Safety Assessment of L-β-Aminoisobutyric Acid (L-BAIBA): Subchronic Toxicity Study in Sprague Dawley Rats

Shanmugasundaram, Devanand; Fan, Qiru; Wang, Mingru; Yi, Ronghua; Wang, Ou

doi:10.1177/10915818221094487

Cited by 5 publications

(3 citation statements)

References 19 publications

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“…Meanwhile, the concentration of L-BAIBA in circulation is negatively related to cardio-metabolic risk factors (Kitase et In addition, it is worthwhile noting that L-BAIBA has excellent pharmacological properties, such as stable property and convenient to store. These evidences suggest that L-BAIBA may be an excellent potential therapeutic agent, and due to its potential medicinal value, there have been toxicological and pharmacokinetic studies on L-BAIBA (Krieger et al 2022 ;Shanmugasundaram et al 2022).…”

Section: Discussionmentioning

confidence: 99%

β-aminoisobutyric Acid, a Metabolite of BCAA, Activates the AMPK/Nrf-2 Pathway to Prevent Ferroptosis and Ameliorates Lung Ischemia-Reperfusion Injury

Zhang

Guo

et al. 2023

Preprint

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Background: Lung ischemia-reperfusion injury is a serious clinical problem and there is no effective treatment. Ischemia-reperfusion (I/R) injury is always accompanied with changed branched chain amino acid (BCAA) metabolism. Enhancing BCAA metabolism can protect against ischemia-reperfusion injury. We believe that this phenomenon is related to bioactive molecules produced by BCAA metabolism. And, L-β-aminoisobutyric acid (L-BAIBA) is a metabolite of valine, a member of BCAA. Methods: Adult C57BL/6 mouse were treated with L-BAIBA (150mg/kg/day) in the drinking water for 10 consecutive days before lung L/R injury. Then, lung function indexes including pathology and respiratory function were detected. Potential mechanisms were delineated by molecular biology experiment analysis in A549 cells, including western blot or immunofluorescence staining or biochemical detection and so on. Results:We find that L-BAIBA can protects lung during I/R injury. Further studies show that L-BAIBA can up-regulate the expression of GPX4 and SLC7A11, thereby inhibit ferroptosis. The regulation of L-BAIBA on the expression of GPX4 and SLC7A11 depends on the Nrf-2 signaling pathway. Interfering Nrf-2 eliminates the protective effect of L-BAIBA. We further find that L-BAIBA regulates Nrf-2 by activating AMPK signaling pathway. Meanwhile, in the presence of compound c, the protective effects of L-BAIBA on lung I/R injury are blocked. Conclusion:Our study reveals that L-BAIBA can alleviate lung I/R injury by inhibiting ferroptosis, which is an promising therapeutic target candidate.

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Section: Discussionmentioning

confidence: 99%

β-aminoisobutyric Acid, a Metabolite of BCAA, Activates the AMPK/Nrf-2 Pathway to Prevent Ferroptosis and Ameliorates Lung Ischemia-Reperfusion Injury

Zhang

Guo

et al. 2023

Preprint

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“…It is also worthwhile noting that L-BAIBA has favorable pharmacological properties, such as stability and convenient storage. L-BAIBA, being a promising therapeutic agent, has been the subject of toxicological and pharmacokinetic studies (Krieger et al 2022 ; Shanmugasundaram et al 2022 ).…”

Section: Discussionmentioning

confidence: 99%

β-aminoisobutyrics acid, a metabolite of BCAA, activates the AMPK/Nrf-2 pathway to prevent ferroptosis and ameliorates lung ischemia-reperfusion injury

Zhang,

Li,

Guo

et al. 2023

Mol Med

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Background Lung ischemia-reperfusion (I/R) injury is a serious clinical problem without effective treatment. Enhancing branched-chain amino acids (BCAA) metabolism can protect against cardiac I/R injury, which may be related to bioactive molecules generated by BCAA metabolites. L-β-aminoisobutyric acid (L-BAIBA), a metabolite of BCAA, has multi-organ protective effects, but whether it protects against lung I/R injury is unclear. Methods To assess the protective effect of L-BAIBA against lung I/R injury, an animal model was generated by clamping the hilum of the left lung, followed by releasing the clamp in C57BL/6 mice. Mice with lung I/R injury were pre-treated or post-treated with L-BAIBA (150 mg/kg/day), given by gavage or intraperitoneal injection. Lung injury was assessed by measuring lung edema and analyzing blood gases. Inflammation was assessed by measuring proinflammatory cytokines in bronchoalveolar lavage fluid (BALF), and neutrophil infiltration of the lung was measured by myeloperoxidase activity. Molecular biological methods, including western blot and immunofluorescence, were used to detect potential signaling mechanisms in A549 and BEAS-2B cells. Results We found that L-BAIBA can protect the lung from I/R injury by inhibiting ferroptosis, which depends on the up-regulation of the expressions of GPX4 and SLC7A11 in C57BL/6 mice. Additionally, we demonstrated that the Nrf-2 signaling pathway is key to the inhibitory effect of L-BAIBA on ferroptosis in A549 and BEAS-2B cells. L-BAIBA can induce the nuclear translocation of Nrf-2. Interfering with the expression of Nrf-2 eliminated the protective effect of L-BAIBA on ferroptosis. A screening of potential signaling pathways revealed that L-BAIBA can increase the phosphorylation of AMPK, and compound C can block the Nrf-2 nuclear translocation induced by L-BAIBA. The presence of compound C also blocked the protective effects of L-BAIBA on lung I/R injury in C57BL/6 mice. Conclusions Our study showed that L-BAIBA protects against lung I/R injury via the AMPK/Nrf-2 signaling pathway, which could be a therapeutic target.

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“…In clinical applications, it is important to achieve drug efficacy without toxic side effects. A toxicological study showed that L-BAIBA can be delivered without adverse effects at 900 mg/kg/day for 90 days, which is the highest level tested ( 83 ). In addition, in human studies, approximately 2–20% Caucasians and 50% Asians were found to be deficient in AGXT2 ( 84 , 85 ), with high urinary D-BAIBA levels.…”

Section: Prospects Of Baiba Being Used As An Exercise Pill?mentioning

confidence: 99%

Signaling metabolite β-aminoisobutyric acid as a metabolic regulator, biomarker, and potential exercise pill

Yang

et al. 2023

Front. Endocrinol.

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Signaling metabolites can effectively regulate the biological functions of many tissues and organs. β-Aminoisobutyric acid (BAIBA), a product of valine and thymine catabolism in skeletal muscle, has been reported to participate in the regulation of lipid, glucose, and bone metabolism, as well as in inflammation and oxidative stress. BAIBA is produced during exercise and is involved in the exercise response. No side effect has been observed in human and rat studies, suggesting that BAIBA can be developed as a pill that confers the benefits of exercise to subjects who, for some reason, are unable to do so. Further, BAIBA has been confirmed to participate in the diagnosis and prevention of diseases as an important biological marker of disease. The current review aimed to discuss the roles of BAIBA in multiple physiological processes and the possible pathways of its action, and assess the progress toward the development of BAIBA as an exercise mimic and biomarker with relevance to multiple disease states, in order to provide new ideas and strategies for basic research and disease prevention in related fields.

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Safety Assessment of L-β-Aminoisobutyric Acid (L-BAIBA): Subchronic Toxicity Study in Sprague Dawley Rats

Cited by 5 publications

References 19 publications

β-aminoisobutyric Acid, a Metabolite of BCAA, Activates the AMPK/Nrf-2 Pathway to Prevent Ferroptosis and Ameliorates Lung Ischemia-Reperfusion Injury

β-aminoisobutyric Acid, a Metabolite of BCAA, Activates the AMPK/Nrf-2 Pathway to Prevent Ferroptosis and Ameliorates Lung Ischemia-Reperfusion Injury

β-aminoisobutyrics acid, a metabolite of BCAA, activates the AMPK/Nrf-2 pathway to prevent ferroptosis and ameliorates lung ischemia-reperfusion injury

Signaling metabolite β-aminoisobutyric acid as a metabolic regulator, biomarker, and potential exercise pill

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