factors; Embryonic Development; HEK293 Cells; Retinoic Acid Receptor alpha; Retinoid X Receptor alpha
PubMed: 37642336
DOI: 10.1021/acs.est.3c05026