Biomedical subjects

Zhibin Chen

Publications and source records attributed to Zhibin Chen.

17 recordsLinked to original sources

PubMed2007

Mitochondrial rRNA and tRNA and hearing function.

The human ear is a delicate sensory apparatus of hearing for normal communication, and its proper functioning is highly dependent on mitochondrial oxidative phosphorylation. The first mitochondrial point mutation for nonsyndromic and aminoglycoside-induced hearing loss was identified in 1993. Since then a number of inherited mitochondrial mutations have been implicated in hearing loss. Most of the molecular defects responsible for mitochondrial disorder-associated hearing loss are mutations in the 12S rRNA gene and tRNA genes. In this review, after a short description of normal hearing mechanisms and mitochondrial genetics, we outline the recent advances that have been made in the identification of deafness-associated mitochondrial mutations, and discuss how mitochondrial dysfunction contributes to hearing loss.

Aminoglycosides↗

PubMed2006

Clinical and genetic features in a Chinese pedigree with autosomal dominant auditory neuropathy.

BACKGROUND: A variety of processes and etiologies are thought to be involved in the pathophysiology of auditory neuropathy (AN). However, little is known about the clinical and molecular characteristics of hereditary AN. OBJECTIVE: To explore the clinical and genetic findings of a Chinese family with AN. METHODS: Seven patients in three consecutive generations of the pedigree were selected. Detailed history collection, physical examination, and audiological evaluations including pure-tone audiometry, acoustic immittance, auditory brainstem responses, cochlear microphonics, and evoked otoacoustic emissions, and mitochondrial DNA analysis were performed. RESULTS: All subjects involved are offspring of a female ancestor in the pedigree. In 6 of them, the hearing impairment started before the age of 9. Audiograms showed bilateral, symmetric, and profound deafness. Other audiological examinations revealed absent acoustic reflexes and auditory brainstem responses, and preserved evoked otoacoustic emissions and cochlear microphonics. One subject was characterized by normal audiological findings except high-frequency hearing loss with later onset. Hearing deterioration was found in 2 subjects who were followed for 26 months. Physical examination and mitochondrial DNA analysis yielded normal results. CONCLUSIONS: Clinical features in the pedigree are consistent with type II AN. Pedigree analysis and molecular findings indicate an autosomal dominant inheritance.

Adolescent↗

PubMed2006

Modeling CTLA4-linked autoimmunity with RNA interference in mice.

The CTLA4 gene is important for T lymphocyte-mediated immunoregulation and has been associated with several autoimmune diseases, in particular, type 1 diabetes. To model the impact of natural genetic variants of CTLA4, we constructed RNA interference (RNAi) "knockdown" mice through lentiviral transgenesis. Variegation of expression was observed in founders but proved surmountable because it reflected parental imprinting, with derepression by transmission from male lentigenics. Unlike the indiscriminate multiorgan autoimmune phenotype of the corresponding knockout mice, Ctla4 knockdown animals had a disease primarily focused on the pancreas, with rapid progression to diabetes. As with the human disease, the knockdown phenotype was tempered by genetic-modifier loci. RNAi should be more pertinent than gene ablation in modeling disease pathogenesis linked to a gene-dosage variation.

Animals↗

PubMed2006

Mitochondrial 12S rRNA A827G mutation is involved in the genetic susceptibility to aminoglycoside ototoxicity.

We have analyzed the clinical and molecular characterization of a Chinese family with aminoglycoside-induced and non-syndromic hearing impairment. Clinical evaluations revealed that only those family members who had a history of exposure to aminoglycoside antibiotics subsequently developed hearing loss, suggesting mitochondrial genome involvement. Sequence analysis of the mitochondrial 12S rRNA and tRNA(Ser(UCN)) genes led to the identification of a homoplasmic A827G mutation in all maternal relatives, a mutation that was identified previously in a few sporadic patients and in another Chinese family with non-syndromic deafness. The pathogenicity of the A827G mutation is strongly supported by the occurrence of the same mutation in two independent families and several genetically unrelated subjects. The A827G mutation is located at the A-site of the mitochondrial 12S rRNA gene which is highly conserved in mammals. It is possible that the alteration of the tertiary or quaternary structure of this rRNA by the A827G mutation may lead to mitochondrial dysfunction, thereby playing a role in the pathogenesis of hearing loss and aminoglycoside hypersensitivity. However, incomplete penetrance of hearing impairment indicates that the A827G mutation itself is not sufficient to produce clinical phenotype but requires the involvement of modifier factors for the phenotypic expression. Indeed, aminoglycosides may contribute to the phenotypic manifestation of the A827G mutation in this family. In contrast with the congenital or early-onset hearing impairment in another Chinese family carrying the A827G mutation, three patients in this pedigree developed hearing loss only after use of aminoglycosides. This discrepancy likely reflects the difference of genetic backgrounds, either mitochondrial haplotypes or nuclear modifier genes, between two families.

Aminoglycosides↗

PubMed2006

Maternally inherited non-syndromic hearing loss associated with mitochondrial 12S rRNA A827G mutation in a Chinese family.

We explored the clinical and molecular characterization of a Chinese family with non-syndromic hearing impairment. Clinical evaluations revealed a possible maternal inheritance pattern, and showed an extremely similar phenotype of hearing loss including the age of onset, severity, and audiometric configuration. Sequence analysis of the mitochondrial 12S rRNA and tRNA(Ser(UCN)) genes led to the identification of a homoplasmic A827G mutation in all maternal relatives, which was absent in other family members and 40 Chinese controls. This mutation has previously been reported sporadically in a few individuals with aminoglycoside-induced and non-syndromic hearing loss. The A827G mutation is located at the A-site of the mitochondrial 12S rRNA gene which is highly evolutionarily conserved in mammals. The occurrence of the A827G mutation in these genetically unrelated subjects strongly suggests that this mutation is involved in the pathogenesis of hearing impairment. However, incomplete penetrance of hearing loss indicates that the A827G mutation alone is not sufficient to produce clinical phenotype but requires the involvement of modifier factors for the phenotypic expression, even though aminoglycosides and GJB2 gene may not contribute to the penetrance of the A827G mutation in this Chinese family. In contrast with the variable phenotype of hearing loss associated with other mitochondrial mutations, all of the patients in our family exhibited strikingly similar clinical features. This discrepancy likely reflects the difference of genetic backgrounds between this pedigree and others.

Asian People↗

PubMed2006

Effect of antisense FosB and CREB on the expression of prodynorphin gene in rats with levodopa-induced dyskinesias.

The effects of antisense FosB and CREB intra-striatum injection on the expression of prodynorphin (PDyn) gene in striatal neurons of Levodopa-induced dyskinesias (LID) rats with Parkinson disease (PD) were explored. PD model in rats was established by 6-OHDA microinjection stereotaxically. The rats were treated with chronic intermittent Levodopa celiac injection for 28 days to get the LID rats. Antisense FosB and cAMP response element-binding protein (CREB) were injected into striatum of all rats respectively. In situ hybridization was used to measure the changes in the expression of PDyn mRNA in striatum and behavior changes were observed. The results showed after administration of antisense FosB, abnormal involuntary movement (AIM) was decreased and the expression of PDyn mRNA in striatum was increased in LID rats as compared with sense FosB group (P<0.01, respectively). As compared with the control group, the expression of PDyn mRNA in striatum was decreased by antisense CREB-treated LID group (P<0.01) and compared with sense CREB treated LID group, antisense CREB-treated LID group showed no changes in AIM scores and the expressions of PDyn mRNA (both P>0.05). In conclusion, FosB protein, which replaced the CREG, could regulate the expression of PDyn mRNA and play critical role in the pathogenesis of LID.

Animals↗

PubMed2005

Where CD4+CD25+ T reg cells impinge on autoimmune diabetes.

Foxp3 is required for the generation and activity of CD4(+)CD25(+) regulatory T (T reg) cells, which are important controllers of autoimmunity, including type-1 diabetes. To determine where T reg cells affect the diabetogenic cascade, we crossed the Foxp3 scurfy mutation, which eliminates T reg cells, with the BDC2.5 T cell receptor (TCR) transgenic mouse line. In this model, the absence of T reg cells did not augment the initial activation or phenotypic characteristics of effector T cells in the draining lymph nodes, nor accelerate the onset of T cell infiltration of the pancreatic islets. However, this insulitis was immediately destructive, causing a dramatic progression to overt diabetes. Microarray analysis revealed that T reg cells in the insulitic lesion adopted a gene expression program different from that in lymph nodes, whereas T reg cells in draining or irrelevant lymph nodes appeared very similar. Thus, T reg cells primarily impinge on autoimmune diabetes by reining in destructive T cells inside the islets, more than during the initial activation in the draining lymph nodes.

Animals↗

PubMed2005

How defects in central tolerance impinge on a deficiency in regulatory T cells.

Both central (thymic) and peripheral (nonthymic) mechanisms are important for the induction and maintenance of T cell tolerance. Mice with a defect in Foxp3, required for the generation and activity of CD4(+)CD25(+) regulatory T cells, exhibit massive lymphoproliferation and severe inflammatory infiltration of multiple organs, in particular the lungs, liver, and skin. We have explored how this phenotype is influenced by an additional defect in central tolerance induction, generated by either crossing in a null mutation of the Aire gene or substituting the nonobese diabetic (NOD) genetic background. The double-deficient mice had fulminant autoimmunity in very early life and a gravely shortened lifespan vis-à-vis single-deficient littermates. They showed massive lymphoproliferation and exacerbated inflammatory damage, particularly in the lungs and liver. Yet, the range of affected sites was not noticeably extended, and, surprisingly, many organs, or regions of organs, remained untouched, suggesting additional important mechanisms to enforce immunological self-tolerance.

Animals↗

PubMed2005

The cellular mechanism of Aire control of T cell tolerance.

Aire promotes the tolerization of thymocytes by inducing the expression of a battery of peripheral-tissue antigens in thymic medullary epithelial cells. We demonstrate that the cellular mechanism by which Aire exerts its tolerance-promoting function is not primarily positive selection of regulatory T cells, but rather negative selection of T effector cells. Surprisingly, supplementing its influence on the transcription of genes encoding peripheral-tissue antigens, Aire somehow enhances the antigen-presentation capability of medullary epithelial cells. Thus, this transcriptional control element promotes central tolerance both by furnishing a specific thymic stromal cell type with a repertoire of self antigens and by better arming such cells to present these antigens to differentiating thymocytes. In Aire's absence, autoimmunity and ultimately overt autoimmune disease develops.

Animals↗

PubMed2004

Feedback inhibition of leptin receptor/Jak2 signaling via Tyr1138 of the leptin receptor and suppressor of cytokine signaling 3.

Leptin is an adipocyte-derived hormone that communicates the status of body energy stores to the brain to regulate feeding and energy balance. The inability of elevated leptin levels to adequately suppress feeding in obesity suggests attenuation of leptin action under these conditions; the activation of feedback circuits due to high leptin levels could contribute to this leptin resistance. Using cultured cells exogenously expressing the long form of the leptin receptor (LRb) or an erythropoietin receptor/LRb chimera, we show that chronic stimulation results in the attenuation of LRb signaling and the establishment of a state in which the receptor is refractory to reactivation. Mutation of LRb Tyr1138 (the site that recruits signal transducer and activator of transcription 3) alleviated this feedback inhibition, suggesting that signal transducer and activator of transcription 3 mediates the induction of a feedback inhibitor, such as suppressor of cytokine signaling 3 (SOCS3), during chronic LRb stimulation. Indeed, manipulation of the expression or activity of the LRb-binding tyrosine phosphatase, SH2-domain containing phosphatase-2, by overexpression of wild-type and dominant negative isoforms or RNA interference-mediated knockdown did not alter the attenuation of LRb signals. In contrast, SOCS3 overexpression repressed LRb signaling, whereas RNA interference-mediated knockdown of SOCS3 resulted in increased LRb signaling that was not attenuated during chronic ligand stimulation. These data suggest that Tyr1138 of LRb and SOCS3 represent major effector pathways for the feedback inhibition of LRb signaling. Furthermore, we show that mice expressing an LRb isoform mutant for Tyr1138 display increased activity of the leptin-dependent growth and immune axes, suggesting that Tyr1138-mediated feedback inhibition may regulate leptin sensitivity in vivo.

Animals↗

PubMed2004

Experimental study on the PAR-1 expression around hemotoma following intracerebral hemorrhage in rats.

In order to explore the PAR-1 mRNA and protein expression around hemotoma following intracerebral hemorrhage and the relation between the PAR-1 expression and thrombin, collagenase VII was stereotaxically injected into right caudate nucleus in rats. The PAR-1 mRNA expression was detected by RT-PCR method and the PAR-1 protein expression by immunohistochemical method respectively. It was found that the PAR-1 mRNA and protein expression around hemotoma was increased at 6 h after intracerebral hemorrhage (P<0.05), peaked at 2 days (P<0.01), and then declined. The change pattern of the PAR-1 mRNA and protein expression was similar to that of intracerebral hemorrhage after thrombin intracerebral injection. The PAR-1 mRNA and protein expression in hirudin group showed no significant difference with control group. These results indicated that the PAR-1 mRNA and protein expression were markedly increased after intracerebral hemorrhage, which may be closely related to thrombin. Upregulation of the PAR-1 expression may involve in neurotoxic injury induced by thrombin.

Animals↗

PubMed2004

Estrogen receptor-alpha gene polymorphisms in patients with periodontitis.

BACKGROUND: Recent studies have shown that estrogen receptor-alpha (ER-alpha) gene polymorphisms are associated with alterations in bone mineral density and osteoporosis. It is unclear whether ER-alpha gene polymorphisms are associated with alveolar bone loss in patients with periodontitis. OBJECTIVE: The aim of this study was to investigate the relationship between ER-alpha gene polymorphisms and periodontitis. METHODS: Ninety patients with aggressive periodontitis, 34 patients with chronic periodontitis and 91 healthy controls were recruited in this study. All these subjects belonged to the Han Chinese race. DNA was extracted from peripheral blood of each subject. The ER-alpha gene was analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) with PvuII and XbaI restriction endonucleases. RESULTS: The detection frequency of XX genotype was significantly higher in the chronic periodontitis patients than in the healthy controls (11.8% vs. 4.4%, p < 0.05). The difference between the female chronic periodontitis patients and healthy controls (26.7% vs. 2.1%, p < 0.01) was statistically significant, but no difference was found between the male patients and controls (p > 0.05). The detection frequency of PvuII ER genotypes was not statistically different among the three groups (p > 0.05). CONCLUSIONS: In female Han Chinese population, the XX genotype may be a risk indicator for chronic periodontitis.

Acute Disease↗

PubMed2003

[Calprotectin and total protein in gingival crevicular fluid during experimental gingivitis].

OBJECTIVE: To measure GCF calprotectin and total protein for evaluating whether the calprotectin could be a sensitive marker for the initial inflammation of gingiva. METHODS: Eleven young male subjects with healthy gingiva, who had no systemic diseases, were selected for this study. GCF samples (4 teeth /person) were collected with strips of filter paper at baseline (0 day), on the 7 th, 14 th, 21 st days (without oral hygiene), and 28 th day (7 days after reestablishing oral hygiene) during experimental gingivitis. The amount of calprotectin was measured by ELISA. The amount of total protein was assessed with protein-dye binding assay. RESULTS: The amount of calprotectin increased during the experimental gingivitis, and reached the highest level on the 21 st day. After oral hygiene was reestablished it reduced to the level of baseline. The amount of total protein had the same tendency as calprotectin. CONCLUSION: The amount of calprotectin and the total protein in GCF can reflect the initial inflammation of gingiva.

Adult↗

PubMed2003

Paradoxical dampening of anti-islet self-reactivity but promotion of diabetes by OX40 ligand.

Costimulatory signals received by diabetogenic T cells during priming by or upon secondary encounter with autoantigen are decisive in determining the outcome of autoimmune attack. The OX40-OX40 ligand (OX40L) costimulatory pathway is known to influence T cell responses, prompting us to examine its role in autoimmune diabetes. A null allele at OX40L completely prevented diabetes development in nonobese diabetic mice and strongly reduced its incidence in a TCR transgenic model (BDC2.5). However, somewhat paradoxically, the initial activation of T cells responsive to islet beta cell Ag was slightly faster and more efficient in the absence of OX40L, with an increased degree of cell proliferation and survival in the deficient hosts. Activated T cell migration into and retention within the islets was also slightly accelerated. When challenged in vitro, splenocytes from BDC2.5.OX40L(o/o) mice showed no altered reactivity to exogenously added peptide, no bias to the Th1 or Th2 phenotype, and no alteration in T cell survival. Thus, the OX40/OX40L axis has the paradoxical effect of dampening the early activation and migration of autoimmune T cells, but sustains the long-term progression to autoimmune destruction.

Adoptive Transfer↗

PubMed2003

[Simultaneous posterior and horizontal canal benign paroxysmal positional vertigo].

OBJECTIVE: To explore effective methods for the diagnosis and treatment of simultaneous posterior and horizontal canal benign paroxysmal positional vertigo (combined BPPV, C-BPPV). METHOD: Epley's maneuver and Barbecue rotation were applied to four cases of C-BPPV separately with an interval of one day. RESULTS: Positional vertigo in all subjects disappeared completely after treatment and yielded excellent resolution of symptoms during period of follow-up. CONCLUSION: Clinical features in C-BPPV are combinations of both posterior and horizontal canal BPPV. Combined particle repositioning procedures of Epley's maneuver and Barbecue rotation is a successful method for treating the disorder.

Adult↗

PubMed2002

Projection of an immunological self shadow within the thymus by the aire protein.

Humans expressing a defective form of the transcription factor AIRE (autoimmune regulator) develop multiorgan autoimmune disease. We used aire- deficient mice to test the hypothesis that this transcription factor regulates autoimmunity by promoting the ectopic expression of peripheral tissue- restricted antigens in medullary epithelial cells of the thymus. This hypothesis proved correct. The mutant animals exhibited a defined profile of autoimmune diseases that depended on the absence of aire in stromal cells of the thymus. Aire-deficient thymic medullary epithelial cells showed a specific reduction in ectopic transcription of genes encoding peripheral antigens. These findings highlight the importance of thymically imposed "central" tolerance in controlling autoimmunity.

Aging↗

PubMed2002

Analysis of N-terminal amino acid sequence of 12 000-protein in gingival crevicular fluid and its clinical significance.

OBJECTIVES: To study the essence of N-terminal amino acid sequence of 12 000-protein in gingival crevicular fluid (GCF). METHODS: GCF samples from patients with RPP and AP were collected. 12 000-protein was separated by SDS-PAGE and transformed to PVDF by electronic transformation. The aim band was cut to be analyzed in 491 Protein Sequencer. RESULTS: The first ten of N-terminal amino acid sequence of 12 000-protein in GCF was Met, Leu, Thr, Glu, Leu, Glu, Lys, Ala, Leu, Asn. Through checking up in MS-Edman, the sequence was similar to "Ca binding protein, MRP8" which is the light subunit of Calprotectin. CONCLUSIONS: Calprotectin is a major protein in granulocytes and monocytes, and is related to many inflammatory diseases, maybe served as a effective marker for evaluating the inflammation of periodontium.

Amino Acid Sequence↗