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Human Genomics Jun 2024Sex-related differences in colorectal (CRC) incidence and mortality are well-documented. However, the impact of sex on metabolic pathways that drive cancer growth is not...
BACKGROUND
Sex-related differences in colorectal (CRC) incidence and mortality are well-documented. However, the impact of sex on metabolic pathways that drive cancer growth is not well understood. High expression of asparagine synthetase (ASNS) is associated with inferior survival for female CRC patients only. Here, we used a CRISPR/Cas9 technology to generate HCT116 ASNS and HCT 116 ASNS cancer cell lines. We examine the effects of ASNS deletion on tumor growth and the subsequent rewiring of metabolic pathways in male and female Rag2/IL2RG mice.
RESULTS
ASNS loss reduces cancer burden in male and female tumor-bearing mice (40% reduction, q < 0.05), triggers metabolic reprogramming including gluconeogenesis, but confers a survival improvement (30 days median survival, q < 0.05) in female tumor-bearing mice alone. Transcriptomic analyses revealed upregulation of G-protein coupled estrogen receptor (GPER1) in tumors from male and female mice with HCT116 ASNS xenograft. Estradiol activates GPER1 in vitro in the presence of ASNS and suppresses tumor growth.
CONCLUSIONS
Our study indicates that inferior survival for female CRC patients with high ASNS may be due to metabolic reprogramming that sustains tumor growth. These findings have translational relevance as ASNS/GPER1 signaling could be a future therapeutic target to improve the survival of female CRC patients.
Topics: Animals; Humans; Female; Male; Mice; Aspartate-Ammonia Ligase; HCT116 Cells; Colorectal Neoplasms; Receptors, Estrogen; Cell Proliferation; Receptors, G-Protein-Coupled; Gene Expression Regulation, Neoplastic; Xenograft Model Antitumor Assays; Heterografts; Sex Factors; Carbon-Nitrogen Ligases with Glutamine as Amide-N-Donor
PubMed: 38886847
DOI: 10.1186/s40246-024-00635-3 -
Nature Communications Jun 2024The eukaryotic asparagine (N)-linked glycan is pre-assembled as a fourteen-sugar oligosaccharide on a lipid carrier in the endoplasmic reticulum (ER). Seven sugars are...
The eukaryotic asparagine (N)-linked glycan is pre-assembled as a fourteen-sugar oligosaccharide on a lipid carrier in the endoplasmic reticulum (ER). Seven sugars are first added to dolichol pyrophosphate (PP-Dol) on the cytoplasmic face of the ER, generating Man5GlcNAc2-PP-Dol (M5GN2-PP-Dol). M5GN2-PP-Dol is then flipped across the bilayer into the lumen by an ER translocator. Genetic studies identified Rft1 as the M5GN2-PP-Dol flippase in vivo but are at odds with biochemical data suggesting Rft1 is dispensable for flipping in vitro. Thus, the question of whether Rft1 plays a direct or an indirect role during M5GN2-PP-Dol translocation has been controversial for over two decades. We describe a completely reconstituted in vitro assay for M5GN2-PP-Dol translocation and demonstrate that purified Rft1 catalyzes the translocation of M5GN2-PP-Dol across the lipid bilayer. These data, combined with in vitro results demonstrating substrate selectivity and rft1∆ phenotypes, confirm the molecular identity of Rft1 as the M5GN2-PP-Dol ER flippase.
Topics: Endoplasmic Reticulum; Saccharomyces cerevisiae Proteins; Saccharomyces cerevisiae; Biological Transport; Oligosaccharides; Dolichol Phosphates; Lipid Bilayers; Phospholipid Transfer Proteins; Intracellular Membranes; Lipopolysaccharides
PubMed: 38886340
DOI: 10.1038/s41467-024-48999-3 -
Medical Oncology (Northwood, London,... Jun 2024Asparagine is a non-essential amino acid crucial for protein biosynthesis and function, and therefore cell maintenance and growth. Furthermore, this amino acid has an... (Review)
Review
Asparagine is a non-essential amino acid crucial for protein biosynthesis and function, and therefore cell maintenance and growth. Furthermore, this amino acid has an important role in regulating several metabolic pathways, such as tricarboxylic acid cycle and the urea cycle. When compared to normal cells, tumor cells typically present a higher demand for asparagine, making it a compelling target for therapy. In this review article, we investigate different facets of asparagine bioavailability intricate role in malignant tumors raised from solid organs. We take a comprehensive look at asparagine synthetase expression and regulation in cancer, including the impact on tumor growth and metastasis. Moreover, we explore asparagine depletion through L-asparaginase as a potential therapeutic method for aggressive solid tumors, approaching different formulations of the enzyme and combinatory therapies. In summary, here we delve into studies about endogenous and exogenous asparagine availability in solid cancers, analyzing therapeutic implications and future challenges.
Topics: Humans; Asparagine; Neoplasms; Aspartate-Ammonia Ligase; Asparaginase; Animals
PubMed: 38879707
DOI: 10.1007/s12032-024-02424-3 -
The Journal of Biological Chemistry Jun 2024Hearing, the ability to sense sounds, and the processing of auditory information are important for perception of the world. Mice lacking expression of neuroplastin (Np),...
Hearing, the ability to sense sounds, and the processing of auditory information are important for perception of the world. Mice lacking expression of neuroplastin (Np), a type-1 transmembrane glycoprotein, display deafness, multiple cognitive deficiencies, and reduced expression of plasma membrane calcium (Ca) ATPases (PMCAs) in cochlear hair cells and brain neurons. In this study, we transferred the deafness causing missense mutations pitch (C315S) and audio-1 (I122N) into human Np (hNp) constructs and investigated their effects at the molecular and cellular level. Computational molecular dynamics show that loss of the disulfide bridge in hNp causes structural destabilization of immunoglobulin-like domain (Ig) III and that the novel asparagine in hNp results in steric constraints and an additional N-glycosylation site in IgII. Additional N-glycosylation of hNp was confirmed by PNGaseF treatment. In comparison to hNp, transfection of hNp and hNp into HEK293T cells resulted in normal mRNA levels but reduced the Np protein levels and their cell surface expression due to proteasomal/lysosomal degradation. Furthermore, hNp and hNp failed to promote exogenous PMCA levels in HEK293T cells. In hippocampal neurons, expression of additional hNp or hNp was less efficient than hNp to elevate endogenous PMCA levels and to accelerate the restoration of basal Ca levels after electrically-evoked Ca transients. We propose that mutations leading to pathological Np variants, as exemplified here by the deafness causing Np mutants, can affect Np-dependent Ca regulatory mechanisms and may potentially cause intellectual and cognitive deficits in humans.
PubMed: 38879011
DOI: 10.1016/j.jbc.2024.107474 -
Heliyon Jun 2024Potato chips are a popular snack, well-liked because of their texture-flavor combination. Potato chips are made by frying slices of potato in vegetable oil to achieve a...
Potato chips are a popular snack, well-liked because of their texture-flavor combination. Potato chips are made by frying slices of potato in vegetable oil to achieve a crispy texture. Frying potato slices initiates the Maillard reaction, resulting in chemical changes that enhance taste, color, and texture, but also undesired acrylamides, which are suspected carcinogens. The application of pulsed electric field (PEF) technology is commonly used in French fry processing operations to prolong cutting blade sharpness and reduce waste, energy consumption, and water usage. Despite these attributes, PEF systems have not yet gained widespread adoption by potato chip producers. In the current study, Lamoka potatoes were PEF-treated prior to continuous frying into potato chips. The effect of specific energy at 0.75 kJ/kg (Low-PEF) and 1.5 kJ/kg (High-PEF) and electric field strength of 1 kV/cm, frequency of 24 kV, and pulse width of 6 μs versus untreated (control) samples was studied, then batches of 250 g of slices were fried at 170 °C or 185 °C for two frying times to obtain potato chips with acrylamide levels below the California Proposition 65 limit (275 ng/g). The Lamoka potato chip product quality metrics that were assessed include moisture, fat, reducing sugars, asparagine, acrylamide, chip color, and texture. PEF treatment of Lamoka potatoes resulted in chips fried in 10 % less time, lower oil content by 8 %, and a decrease of reducing sugars by 19.2 %, asparagine by 42.0 %, and acrylamide by 28.9 %. The PEF fried chips were lighter in color but maintained textural attributes compared to continuous frying cooking. The process of frying potato slices at 170 °C for 150 s with High-PEF yielded potato chips with acrylamide content below the California Proposition 65 limit; which speaks to the health implications for consumers and the quality and safety of these chips.
PubMed: 38873662
DOI: 10.1016/j.heliyon.2024.e31790 -
Food Chemistry Jun 2024This study aimed to upcycle a byproduct of the edible oil industry, cold-pressed nettle seed meal (CPNSM), into a plant-based emulsifier, thereby increasing the...
This study aimed to upcycle a byproduct of the edible oil industry, cold-pressed nettle seed meal (CPNSM), into a plant-based emulsifier, thereby increasing the sustainability of the food system. The protein content of the nettle seed protein (NSP) powder was 48.3% with glutamic acid (16.6%), asparagine (10.7%), and arginine (9.7%) being the major amino acids. NSPs had a denaturation temperature of 66.6 °C and an isoelectric point of pH 4.3. They could be used as emulsifiers to form highly viscous coarse corn oil-in-water emulsions (10% oil, 4% NSP). Nevertheless, 10-fold diluted emulsions exhibited rapid creaming under different pH (2-9), salt (0-500 mM NaCl) and temperature (>40 °C) conditions, but they were relatively stable to aggregation. Our findings suggest that NSPs could be used as emulsifiers in highly viscous or gelled foods, like dressings, sauces, egg, cheese, or meat analogs.
PubMed: 38852455
DOI: 10.1016/j.foodchem.2024.139878 -
The Journal of Physical Chemistry. B Jun 2024Particulate MMO (pMMO) catalyzes the oxidation of methane to methanol and also ammonia to hydroxylamine. Experimental characterization of the active site has been very...
Particulate MMO (pMMO) catalyzes the oxidation of methane to methanol and also ammonia to hydroxylamine. Experimental characterization of the active site has been very difficult partly because the enzyme is membrane-bound. However, recently, there has been major progress mainly through the use of cryogenic electron microscopy (cryoEM). Electron paramagnetic resonance (EPR) and X-ray spectroscopy have also been employed. Surprisingly, the active site has only one copper. There are two histidine ligands and one asparagine ligand, and the active site is surrounded by phenyl alanines but no charged amino acids in the close surrounding. The present study is the first quantum chemical study using a model of that active site (Cu). Low barrier mechanisms have been found, where an important part is that there are two initial proton-coupled electron transfer steps to a bound O ligand before the substrate enters. Surprisingly, this leads to large radical character for the oxygens even though they are protonated. That result is very important for the ability to accept a proton from the substrates. Methods have been used which have been thoroughly tested for redox enzyme mechanisms.
Topics: Oxidation-Reduction; Methane; Oxygenases; Ammonia; Catalytic Domain; Models, Molecular; Electron Spin Resonance Spectroscopy
PubMed: 38850249
DOI: 10.1021/acs.jpcb.4c01807 -
Amino Acids Jun 2024Biomarkers that accurately reflect renal function are essential in management of chronic kidney diseases (CKD). However, in children, age/physique and medication often...
Biomarkers that accurately reflect renal function are essential in management of chronic kidney diseases (CKD). However, in children, age/physique and medication often alter established renal biomarkers. We studied whether amino acid enantiomers in body fluids correlate with renal function and whether they are influenced by physique or steroid medication during development. We conducted a prospective study of children 2 to 18 years old with and without CKD. We analyzed associations of serine/asparagine enantiomers in body fluids with major biochemical parameters as well as physique. To study consequences of kidney dysfunction and steroids on serine/asparagine enantiomers, we generated juvenile mice with uninephrectomy, ischemic reperfusion injury, or dexamethasone treatment. We obtained samples from 27 children, of which 12 had CKD due to congenital (n = 7) and perinatal (n = 5) causes. Plasma D-asparagine and the D/L-serine ratio had robust, positive linear associations with serum creatinine and cystatin C, and detected CKD with high sensitivity and specificity, uninfluenced by body size or biochemical parameters. In the animal study, kidney dysfunction increased plasma D-asparagine and the D/L-serine ratio, but dexamethasone treatment did not. Thus, plasma D-asparagine and the D/L-serine ratio can be useful markers for renal function in children.
Topics: Child; Animals; Humans; Asparagine; Renal Insufficiency, Chronic; Child, Preschool; Serine; Mice; Male; Female; Adolescent; Biomarkers; Prospective Studies; Dexamethasone; Stereoisomerism; Creatinine; Kidney
PubMed: 38844708
DOI: 10.1007/s00726-024-03400-x -
Environmental Science & Technology Jun 2024The Cu(II)/HO system is recognized for its potential to degrade recalcitrant organic contaminants and inactivate microorganisms in wastewater. We investigated its unique...
The Cu(II)/HO system is recognized for its potential to degrade recalcitrant organic contaminants and inactivate microorganisms in wastewater. We investigated its unique dual oxidation strategy involving the selective oxidation of copper-complexing ligands and enhanced oxidation of nonchelated organic compounds. L-Histidine (His) and benzoic acid (BA) served as model compounds for basic biomolecular ligands and recalcitrant organic contaminants, respectively. In the presence of both His and BA, the Cu(II)/HO system rapidly degraded His complexed with copper ions within 30 s; however, BA degraded gradually with a 2.3-fold efficiency compared with that in the absence of His. The primary oxidant responsible was the trivalent copper ion [Cu(III)], not hydroxyl radical (OH), as evidenced by OH scavenging, hydroxylated BA isomer comparison with UV/HO (a OH generating system), electron paramagnetic resonance, and colorimetric Cu(III) detection via periodate complexation. Cu(III) selectively oxidized His owing to its strong chelation with copper ions, even in the presence of excess -butyl alcohol. This selectivity extended to other copper-complexing ligands, including L-asparagine and L-aspartic acid. The presence of His facilitated HO-mediated Cu(II) reduction and increased Cu(III) production, thereby enhancing the degradation of BA and pharmaceuticals. Thus, the Cu(II)/HO system is a promising option for dual-target oxidation in diverse applications.
Topics: Copper; Histidine; Oxidation-Reduction; Hydrogen Peroxide; Catalysis; Iron; Hydroxyl Radical; Benzoic Acid
PubMed: 38843408
DOI: 10.1021/acs.est.4c03689 -
Frontiers in Psychiatry 2024Understanding the mechanisms underlying maternal postpartum depression (PPD) and its effects on offspring development is crucial. However, research on the association...
INTRODUCTION
Understanding the mechanisms underlying maternal postpartum depression (PPD) and its effects on offspring development is crucial. However, research on the association between maternal PPD, gut microbiota, and offspring neurodevelopment remains limited. This study aimed to examine the association of maternal PPD symptoms with early gut microbiome, gut metabolome, and neurodevelopment in infants at 6 months.
METHODS
Maternal PPD symptoms were assessed using the Edinburgh Postpartum Depression Scale (EPDS) at 42 days postpartum. Infants stool samples collected at 42 days after birth were analyzed using 16S rRNA sequencing and liquid chromatography-mass spectrometry (LC-MS) detection. Infant neurodevelopment was measured at 6 months using the Ages and Stages Questionnaire, Third Edition (ASQ-3). Correlations between gut microbiota, metabolites and neurodevelopment were identified through co-occurrence network analysis. Finally, mediation analyses were conducted to determine potential causal pathways.
RESULTS
A total of 101 mother-infant dyads were included in the final analysis. Infants born to mothers with PPD symptoms at 42 days postpartum had lower neurodevelopmental scores at 6 months. These infants also had increased alpha diversity of gut microbiota and were abundant in and , while depleted abundance of , , and Furthermore, alterations were observed in metabolite levels linked to the Alanine, aspartate, and glutamate metabolic pathway, primarily characterized by decreases in N-Acetyl-L-aspartic acid, L-Aspartic acid, and L-Asparagine. Co-occurrence network and mediation analyses revealed that N-Acetyl-L-aspartic acid and L-Aspartic acid levels mediated the relationship between maternal PPD symptoms and the development of infant problem-solving skills.
CONCLUSIONS
Maternal PPD symptoms are associated with alterations in the gut microbiota and neurodevelopment in infants. This study provides new insights into potential early intervention for infants whose mother experienced PPD. Further research is warranted to elucidate the biological mechanisms underlying these associations.
PubMed: 38835546
DOI: 10.3389/fpsyt.2024.1385229