Methylenetetrahydrofolate reductase deficiency alters cellular response after ischemic stroke in male mice

Abato, Jamie E; Moftah, Mahira; Cron, Greg O.; Smith, Patrice D.; Jadavji, Nafisa M.

doi:10.1080/1028415x.2020.1769412

Cited by 13 publications

(14 citation statements)

References 41 publications

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“…Cellular ROS level is closely linked to various bone diseases and increased ROS level induced by RANKL has been reported to enhance osteoclastogenesis 28,29 . It is tightly regulated by Nrf2, which can promote the expression of antioxidant enzymes such as HO1and NQO1 30 . We found that the inhibition of MAT2A increased the expression of Nrf2, further affecting the ROS level.…”

Section: Discussionmentioning

confidence: 63%

“…28,29 It is tightly regulated by Nrf2, which can promote the expression of antioxidant enzymes such as HO1and NQO1. 30 We found that the inhibition of MAT2A increased the expression of Nrf2, further affecting the ROS level. Interestingly, combined with the results of a quasitargeted metabolomics assay, glutathione metabolism was also changed by sh RNA-MAT2A.…”

Section: Discussionmentioning

confidence: 72%

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Inhibition of MAT2A suppresses osteoclastogenesis and prevents ovariectomy‐induced bone loss

et al. 2022

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Methionine adenosyltransferase II alpha (MAT2A) is the key enzyme to transform methionine and adenosine‐triphosphate (ATP) to S‐adenosylmethionine (SAM), a general methyl‐group donor in vitro. MAT2A has been reported to participate in the NF‐κB pathway and maintain the methylated modification, which also affects osteoclastogenesis. In this study, we found the expression of MAT2A was increased upon RANKL stimulation. Pharmacological inhibition of MAT2A by its selective inhibitor AG‐270 or genetic silencing by MAT2A‐shRNA suppressed osteoclast formation and function in vitro. In vivo treatment with the inhibitor AG‐270 also prevented OVX‐induced bone loss. Further study revealed that the inhibition of MAT2A affected osteoclast differentiation mainly by suppressing crucial transcription factors and reactive oxygen species induced by RANKL. A quasi‐targeted metabolomics assay performed by LC‐MS/MS indicated that SAM was reduced by MAT2A knockdown, and the administration of SAM partly rescued the effects of MAT2A inhibition on osteoclastogenesis. These findings revealed that MAT2A is crucial for osteoclastogenesis and might be a potential target for the treatment of osteoporosis attributed to osteoclast dysfunction.

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Section: Discussionmentioning

confidence: 63%

Section: Discussionmentioning

confidence: 72%

Inhibition of MAT2A suppresses osteoclastogenesis and prevents ovariectomy‐induced bone loss

et al. 2022

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“…After mice were habituated to the Midwestern University animal facility, mice were randomly assigned to control or vitamin B12 deficient groups and placed on diets for 4 weeks. At 18 months of age, ischemic stroke was induced in animals using the photothrombosis model (Abato et al 2020; Jadavji et al 2018; Jadavji et al 2017; Labat-gest & Tomasi 2013; Lee et al 2004); this corresponds to middle-age in humans (Flurkey et al 2007). The ischemic stroke damaged the sensorimotor cortex, which allows for motor function assessment.…”

Section: Methodsmentioning

confidence: 99%

Ischemic stroke and dietary vitamin B12 deficiency in old-aged females impaired motor function, increased ischemic damage size, and changed metabolite profiles in brain and cecum tissue

Poole

Jasbi

Pascual

et al. 2022

Preprint

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The global population is aging and the prevalence of age-related diseases, such as stroke, is predicted to increase. A vitamin B12 deficiency (vit. B12 def.) is common in the elderly, because of changes in metabolism. Clinical studies have reported that a vit. B12 def results in worse outcome after stroke, the mechanisms through which a vit. B12 def. changes the brain requires further investigation. This study investigated the role of vit. B12 def. on stroke outcome and mechanisms using aged female mice. Eighteen month old females were put on a control or vit. B12 def. diet for four weeks, after which an ischemic stroke was induced in the sensorimotor cortex. After damage, motor function was measured and animals were euthanized and tissues were collected for analysis. Vit. B12 def. animals had increased levels of total homocysteine in plasma and liver, choline levels were also increased in the liver. Vit. B12 def. had larger damage volume in brain tissue and more apoptosis. In the cecum, changes in creatinine and methylmalonic acid were observed in vit. B12 def animals, pathway analysis showed dysfunction in B12 transport. Analysis of mitochondrial metabolomics in brain tissue showed reduced levels of metabolites involved in the TCA cycle in vit. B12 def animals. Meanwhile, pathway analysis showed significant, widespread dysfunction in phenylalanine, tyrosine, and tryptophan biosynthesis. Motor function after stroke was impaired in vit. B12 def. animals. A dietary vitamin B12 deficiency impairs motor function through increased apoptosis and changes in mitochondrial metabolism in brain tissue.

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“…After mice were habituated to the Midwestern University animal facility, mice were randomly assigned to control or vitamin B12 deficient groups and placed on diets for 4 weeks. At 11 months of age, ischemic stroke was induced in animals using the photothrombosis model (Abato et al, 2020;Jadavji et al, 2018Jadavji et al, , 2017Labat-gest and Tomasi, 2013;Lee et al, 2004) this corresponds to middle aged in humans (Flurkey et al, 2007). The ischemic stroke damaged the sensorimotor cortex, which allows for motor function assessment.…”

Section: Experimental Designmentioning

confidence: 99%

“…Briefly, after mice were habituated to the Midwestern University animal facility for a period of one week, mice were randomly assigned to control or vitamin B12 deficient groups and placed on diets for 4 weeks. At 11 months of age, ischemic stroke was induced in animals using the photothrombosis model (10)(11)(12)(13)(14). The age of the mice corresponds to middle aged in humans (15).…”

Section: Experimental Designmentioning

confidence: 99%

Dietary vitamin B12 deficiency impairs motor function and changes neuronal survival and choline metabolism after ischemic stroke in middle aged male and female mice

Yahn

Wasek

Malysheva

et al. 2021

Preprint

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The majority of the population is growing older, in 2000, 10% of the total population of the world was over 60 years old and the proportion is projected to increase to 21% by 2050. Currently, ischemic stroke predominately affects the elderly. Nutrition is a modifiable risk factor for stroke, as people age their ability to absorb some nutrients decreases. A primary example is vitamin B12, most older adults are deficient in vitamin B12 because of changes in breakdown and absorption of the vitamin that take place during the aging process. Using a mouse model system, we investigated the role of vitamin B12 deficiency in ischemic stroke outcome and investigate mechanistic changes in ischemic versus non-ischemic brain tissue. At 10-weeks of age male and female C57Bl/6J mice were put on control or vitamin B12 deficient diets for 4-weeks prior to ischemic damage. At 14 weeks of age, we induced ischemic stroke in the sensorimotor cortex using the photothrombosis model. Animals were continued on diets for 4 weeks after damage. At 18 weeks of age, we assessed stroke outcome using the accelerating rotarod and forepaw placement tasks. After the collection of behavioral data, we euthanized animals and collected brain, blood, and liver tissues to assess histological and biochemical measurements. All animals maintained on the vitamin B12 deficient diet had increased levels of total homocysteine in plasma and liver tissue. Male and female mice maintained on a vitamin B12 deficient diet had impairments in balance and coordination on the accelerating rotarod compared to control diet animals after ischemic stroke. In ischemic brain tissue no difference between groups in lesion volume was observed. More neuronal survival was present in ischemic brain tissue of the vitamin B12 deficient group compared to controls. There were changes in choline metabolites in ischemic brain tissue as a result of diet and sex. In conclusion, the data presented in this study confirms that a vitamin B12 deficiency impacts motor function in older adult male and female mice after ischemic stroke. The mechanisms driving this change may be a result of neuronal survival and compensation in choline metabolism within the damaged brain tissue.

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Methylenetetrahydrofolate reductase deficiency alters cellular response after ischemic stroke in male mice

Cited by 13 publications

References 41 publications

Inhibition of MAT2A suppresses osteoclastogenesis and prevents ovariectomy‐induced bone loss

Inhibition of MAT2A suppresses osteoclastogenesis and prevents ovariectomy‐induced bone loss

Ischemic stroke and dietary vitamin B12 deficiency in old-aged females impaired motor function, increased ischemic damage size, and changed metabolite profiles in brain and cecum tissue

Dietary vitamin B12 deficiency impairs motor function and changes neuronal survival and choline metabolism after ischemic stroke in middle aged male and female mice

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