scholarly journals Systemic metabolite profiling reveals sexual dimorphism of AIBP control of metabolism in mice

PLoS ONE ◽  
2021 ◽  
Vol 16 (4) ◽  
pp. e0248964
Author(s):  
Jun-dae Kim ◽  
Lingping Zhu ◽  
Quan Sun ◽  
Longhou Fang
Keyword(s):  
Sexual Dimorphism ◽  
Knockout Mice ◽  
Metabolite Profiling ◽  
Krebs Cycle ◽  
Leigh Syndrome ◽  
Metabolite Profile ◽  
Cellular Functions ◽  
Metabolic Basis ◽  
And Control ◽  
Cellular Cholesterol Efflux

Emerging studies indicate that APOA-I binding protein (AIBP) is a secreted protein and functions extracellularly to promote cellular cholesterol efflux, thereby disrupting lipid rafts on the plasma membrane. AIBP is also present in the mitochondria and acts as an epimerase, facilitating the repair of dysfunctional hydrated NAD(P)H, known as NAD(P)H(X). Importantly, AIBP deficiency contributes to lethal neurometabolic disorder, reminiscent of the Leigh syndrome in humans. Whereas cyclic NADPHX production is proposed to be the underlying cause, we hypothesize that an unbiased metabolic profiling may: 1) reveal new clues for the lethality, e.g., changes of mitochondrial metabolites., and 2) identify metabolites associated with new AIBP functions. To this end, we performed unbiased and profound metabolic studies of plasma obtained from adult AIBP knockout mice and control littermates of both genders. Our systemic metabolite profiling, encompassing 9 super pathways, identified a total of 640 compounds. Our studies demonstrate a surprising sexual dimorphism of metabolites affected by AIBP deletion, with more statistically significant changes in the AIBP knockout female vs male when compared with the corresponding controls. AIBP knockout trends to reduce cholesterol but increase the bile acid precursor 7-HOCA in female but not male. Complex lipids, phospholipids, sphingomyelin and plasmalogens were reduced, while monoacylglycerol, fatty acids and the lipid soluble vitamins E and carotene diol were elevated in AIBP knockout female but not male. NAD metabolites were not significantly different in AIBP knockout vs control mice but differed for male vs female mice. Metabolites associated with glycolysis and the Krebs cycle were unchanged by AIBP knockout. Importantly, polyamine spermidine, critical for many cellular functions including cerebral cortex synapses, was reduced in male but not female AIBP knockout. This is the first report of a systemic metabolite profile of plasma samples from AIBP knockout mice, and provides a metabolic basis for future studies of AIBP regulation of cellular metabolism and the pathophysiological presentation of AIBP deficiency in patients.

scholarly journals Sensory Metabolite Profiling in a Date Pit Based Coffee Substitute and in Response to Roasting as Analyzed via Mass Spectrometry Based Metabolomics

Molecules ◽  
2019 ◽  
Vol 24 (18) ◽  
pp. 3377 ◽  
Author(s):  
Mohamed A. Farag ◽  
Asmaa M. Otify ◽  
Aly M. El-Sayed ◽  
Camilia G. Michel ◽  
Shaimaa A. ElShebiney ◽  
...  
Keyword(s):  
Metabolite Profiling ◽  
Headspace Analysis ◽  
Metabolite Profile ◽  
Phoenix Dactylifera ◽  
Primary Metabolite ◽  
Phoenix Dactylifera L ◽  
Coffee Substitute ◽  
Headspace Spme ◽  
Spme Headspace ◽  
Date Pits

Interest in developing coffee substitutes is on the rise, to minimizing its health side effects. In the Middle East, date palm (Phoenix dactylifera L.) pits are often used as a coffee substitute post roasting. In this study, commercially-roasted date pit products, along with unroasted and home-prepared roasted date pits, were subjected to analyses for their metabolite composition, and neuropharmacological evaluation in mice. Headspace SPME-GCMS and GCMS post silylation were employed for characterizing its volatile and non-volatile metabolite profile. For comparison to roasted coffee, coffee product was also included. There is evidence that some commercial date pit products appear to contain undeclared additives. SPME headspace analysis revealed the abundance of furans, pyrans, terpenoids and sulfur compounds in roasted date pits, whereas pyrroles and caffeine were absent. GCMS-post silylation employed for primary metabolite profiling revealed fatty acids’ enrichment in roasted pits versus sugars’ abundance in coffee. Biological investigations affirmed that date pit showed safer margin than coffee from its LD50, albeit it exhibits no CNS stimulant properties. This study provides the first insight into the roasting impact on the date pit through its metabolome and its neuropharmacological aspects to rationalize its use as a coffee substitute.

scholarly journals Pyrrolidinyl Synthetic Cathinones α-PHP and 4F-α-PVP Metabolite Profiling Using Human Hepatocyte Incubations

2020 ◽  
Vol 22 (1) ◽  
pp. 230
Author(s):  
Jeremy Carlier ◽  
Xingxing Diao ◽  
Raffaele Giorgetti ◽  
Francesco P. Busardò ◽  
Marilyn A. Huestis
Keyword(s):  
Metabolite Profiling ◽  
Human Liver ◽  
Liver Microsomes ◽  
Drug Market ◽  
Metabolite Profile ◽  
Illegal Drug ◽  
Human Hepatocyte ◽  
Synthetic Cathinones ◽  
Metabolic Fate ◽  
Analytical Standards

For more than ten years, new synthetic cathinones (SCs) mimicking the effects of controlled cocaine-like stimulants have flooded the illegal drug market, causing numerous intoxications and fatalities. There are often no data on the pharmacokinetics of these substances when they first emerge onto the market. However, the detection of SC metabolites is often critical in order to prove consumption in clinical and forensic settings. In this research, the metabolite profile of two pyrrolidinyl SCs, α-pyrrolidinohexaphenone (α-PHP) and 4′′-fluoro-α-pyrrolidinovalerophenone (4F-α-PVP), were characterized to identify optimal intake markers. Experiments were conducted using pooled human hepatocyte incubations followed by liquid chromatography–high-resolution tandem mass spectrometry and data-mining software. We suggest α-PHP dihydroxy-pyrrolidinyl, α-PHP hexanol, α-PHP 2′-keto-pyrrolidinyl-hexanol, and α-PHP 2′-keto-pyrrolidinyl as markers of α-PHP use, and 4F-α-PVP dihydroxy-pyrrolidinyl, 4F-α-PVP hexanol, 4F-α-PVP 2′-keto-pyrrolidinyl-hexanol, and 4F-α-PVP 2′-keto-pyrrolidinyl as markers of 4F-α-PVP use. These results represent the first data available on 4F-α-PVP metabolism. The metabolic fate of α-PHP was previously studied using human liver microsomes and urine samples from α-PHP users. We identified an additional major metabolite (α-PHP dihydroxy-pyrrolidinyl) that might be crucial for documenting exposure to α-PHP. Further experiments with suitable analytical standards, which are yet to be synthesized, and authentic specimens should be conducted to confirm these results.

The Na+-K+-ATPase α2-subunit isoform modulates contractility in the perinatal mouse diaphragm

2004 ◽  
Vol 287 (5) ◽  
pp. C1300-C1310 ◽  
Author(s):  
Tatiana L. Radzyukevich ◽  
Amy E. Moseley ◽  
Daniel A. Shelly ◽  
Gregory A. Redden ◽  
Michael M. Behbehani ◽  
...  
Keyword(s):  
Action Potential ◽  
Knockout Mice ◽  
Dominant Mode ◽  
Resting Potential ◽  
Force Frequency ◽  
Cellular Functions ◽  
Tetanic Force ◽  
Potential Threshold ◽  
Rate Of Activation

This study uses genetically altered mice to examine the contribution of the Na+-K+-ATPase α2 catalytic subunit to resting potential, excitability, and contractility of the perinatal diaphragm. The α2 protein is reduced by 38% in α2-heterozygous and absent in α2-knockout mice, and α1-isoform is upregulated 1.9-fold in α2-knockout. Resting potentials are depolarized by 0.8–4.0 mV in heterozygous and knockout mice. Action potential threshold, overshoot, and duration are normal. Spontaneous firing, a developmental function, is impaired in knockout diaphragm, but this does not compromise its ability to fire evoked action potential trains, the dominant mode of activation near birth. Maximum tetanic force, rate of activation, force-frequency and force-voltage relationships, and onset and magnitude of fatigue are not changed. The major phenotypic consequence of reduced α2 content is that relaxation from contraction is 1.7-fold faster. This finding reveals a distinct cellular role of the α2-isoform at a step after membrane excitation, which cannot be restored simply by increasing α1 content. Na+/Ca2+ exchanger expression decreases in parallel with α2-isoform, suggesting that Ca2+ extrusion is affected by the altered α2 genotype. There are no major compensatory changes in expression of sarcoplasmic reticulum Ca2+-ATPase, phospholamban, or plasma membrane Ca2+-ATPase. These results demonstrate that the Na+-K+-ATPase α1-isoform alone is able to maintain equilibrium K+ and Na+ gradients and to substitute for α2-isoform in most cellular functions related to excitability and force. They further indicate that the α2-isoform contributes significantly less at rest than expected from its proportional content but can modulate contractility during muscle contraction.

scholarly journals Pathway Analysis of a Transcriptome and Metabolite Profile to Elucidate a Compensatory Mechanism for Taurine Deficiency in the Heart of Taurine Transporter Knockout Mice

J ◽  
2018 ◽  
Vol 1 (1) ◽  
pp. 57-70
Author(s):  
Takashi Ito ◽  
Shigeru Murakami ◽  
Stephen Schaffer
Keyword(s):  
Pathway Analysis ◽  
Knockout Mice ◽  
Metabolite Profile ◽  
Integrated Analysis ◽  
Compensatory Mechanism ◽  
Compensatory Mechanisms ◽  
Taurine Transporter ◽  
Kegg Pathway Database ◽  
Taurine Deficiency ◽  
Pathway Analyses

Taurine, which is abundant in mammalian tissues, especially in the heart, is essential for cellular osmoregulation. We previously reported that taurine deficiency leads to changes in the levels of several metabolites, suggesting that alterations in those metabolites might compensate in part for tissue taurine loss, a process that would be important in maintaining cardiac homeostasis. In this study, we investigated the molecular basis for changes in the metabolite profile of a taurine-deficient heart using pathway analysis based on the transcriptome and metabolome profile in the hearts of taurine transporter knockout mice (TauTKO mice), which have been reported by us. First, the genes associated with transport activity, such as the solute carrier (SLC) family, are increased in TauTKO mice, while the established transporters for metabolites that are elevated in the TauTKO heart, such as betaine and carnitine, are not altered by taurine deficiency. Second, the integrated analysis using transcriptome and metabolome data revealed significant increases and/or decreases in the genes involved in Arginine metabolism, Ketone body degradation, Glycerophospholipid metabolism, and Fatty acid metabolism in the KEGG pathway database. In conclusion, these pathway analyses revealed genetic compensatory mechanisms involved in the control of the metabolome profile of the taurine-deficient heart.

scholarly journals NAC-NOR mutations in tomato Penjar accessions attenuate multiple metabolic processes and prolong the fruit shelf life

2017 ◽  
Author(s):  
Rakesh Kumar ◽  
Vajir Tamboli ◽  
Rameshwar Sharma ◽  
Yellamaraju Sreelakshmi
Keyword(s):  
Amino Acids ◽  
Cell Wall ◽  
Shelf Life ◽  
Krebs Cycle ◽  
Metabolic Processes ◽  
Cell Wall Modification ◽  
Metabolic Basis ◽  
Fruit Shelf Life ◽  
Krebs Cycle Intermediates ◽  
Reduced Water

AbstractSeveral Penjar accessions of tomato (Solanum lycopersicum), widely grown in the Mediterranean region, exhibit prolonged shelf life, and harbor alcobaca mutation with valine-106-aspartic acid substitution in the NAC-NOR protein. To uncover the metabolic basis underlying the prolonged shelf life, we compared four Penjar accessions to Ailsa Craig (AC). Three accessions bore alcobaca mutation, whereas fourth was a novel NAC-NOR allele with only six amino acids in the encoded protein. The cuticle composition among Penjars varied widely during the progression of fruit ripening. All Penjars exhibited delayed ripening, prolonged on-vine and off-vine shelf life, low ethylene emission and carotenoid levels albeit with accession-specific differences. Metabolic profiling revealed shifts in Krebs cycle intermediates, amino acids, and β-aminobutyric acid levels indicating the attenuation of respiration in Penjars during post-harvest storage. The prolonged shelf life of Penjar fruits was associated with a concerted downregulation of a number of cell-wall modifying genes and cell-wall-related metabolites. The accumulation of higher ABA and sucrose levels at the onset of senescence in Penjar fruits likely contribute to reduced water loss. Our analyses reveal that in addition to specialized cuticle composition, the attenuation of various metabolic processes by NAC-NOR mutation likely prolongs the shelf life of Penjar fruits.HighlightThe prolonged shelf life of tomato Penjar accessions bearing mutations in NAC-NOR transcription factor appears to be regulated by a combined effect of attenuation of respiration, altered cuticle composition, enhanced ABA and sucrose levels in fruits and downregulation of cell wall modification

scholarly journals A single Na+-Pi cotransporter in Toxoplasma plays key roles in phosphate import and control of parasite osmoregulation

2020 ◽  
Vol 16 (12) ◽  
pp. e1009067
Author(s):  
Beejan Asady ◽  
Claudia F. Dick ◽  
Karen Ehrenman ◽  
Tejram Sahu ◽  
Julia D. Romano ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Critical Role ◽  
Inorganic Ions ◽  
Phosphate Transport ◽  
Cellular Functions ◽  
Growth Defects ◽  
Binding Domains ◽  
Cytoplasmic Vesicles ◽  
Survival Mode ◽  
And Control

Inorganic ions such as phosphate, are essential nutrients required for a broad spectrum of cellular functions and regulation. During infection, pathogens must obtain inorganic phosphate (Pi) from the host. Despite the essentiality of phosphate for all forms of life, how the intracellular parasite Toxoplasma gondii acquires Pi from the host cell is still unknown. In this study, we demonstrated that Toxoplasma actively internalizes exogenous Pi by exploiting a gradient of Na+ ions to drive Pi uptake across the plasma membrane. The Na+-dependent phosphate transport mechanism is electrogenic and functionally coupled to a cipargarmin sensitive Na+-H+-ATPase. Toxoplasma expresses one transmembrane Pi transporter harboring PHO4 binding domains that typify the PiT Family. This transporter named TgPiT, localizes to the plasma membrane, the inward buds of the endosomal organelles termed VAC, and many cytoplasmic vesicles. Upon Pi limitation in the medium, TgPiT is more abundant at the plasma membrane. We genetically ablated the PiT gene, and ΔTgPiT parasites are impaired in importing Pi and synthesizing polyphosphates. Interestingly, ΔTgPiT parasites accumulate 4-times more acidocalcisomes, storage organelles for phosphate molecules, as compared to parental parasites. In addition, these mutants have a reduced cell volume, enlarged VAC organelles, defects in calcium storage and a slightly alkaline pH. Overall, these mutants exhibit severe growth defects and have reduced acute virulence in mice. In survival mode, ΔTgPiT parasites upregulate several genes, including those encoding enzymes that cleave or transfer phosphate groups from phosphometabolites, transporters and ions exchangers localized to VAC or acidocalcisomes. Taken together, these findings point to a critical role of TgPiT for Pi supply for Toxoplasma and also for protection against osmotic stresses.

scholarly journals Metabolite Profiling of 96% Ethanol Extract from Marsilea crenata Presl. Leaves Using UPLC-QToF-MS/MS and Anti-Neuroinflammatory Predicition Activity with Molecular Docking

2019 ◽  
Vol 4 (6) ◽  
pp. 261-270
Author(s):  
Burhan Ma’arif ◽  
Denis ◽  
Arief Suryadinata ◽  
Artabah ◽  
Hening Laswati ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Metabolite Profiling ◽  
Ethanol Extract ◽  
Metabolite Profile ◽  
The Body ◽  
Amine Hydrochloride ◽  
17Β Estradiol

Phytoestrogen is a group of compounds that can replace the estrogen function in the body. One of its roles was as anti-neuroinflammatory by inhibiting the microglia M1 polarity activation. Marsilea crenata Presl. is a plant that suspected to contain phytoestrogens. The aim of this research was to determine the metabolite profile of 96% ethanol extract of M. crenata using UPLC-QToF-MS/MS, and prediction the anti-neuroinflammatory activity of compounds with molecular docking. The 100 ppm of 96% ethanol extract in DCM and methanol were injected 5 µl each into the UPLC-QToF-MS/MS, and then analyzed by Masslynx 4.1 software to determine the compounds. The result of metabolite profiling shows a total 59 compounds in both DCM and methanol. Molecular docking was done with Autodock 4.2.6. After being analyzed, there are 3 compounds that are predicted to have activities similar to 17β-estradiol, they are prochlorperazine, 12-Aminododecanoic acid, and 1-methyl-2-[(4-methylpiperazin-1-yl)methyl]benzimidaol-5-amine hydrochloride. The results showed that the three compounds were predicted to be phytoestrogen compounds from M. crenata leaves, which have potential as anti-neuroinflammatory.

Sign in / Sign up

Export Citation Format

Share Document