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Abstract Background 2-Hydroxybenzylamine (2-HOBA) is a selective dicarbonyl electrophile scavenger being developed as a nutritional supplement to help protect against the development of conditions associated with dicarbonyl electrophile formation, such as the cognitive decline observed with Mild Cognitive Impairment or Alzheimer’s disease. Methods This study evaluated the safety, tolerability, and pharmacokinetics of repeated oral doses of 2-HOBA acetate (500 or 750 mg) administered to healthy volunteers every eight hours for two weeks. The effects of 2-HOBA on cyclooxygenase function and cerebrospinal fluid penetrance of 2-HOBA were also investigated. Results Repeated oral administration of 2-HOBA was found to be safe and well-tolerated up to 750 mg TID for 15 days. 2-HOBA was absorbed within 2 h of administration, had a half-life of 2.10–3.27 h, and an accumulation ratio of 1.38–1.52. 2-HOBA did not interfere with cyclooxygenase function and was found to be present in cerebrospinal fluid 90 min after dosing. Conclusions Repeated oral administration of 2-HOBA was found to be safe and well-tolerated. These results support continued development of 2-HOBA as a nutritional supplement. Trial registration Studies are registered at ClinicalTrials.gov (NCT03555682 Registered 13 June 2018, NCT03554096 Registered 12 June 18).

Abstract Background 2-Hydroxybenzylamine (2-HOBA) is a selective scavenger of dicarbonyl electrophiles that protects proteins and lipids from being modified by these electrophiles. It is currently being developed for use as a nutritional supplement to help maintain good health and protect against the development of conditions associated with dicarbonyl electrophile formation, such as the cognitive decline associated with Mild Cognitive Impairment and Alzheimer’s disease. Methods In this first-in-human study, the safety, tolerability, and pharmacokinetics of six ascending single oral doses of 2-HOBA acetate were tested in eighteen healthy human volunteers. Results Reported adverse events were mild and considered unlikely to be related to 2-HOBA. There were no clinically significant changes in vital signs, ECG recordings, or clinical laboratory parameters. 2-HOBA was fairly rapidly absorbed, with a tmax of 1–2 h, and eliminated, with a t1/2 of approximately 2 h. Both tmax and t1/2 were independent of dose level, while Cmax and AUC increased proportionally with dose level. Conclusions 2-HOBA acetate was safe and well-tolerated at doses up to 825 mg in healthy human volunteers, positioning it as a good candidate for continued development as a nutritional supplement. Trial registration This study is registered at ClinicalTrials.gov (NCT03176940).

Background: 2-Hydroxybenzylamine (2-HOBA) is a selective dicarbonyl electrophile scavenger being developed as a nutritional supplement to help protect against the development of conditions associated with dicarbonyl electrophile formation, such as the cognitive decline observed with Mild Cognitive Impairment or Alzheimer's disease. Methods: This study evaluated the safety, tolerability, and pharmacokinetics of repeated oral doses of 2-HOBA acetate (500 or 750 mg) administered to healthy volunteers every eight hours for two weeks. The effects of 2-HOBA on cyclooxygenase function and cerebrospinal fluid penetrance of 2-HOBA were also investigated. Results: Repeated oral administration of 2-HOBA was found to be safe and well-tolerated up to 750 mg TID for 15 days. 2-HOBA was absorbed within 2 h of administration, had a half-life of 2.10–3.27 h, and an accumulation ratio of 1.38–1.52. 2-HOBA did not interfere with cyclooxygenase function and was found to be present in cerebrospinal fluid 90 min after dosing. Conclusions: Repeated oral administration of 2-HOBA was found to be safe and well-tolerated. These results support continued development of 2-HOBA as a nutritional supplement. Trial registration: Studies are registered at ClinicalTrials.gov (NCT03555682 Registered 13 June 2018, NCT03554096 Registered 12 June 18). [ABSTRACT FROM AUTHOR]

Abstract 2-hydroxybenzylamine (2-HOBA), a naturally occurring compound found in buckwheat, has potential for use as a nutrition supplement due to its ability to protect against the damaging effects of oxidative stress. In a series of rodent toxicity studies, 2-HOBA acetate was well-tolerated and did not produce any toxic effects over 28 or 90 days of repeated oral administration. However, it remained necessary to test the potential toxicity of 2-HOBA acetate in a non-rodent species. In this investigation, 2-HOBA acetate was orally administered to male and female New Zealand White Rabbits for 90 days at doses of 100, 500, and 1000 mg·kg BW−1·day−1 (n = 5 per sex/group). As previously observed in rodents, 2-HOBA acetate administration was well tolerated. No toxic effects of 2-HOBA acetate were detected in body weight, feed consumption, hematology, blood chemistry, urine chemistry, organ weights, gross pathology or histopathology. Based on these findings, the no-observed-adverse-effect-level of 2-HOBA acetate in rabbits was determined to be 1000 mg·kg BW−1·day−1, which was the highest dose tested. These results provide further support for the safety of 2-HOBA acetate administration. Highlights • Daily oral administration of 2-hydroxybenzylamine at doses up to 1000 mg kg BW−1 ·day−1 for 90 days was examined in rabbits. • 2-Hydroxybenzylamine acetate did not induce any toxicological effects in rabbits. • These findings provide additional support for the safety of 2-hydroxybenzylamine consumption. [ABSTRACT FROM AUTHOR]

Abstract 2-Hydroxybenzylamine (2-HOBA), a naturally occurring compound found in buckwheat, can protect cells and tissues from oxidative stress. In this study, 2-HOBA acetate was orally administered to male and female rats for 90 consecutive days at doses of 100, 500, and 1000 mg·kg BW−1·d−1 (n = 20 per sex/group). Subchronic administration of 2-HOBA was well tolerated at all dose levels. 2-HOBA-treated male rats were slightly heavier in the last weeks of the study, but this difference was very small (<5%), did not show a dose–response relationship, and was not observed in female rats. Similarly, some statistically significant changes in serum biochemistry and hematology parameters were noted, but these were not considered to be of biological or toxicological significance. Sporadic differences in organ weights were observed between groups, but all were small (<10%) and unlikely to indicate toxicity. The incidence of histopathological lesions was similar between treated and control groups across all organs. Based upon these findings, the no-observed-adverse-effect level was determined to be ≥ 1000 mg·kg BW−1·d−1, which was the highest dose tested. These results further support no toxicity associated with oral consumption of 2-HOBA acetate in rats and the continued development of 2-HOBA as a dietary supplement or functional food. Highlights • Ninety days of daily oral administration of 2-hydroxybenzylamine (2-HOBA) acetate was tested in rats. • 2-HOBA doses up to 1000 mg·kg BW−1·d−1 did not induce toxicological effects. • These results provide additional support for the safety of 2-HOBA as a functional food agent or dietary supplement. [ABSTRACT FROM AUTHOR]

Abstract 2-hydroxybenzylamine (2-HOBA), a compound naturally found in buckwheat, has been shown to protect cells and tissues from the damaging effects of oxidative stress. The purpose of this report was to evaluate 2-HOBA in preclinical oral rodent toxicity studies. This report includes the results from three oral toxicity studies in rodents: a preliminary 28-day feeding study in mice, a 14-day acute oral toxicity study in rats, and a 28-day repeated dose oral toxicity study in rats. The preliminary mouse feeding study showed no adverse effects of 2-HOBA at concentrations up to 0.456% by weight in feed, but decreased food intake and weight loss were observed at 1.56% 2-HOBA in the diet, likely due to poor palatability. In the acute dosing study, 2000 mg/kg BW 2-HOBA resulted in mortality in one of the six tested female rats, indicating a median lethal dose of 2500 mg/kg BW. In the 28-day repeated oral dose study, small differences were observed between 2-HOBA treated and control group rats, but none of these differences were determined to be of toxicological significance. Together, these studies support the lack of toxicity of oral administration of 2-HOBA acetate at doses up to 1000 mg/kg BW d−1 in rodents. Highlights • 2-HOBA (up to 0.456% of feed) over 28 days did not cause adverse effects in mice. • 2-HOBA is a low-toxicity compound when given as an acute oral dose in rats. • Daily 2-HOBA administration did not induce toxic effects in a 28-day rat study. • These results support the safety of 2-HOBA for use as a dietary supplement. [ABSTRACT FROM AUTHOR]

Posttranslational modification by isolevuglandins (isoLGs), arachidonate oxidation products, is an important yet understudied process associated with altered protein properties. This type of modification is detected in cytochrome P450 27A1 (CYP27A1), a multifunction enzyme expressed in almost every cell and involved in the metabolism of cholesterol and other sterols. Previously, the CYP27A1 Lys358-isoLG adduct was found in human retina afflicted with age-related macular degeneration. Yet, the effect of Lys358 modification on enzyme activity was not investigated. Herein, we characterized catalytic properties of Lys358 as well as Lys476 CYP27A1 mutants before and after isoLG treatment and quantified the extent of modification by multiple reaction monitoring. The K358R mutant was less susceptible to isoLG-induced loss of catalytic activity than the wild type (WT), whereas the K476R mutant was nearly as vulnerable as the WT. Both mutants showed less isoLG modification than WT. Thus, modification of Lys358, a residue involved in redox partner interactions, is the major contributor to isoLG-associated loss of CYP27A1 activity. Our data show the specificity of isoLG modification, provide direct evidence that isoLG adduction impairs enzyme activity, and support our hypothesis that isoLG modification in the retina is detrimental to CYP27A1 enzyme activity, potentially disrupting cholesterol homeostasis.

Conversion of primary amino groups to pyrrole derivatives occurs by modifying lysine residues of proteins with lipid peroxidation products. Pyrrolated proteins exhibit electronegativity and electronic properties and are recognized by DNA-binding molecules, such as anti-DNA autoantibodies and DNA intercalators. This review summarizes the state of knowledge about the chemistry of this unique conversion reaction of proteins into DNA mimetics by lipid peroxidation. [ABSTRACT FROM AUTHOR]

Abstract: Isoketals (IsoKs) are γ-ketoaldehydes formed via the isoprostane pathway of arachidonic acid peroxidation and are among the most reactive by-products of lipid peroxidation. IsoKs selectively adduct to protein lysine residues and are highly cytotoxic, but the targets and molecular events involved in IsoK-induced cell death are poorly defined. Our previous work established that physiologically relevant aldehydes induce mitochondrial dysfunction (Kristal et al., J. Biol. Chem. 271:6033–6038; 1996). We therefore examined whether IsoKs induced mitochondrial dysfunction. Incubation of mitochondria with synthetic IsoKs in the presence or absence of Ca2+ was associated with alterations in mitochondrial respiration, membrane potential (ΔΨ), and pyridine nucleotide redox state. IsoKs dose dependently (0.5–4µM) accelerated liver mitochondria swelling induced by low concentrations of Ca2+ and Zn2+ or by the prooxidant tert-butylhydroperoxide, and release of cytochrome c, with similar observations in heart/brain mitochondria. The mitochondrial permeability transition (mPT) inhibitor cyclosporine A delayed IsoK-induced mitochondria dysfunction. The actions of IsoKs are consistent with interactions with cytochrome c, a protein rich in lysine residues. Direct reaction of IsoKs with select lysines in cytochrome c was demonstrated using high-resolution mass spectrometry. Overall, these results suggest that IsoKs may, in part, mediate their cytotoxic effects through induction of the mPT and subsequent activation of downstream cell death cascades. [Copyright &y& Elsevier]

Oxidation of arachidonic acid leads to the formation of highly reactive γ-ketoaldehydes now termed isoketals. Isoketals react with proteins at a rate that far exceeds other well studied products of lipid peroxidation such as 4-hydroxynonenal and demonstrate a remarkable proclivity to crosslink these proteins. For these reasons, isoketals have the potential to significantly alter protein function and contribute to disease processes. This article reviews the chemistry of isoketal formation, of their adduction to proteins, and of their proclivity to crosslink proteins, as well as their effects on protein function, and their potential role in diseases associated with oxidative injury. [Copyright &y& Elsevier]