Bei Chen

Huazhong University of Science and Technology, Wuhan, Hubei, China

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Publications (5)13.7 Total impact

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    ABSTRACT: Mitochondrial DNA (mtDNA) mutations, especially deletions, have been suggested to play an important role in aging and degenerative diseases. In particular, the common deletion in humans and rats (4977bp and 4834bp deletion, respectively) has been shown to accumulate with age in post-mitotic tissues with high energetic demands. Among numerous deletions, the common deletion has been proposed to serve as a molecular marker for aging and play a critical role in presbyacusis. However, so far no previous publication has quantified the contribution of common deletion to the total burden of mtDNA deletions in tissues during aging process. In the present study, we established a rat model with various degrees of aging in inner ear induced by three different doses of d-galactose (d-gal) administration. Firstly, multiple mtDNA deletions in inner ear were detected by nested PCR and long range PCR. In addition to the common deletion, three novel mtDNA deletions were identified. All four deletions, located in the major arc of mtDNA, are flanked by direct repeats and involve the cytochrome c oxidase (COX) subunit III gene, encoded by mtDNA. Additionally, absolute quantitative real-time PCR assay was used to detect the level of common deletion and total deletion burden of mtDNA. The quantitative data show that the common deletion is the most frequent type of mtDNA deletions, exceeding 67.86% of the total deletion burden. Finally, increased mtDNA copy number, reduced COX activity and mosaic ultrastructural impairments in inner ear were identified in d-gal-induced aging rats. The increase of mtDNA replication may contribute to the accelerated accumulation of mtDNA deletions, which may result in impairment of mitochondrial function in inner ear. Taken together, these findings suggest that the common deletion may serve as an ideal molecular marker to assess the mtDNA damage in inner ear during aging.
    Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 07/2011; 712(1-2):11-9. · 3.90 Impact Factor
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    ABSTRACT: Oxidative damage to mtDNA is associated with excessive reactive oxygen species production. The mitochondrial common deletion (mtDNA 4977-bp and 4834-bp deletion in humans and rats, respectively) is the most typical and frequent form of mtDNA damage associated with aging and degenerative diseases. The accumulation of the mitochondrial common deletion has been proposed to play a crucial role in age-related hearing loss (presbycusis). However, the mechanisms underlying the formation and accumulation of mtDNA deletions are still obscure. In the present study, a rat mimetic aging model induced by D-Gal was used to explore the origin of deletion mutations and how mtDNA repair systems modulate this process in the inner ear during aging. We found that the mitochondrial common deletion was greatly increased and mitochondrial base excision repair capacity was significantly reduced in the inner ear in D-Gal-treated rats as compared with controls. The overexpression of mitochondrial transcription factor A induced by D-Gal significantly stimulated mtDNA replication, resulting in an increase in mtDNA copy number. In addition, an age-related loss of auditory sensory cells in the inner ear was observed in D-Gal-treated rats. Taken together, our data suggest that mitochondrial base excision repair capacity deficiency and an increase in mtDNA replication resulting from mitochondrial transcription factor A overexpression may contribute to the accumulation of mtDNA deletions in the inner ear during aging. This study also provides new insights into the development of presbycusis.
    FEBS Journal 05/2011; 278(14):2500-10. · 4.25 Impact Factor
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    ABSTRACT: Aging has been associated with mitochondrial DNA (mtDNA) common deletion (CD). Age changes in the central auditory system are well known to affect speech perception. Base excision repair (BER) is the major type of DNA repair in mitochondria. The current study was designed to investigate potential causative mechanisms of central presbycusis by using a rat mimetic aging model induced by subcutaneous administration of D-galactose (D-gal). Quantitative real-time PCR and Western blotting analyses were performed to identify the mtDNA 4834 bp deletion and selected mitochondrial DNA repair enzymes, DNA polymerase γ (pol γ) and 8-oxoguanine DNA glycosylase (OGG1). Cell apoptosis in the auditory cortex was detected using terminal deoxynucleotidyltransferase mediated UTP nick-end labeling (TUNEL). Our data showed that mtDNA 4834 bp deletion and TUNEL-positive cells were significantly increased and the expression of pol γ and OGG1 were remarkably down-regulated in the auditory cortex in D-gal-treated rats compared to control rats. During aging, increased mtDNA damage likely results from decreased DNA repair capacity in the auditory cortex. DNA repair enzymes such as pol γ and OGG1 may provide novel pharmacological targets to promote DNA repair and rescue the central auditory system in patients with degenerative diseases.
    Molecular Biology Reports 11/2010; 38(6):3635-42. · 2.51 Impact Factor
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    ABSTRACT: The protective roles of alpha-lipoic acid in the rat model of mitochondrial DNA (mtDNA) 4834bp deletion in inner ear were investigated. Forty female Wistar rats at 4 weeks of age were divided into four groups: group A (D-galactose group, n=10), group B (D-galactose+alpha-lipoic acid group, n=10), group C (alpha-lipoic acid group, n=10), and group D (control group, n=10). Auditory brainstem response (ABR) was used to detect the hearing threshold. Colorimetry was used to analyze activity of superoxide dismutase (SOD) and concentration of malondialdehyde (MDA). The percentage of mtDNA4834bp deletion in inner ear was identified by real-time PCR. There was no significant difference in ABR threshold shift among all groups. The percentage of mtDNA4834bp deletion in group A was higher than that in other groups, but there was no significant difference in percentage of mtDNA4834bp deletion among groups B, C, and D. The activity of SOD in group A was lower than that in other groups. The concentration of MDA in group A was higher than that in other groups. It was concluded that there was no significant hearing loss when the percentage of mtDNA4834bp deletion was lower than 12.5%. Alpha-lipoic acid could prevent the reactive oxygen species (ROS)-induced mtDNA4834bp deletion in inner ear of rats.
    Journal of Huazhong University of Science and Technology 08/2010; 30(4):514-8. · 0.58 Impact Factor
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    ABSTRACT: One of the most common complaints among aging individuals is difficulty in understanding speech in a compromised listening environment, such as when background noise is present. Age-related hearing loss (presbycusis) is associated with both peripheral and central neural processing deficits, as it occurs even in those with only a mild peripheral hearing impairment. The current study was designed to investigate potential causative mechanisms of this impairment by using a rat model in which presbycusis is inducible by administration of D-galactose (D-gal). One group of these rats was injected subcutaneously with 150 mg D-gal daily for 8 weeks, while control animals received vehicle only. These groups were compared to naturally aged rats (24 months) that had received no other treatment. Central auditory function of the three groups was evaluated by measuring the auditory brainstem response (ABR) and middle latency response (MLR). A TaqMan real time PCR assay was used to quantify a 4834-bp deletion in the mitochondrial DNA (mtDNA) of the auditory cortex (AC), inferior colliculus (IC) and cochlear nucleus (CN). We assessed changes in lipid peroxidation levels and apoptosis rates, and examined pathological changes corresponding to D-gal-induced aging and natural aging. Both groups of aged rats exhibited delayed ABR latencies (III, IV, V), MLR Pa latency, and I-IV interpeak latency. Moreover, increased mtDNA 4834 bp deletion rates, lipid peroxidation levels, rates of neuronal apoptosis and neurodegenerative changes in the AC, IC and CN were similar among the D-gal induced and NA rats. However, the threshold of ABR in the D-gal group showed no significant change from the control group. These observations suggest that age-related central auditory dysfunction and its corresponding pathological changes are present in both naturally aging rats and the D-gal mimetic aging model. Oxidative stress, large-scale mtDNA 4834 bp deletion, and apoptosis are likely to be involved in the progressive weakening of the central auditory system associated with the aging process.
    Brain research 07/2010; 1344:43-53. · 2.46 Impact Factor

Publication Stats

32 Citations
13.70 Total Impact Points

Institutions

  • 2010–2011
    • Huazhong University of Science and Technology
      • Department of Otorhinolaryngology, Head and Neck Surgery
      Wuhan, Hubei, China