Chronic mild Hyperhomocysteinemia impairs energy metabolism, promotes DNA damage and induces a Nrf2 response to oxidative stress in rats brain

Santos, Tiago Marcon dos; Siebert, Cassiana; Oliveira, Micaela Federizzi de; Manfredini, Vanusa; Wyse, Ângela T. S.

doi:10.1007/s10571-019-00674-8

Cited by 27 publications

(20 citation statements)

References 103 publications

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“…In our experiment, in the Met-C group was the level of Hcy increased 1.5-fold in comparison to the naïve control animals that matches the criteria for mild hHcy [ 35 , 36 ]. Dos Santos et al [ 37 ] demonstrated in their hHcy model (subcutaneous injection of DL-Hcy in the lower dose of 0.03 μmol/g of the body weight of male Wistar rats twice a day for 30 days that this dose increases rats Hcy plasma concentration, similarly described in the moderate hHcy patients. More importantly, Nuru et al [ 38 ] demonstrated that high Met diet (1.2%), low folate (0.08 mg/Kg) and low vitamin B6/B12 (0.01 mg/Kg; 10.4 μg/Kg) lead to significant neuronal damage which, interestingly precedes vascular dysfunction.…”

Section: Discussionmentioning

confidence: 91%

Effect of Methionine Diet on Time-Related Metabolic and Histopathological Changes of Rat Hippocampus in the Model of Global Brain Ischemia

et al. 2020

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Hyperhomocysteinemia (hHcy) represents a strong risk factor for atherosclerosis-associated diseases, like stroke, dementia or Alzheimer’s disease. A methionine (Met)-rich diet leads to an elevated level of homocysteine in plasma and might cause pathological alterations across the brain. The hippocampus is being constantly studied for its selective vulnerability linked with neurodegeneration. This study explores metabolic and histo-morphological changes in the rat hippocampus after global ischemia in the hHcy conditions using a combination of proton magnetic resonance spectroscopy and magnetic resonance-volumetry as well as immunohistochemical analysis. After 4 weeks of a Met-enriched diet at a dose of 2 g/kg of animal weight/day, adult male Wistar rats underwent 4-vessel occlusion lasting for 15 min, followed by a reperfusion period varying from 3 to 7 days. Histo-morphological analyses showed that the subsequent ischemia-reperfusion insult (IRI) aggravates the extent of the sole hHcy-induced degeneration of the hippocampal neurons. Decreased volume in the grey matter, extensive changes in the metabolic ratio, deeper alterations in the number and morphology of neurons, astrocytes and their processes were demonstrated in the hippocampus 7 days post-ischemia in the hHcy animals. Our results suggest that the combination of the two risk factors (hHcy and IRI) endorses and exacerbates the rat hippocampal neurodegenerative processes.

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Section: Discussionmentioning

confidence: 91%

Effect of Methionine Diet on Time-Related Metabolic and Histopathological Changes of Rat Hippocampus in the Model of Global Brain Ischemia

et al. 2020

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“…Recent studies on animal models of chronic HHcy showed inhibition of ETC complexes I, IV, and V in hippocampus [ 42 , 43 ], complex IV in amygdala [ 44 ], and complexes IV and V in cerebral cortex [ 42 ]. Complex II activity increased while complex IV activity decreased in amygdala of rats after chronic mild HHcy [ 45 ]. Studies showing ETC complex I inhibition, motor abnormalities, reduction of striatal dopamine level and degeneration of midbrain dopaminergic neurons in rats after infusion of Hcy into substantia nigra [ 46 ], and chronic Hcy treatment of mice [ 47 ] suggest involvement of Hcy-related dysfunction of ETC in Parkinson’s disease.…”

Section: Homocysteine and Mitochondrial Energy Metabolismmentioning

confidence: 99%

“…Similarly, acute treatment of neuron cells with high concentration of Hcy, which inhibited mitochondrial respiration, reduced the ROS level [ 54 ]. Moreover, ROS production and/or oxidative damage was unchanged in brain [ 45 ] and heart [ 36 ] of rats with chronic mild HHcy. As mentioned earlier, there are several potential mechanisms explaining how Hcy can modulate ROS production, including auto-oxidation of Hcy and altered gene expression and/or post-translational modifications of prooxidant/antioxidant proteins.…”

Section: Homocysteine and Mitochondrial Oxidative Stressmentioning

confidence: 99%

“…Interestingly, chronic HHcy in mice was associated with elevated activity of cytosolic Cu/ZnSOD and catalase in the nucleus caudatus putamen and substantia nigra [ 47 ]. Similarly, chronic mild HHcy in rats increased activities of SOD, catalase, and GPx in the amygdala and prefrontal cortex [ 45 ]. Increases in antioxidant defense in these tissues was associated with upregulation of Nrf2 (see below) and elimination of ROS production as detected by unchanged 2′,7′-dihydrodichlorofluorescein (DCFH) oxidation.…”

Section: Homocysteine and Mitochondrial Oxidative Stressmentioning

confidence: 99%

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Homocysteine and Mitochondria in Cardiovascular and Cerebrovascular Systems

Kaplán

Tatarková

Sivoňová

et al. 2020

IJMS

112

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Elevated concentration of homocysteine (Hcy) in the blood plasma, hyperhomocysteinemia (HHcy), has been implicated in various disorders, including cardiovascular and neurodegenerative diseases. Accumulating evidence indicates that pathophysiology of these diseases is linked with mitochondrial dysfunction. In this review, we discuss the current knowledge concerning the effects of HHcy on mitochondrial homeostasis, including energy metabolism, mitochondrial apoptotic pathway, and mitochondrial dynamics. The recent studies suggest that the interaction between Hcy and mitochondria is complex, and reactive oxygen species (ROS) are possible mediators of Hcy effects. We focus on mechanisms contributing to HHcy-associated oxidative stress, such as sources of ROS generation and alterations in antioxidant defense resulting from altered gene expression and post-translational modifications of proteins. Moreover, we discuss some recent findings suggesting that HHcy may have beneficial effects on mitochondrial ROS homeostasis and antioxidant defense. A better understanding of complex mechanisms through which Hcy affects mitochondrial functions could contribute to the development of more specific therapeutic strategies targeted at HHcy-associated disorders.

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“…Homocysteine can only be derived from the catabolism of methionine . Hyperhomocysteinemia is more pronounced in diabetic patients with concurrent renal, retinal or cardiovascular complications, diabetes‐related heart disease, and stroke . Homocysteine has become an important diagnostic molecule for diabetes, and it is of great significance to develop Hcy compounds with potential clinical application value.…”

Section: Discussionmentioning

confidence: 99%

A compound reflects the level of homocysteine based on Rhodamine B and its ability to respond to homocysteine in the plasma of diabetic patients

Zhao

Cheng

Zhu

2020

Clinical Laboratory Analysis

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Background:The level of homocysteine (Hcy) is significantly elevated in the plasma of patients with diabetes. The increased plasma Hcy level is positively correlated with the severity of the disease and is one of the important causes of diabetic complications. Methods:We designed and synthesized a compound could reflect the level of Hcy based on rhodamine B, and the structure was verified by 1H-NMR and EI-HRMS.Then, the linearity, repeatability, selectivity, and cellar toxicity, the effects of the fluid viscosity and pH of compound on Hcy were measured; meanwhile, the response of Hcy level in the plasma of diabetic patients was detected.Results: This is a novel compound that has never been reported. The compound showed a satisfactory linear range and repeatability at the viscosity and pH of physiological fluid. In addition, the compound was capable of evading the interference from other amino acids and metal ions, and it exhibited high selectivity toward Hcy. Conclusion:The compound showed increased responsiveness to plasma Hcy in patients with diabetes in comparison with healthy individuals and effectively reflected plasma Hcy levels in healthy individuals and diabetic patients. Therefore, the compound is expected to be used in the diagnosis of diabetes mellitus. K E Y W O R D Sdiabetic patients, homocysteine, rhodamine B

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Chronic mild Hyperhomocysteinemia impairs energy metabolism, promotes DNA damage and induces a Nrf2 response to oxidative stress in rats brain

Cited by 27 publications

References 103 publications

Effect of Methionine Diet on Time-Related Metabolic and Histopathological Changes of Rat Hippocampus in the Model of Global Brain Ischemia

Effect of Methionine Diet on Time-Related Metabolic and Histopathological Changes of Rat Hippocampus in the Model of Global Brain Ischemia

Homocysteine and Mitochondria in Cardiovascular and Cerebrovascular Systems

A compound reflects the level of homocysteine based on Rhodamine B and its ability to respond to homocysteine in the plasma of diabetic patients

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