Development and validation of a LC-MS/MS method for quantitation of 3-hydroxypentanoic acid and 3-oxopentanoic acid in human plasma and its application to a clinical study of glucose transporter type I deficiency (G1D) syndrome

Kallem, Raja Reddy; Primeaux, Sharon; Avila, Adrian; Pascual, Juan M.; Putnam, William C.

doi:10.1016/j.jpba.2021.114335

Cited by 4 publications

(5 citation statements)

References 9 publications

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“…Figure 3 illustrates C5 ketosis for beta-hydroxy pentanoate and beta-keto pentanoate in select subjects as a function of C7 administration. These values were commensurate with previous measurements 27 and with determinations made at the maximum tolerable dose 21 . There was no correlation between these values and previous beta-hydroxybutyrate levels, or between these values and compatibility with the ketogenic diet.…”

Section: Resultssupporting

confidence: 90%

“…The biochemical basis for this intervention were substantiated by multiplet 13 C-nuclear magnetic resonance (NMR) spectroscopy 32 , gas chromatography-mass spectrometry (GC–MS) and liquid chromatography-mass spectrometry (LC–MS) studies of the metabolism of infused [5,6,7- 13 C 3 ]heptanoate in a G1D mouse model faithful to the most common human disorder phenotype 16 . This metabolic substrate is primarily metabolized in the liver, producing blood [3,4,5- 13 C 3 ] C5 ketones 27 . This work revealed enrichment in heptanoate-derived plasma glucose via neoglucogenesis and increased cerebral acetyl coenzyme A and glutamine concentrations.…”

Section: Discussionmentioning

confidence: 99%

“…The subjects were also surveyed for clinical manifestations on day 5 and via telephone on day 30. Additional determinations of the C5 ketones β-hydroxypentanoate and β-ketopentanoate were performed in 5 subjects (participants 6, 7, 8, 9 and 10) at baseline and approximately 2 h approximately after the first C7 dose and 10 min after the last C7 dose on day 2, as previously described 27 .…”

Section: Methodsmentioning

confidence: 99%

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Combination of triheptanoin with the ketogenic diet in Glucose transporter type 1 deficiency (G1D)

Avila

Málaga

Sirsi

et al. 2023

Sci Rep

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Fuel influx and metabolism replenish carbon lost during normal neural activity. Ketogenic diets studied in epilepsy, dementia and other disorders do not sustain such replenishment because their ketone body derivatives contain four carbon atoms and are thus devoid of this anaplerotic or net carbon donor capacity. Yet, in these diseases carbon depletion is often inferred from cerebral fluorodeoxyglucose-positron emission tomography. Further, ketogenic diets may prove incompletely therapeutic. These deficiencies provide the motivation for complementation with anaplerotic fuel. However, there are few anaplerotic precursors consumable in clinically sufficient quantities besides those that supply glucose. Five-carbon ketones, stemming from metabolism of the food supplement triheptanoin, are anaplerotic. Triheptanoin can favorably affect Glucose transporter type 1 deficiency (G1D), a carbon-deficiency encephalopathy. However, the triheptanoin constituent heptanoate can compete with ketogenic diet-derived octanoate for metabolism in animals. It can also fuel neoglucogenesis, thus preempting ketosis. These uncertainties can be further accentuated by individual variability in ketogenesis. Therefore, human investigation is essential. Consequently, we examined the compatibility of triheptanoin at maximum tolerable dose with the ketogenic diet in 10 G1D individuals using clinical and electroencephalographic analyses, glycemia, and four- and five-carbon ketosis. 4 of 8 of subjects with pre-triheptanoin beta-hydroxybutyrate levels greater than 2 mM demonstrated a significant reduction in ketosis after triheptanoin. Changes in this and the other measures allowed us to deem the two treatments compatible in the same number of individuals, or 50% of persons in significant beta-hydroxybutyrate ketosis. These results inform the development of individualized anaplerotic modifications to the ketogenic diet.ClinicalTrials.gov registration NCT03301532, first registration: 04/10/2017.

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Section: Resultssupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Combination of triheptanoin with the ketogenic diet in Glucose transporter type 1 deficiency (G1D)

Avila

Málaga

Sirsi

et al. 2023

Sci Rep

Self Cite

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“…The following morning, two doses were administered at approximately 6 AM (before breakfast) and 10 AM (before lunch), each containing ¼ of the total daily dose. Before lunch, at 12–1 PM, blood was collected for determination of ketone bodies as described 31 , approximately 21 h after the baseline analysis. Figure 2 illustrates this experimental sequence.…”

Section: Methodsmentioning

confidence: 99%

Maximum dose, safety, tolerability and ketonemia after triheptanoin in glucose transporter type 1 deficiency (G1D)

Málaga

Avila

Primeaux

et al. 2023

Sci Rep

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Augmentation of anaplerosis, or replenishment of carbon lost during intermediary metabolic transitions, is desirable in energy metabolism defects. Triheptanoin, the triglyceride of 7-carbon heptanoic acid, is anaplerotic via direct oxidation or 5-carbon ketone body generation. In this context, triheptanoin can be used to treat Glucose transporter type 1 deficiency encephalopathy (G1D). An oral triheptanoin dose of 1 g/Kg/day supplies near 35% of the total caloric intake and impacted epilepsy and cognition in G1D. This provided the motivation to establish a maximum, potentially greater dose. Using a 3 + 3 dose-finding approach useful in oncology, we studied three age groups: 4–6, 6.8–10 and 11–16 years old. This allowed us to arrive at a maximum tolerated dose of 45% of daily caloric intake for each group. Safety was ascertained via analytical blood measures. One dose-limiting toxicity, occurring in 1 of 6 subjects, was encountered in the middle age group in the context of frequently reduced gastrointestinal tolerance for all groups. Ketonemia following triheptanoin was determined in another group of G1D subjects. In them, β-ketopentanoate and β-hydroxypentanoate concentrations were robustly but variably increased. These results enable the rigorous clinical investigation of triheptanoin in G1D by providing dosing and initial tolerability, safety and ketonemic potential.ClinicalTrials.gov registration: NCT03041363, first registration 02/02/2017.

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“…A peak demonstrated an [M-H]- m/z at 165 and a daughter ion at m/z 119 [M-H-HCOOH]-; it was assigned as arabinonic acid ( Moreira et al, 2014 ). A peak demonstrated an [M-H]- m/z at 115 and a daughter ion at m/z 71 [M-H-CO 2 ]-; it was assigned as 3-oxopentanoic acid ( Kallem et al, 2021 ). A peak demonstrated an [M-H]- m/z at 137 and daughter ions at m/z 109 [M-H-CO]-, 108 [M-2H-CO]-, 93 [M-H-CO 2 ]-, 92 [M-2H-CO 2 ]-, 81, and 65; it was assigned as 3-hydroxybenzoic acid ( Ammar et al, 2020 ; Ghareeb et al, 2023 ).…”

Section: Resultsmentioning

confidence: 99%

Bio-fabricated zinc oxide nanoparticles mediated by endophytic fungus Aspergillus sp. SA17 with antimicrobial and anticancer activities: in vitro supported by in silico studies

Abdelrahman,

El Hawary,

Mohsen

et al. 2024

Front. Microbiol.

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IntroductionIn recent years, the world’s attention has been drawn to antimicrobial resistance (AMR) because to the frightening prospect of growing death rates. Nanomaterials are being investigated due to their potential in a wide range of technical and biological applications.MethodsThe purpose of this study was to biosynthesis zinc oxide nanoparticles (ZnONPs) using Aspergillus sp. SA17 fungal extract, followed by characterization of the produced nanoparticles (NP) using electron microscopy (TEM and SEM), UV-analysis, X-ray diffraction (XRD), and Fourier-transform infrared spectroscopy (FT-IR).Results and DiscussionThe HR-TEM revealed spherical nanoparticles with an average size of 7.2 nm, and XRD validated the crystalline nature and crystal structure features of the generated ZnONPs, while the zeta potential was 18.16 mV, indicating that the particles’ surfaces are positively charged. The FT-IR was also used to identify the biomolecules involved in the synthesis of ZnONPs. The antibacterial and anticancer properties of both the crude fungal extract and its nano-form against several microbial strains and cancer cell lines were also investigated. Inhibition zone diameters against pathogenic bacteria ranged from 3 to 13 mm, while IC50 values against cancer cell lines ranged from 17.65 to 84.55 M. Additionally, 33 compounds, including flavonoids, phenolic acids, coumarins, organic acids, anthraquinones, and lignans, were discovered through chemical profiling of the extract using UPLC-QTOF-MS/MS. Some molecules, such pomiferin and glabrol, may be useful for antibacterial purposes, according to in silico study, while daidzein 4’-sulfate showed promise as an anti-cancer metabolite.

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Development and validation of a LC-MS/MS method for quantitation of 3-hydroxypentanoic acid and 3-oxopentanoic acid in human plasma and its application to a clinical study of glucose transporter type I deficiency (G1D) syndrome

Cited by 4 publications

References 9 publications

Combination of triheptanoin with the ketogenic diet in Glucose transporter type 1 deficiency (G1D)

Combination of triheptanoin with the ketogenic diet in Glucose transporter type 1 deficiency (G1D)

Maximum dose, safety, tolerability and ketonemia after triheptanoin in glucose transporter type 1 deficiency (G1D)

Bio-fabricated zinc oxide nanoparticles mediated by endophytic fungus Aspergillus sp. SA17 with antimicrobial and anticancer activities: in vitro supported by in silico studies

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