A/J and C57BL/6 J (B6) mice share a mutation in Cdh23 (ahl allele) and are characterized by age-related hearing loss. However, hearing loss occurs much earlier in A/J mice at about four weeks of age. Recent study has revealed that a mutation in citrate synthase (Cs) is one of the main contributors, but the mechanism is largely unknown. In the present study, we showed that A/J mice displayed more severe degeneration of hair cells, spiral ganglion neurons, and stria vascularis in the cochleae compared with B6 mice. Moreover, messenger RNA accumulation levels of caspase-3 and caspase-9 in the inner ears of A/J mice were significantly higher than those in B6 mice at 2 and 8 weeks of age. Immunohistochemistry localized caspase-3 expression mainly to the hair cells, spiral ganglion neurons, and stria vascularis in cochleae. In vitro transfection with Cs short hairpin RNA (shRNA) alone or cotransfection with Cs shRNA and Cdh23 shRNA significantly increased the levels of caspase-3 in an inner ear cell line (HEI-OC1). Finally, a pan-caspase inhibitor Z-VAD-FMK could preserve the hearing of A/J mice by lowering about 15 decibels of the sound pressure level for the auditory-evoked brainstem response thresholds. In conclusion, our results suggest that caspase-mediated apoptosis in the cochleae, which may be related to a Cs mutation, contributes to the early onset of hearing loss in A/J mice.
Follicular helper CD4+ T (TFH) cells are a specialized subset of effector T cells that play a central role in orchestrating adaptive immunity. TFH cells mainly promote germinal center (GC) formation, provide help to B cells for immunoglobulin affinity maturation and class-switch recombination of B cells, and facilitate production of long-lived plasma cells and memory B cells. TFH cells express the nuclear transcriptional repressor B cell lymphoma 6 (Bcl-6), the chemokine (C-X-C motif) receptor 5 (CXCR5), the CD28 family members programmed cell death protein-1 (PD-1) and inducible costimulator (ICOS) and are also responsible for the secretion of interleukin-21 (IL-21) and IL-4. Follicular regulatory CD4+ T (TFR) cells, as a regulatory counterpart of TFH cells, participate in the regulation of GC reactions. TFR cells not only express markers of TFH cells but also express markers of regulatory T (Treg) cells containing FOXP3, glucocorticoid-induced tumor necrosis factor receptor (GITR), cytotoxic T lymphocyte antigen 4 (CTLA-4), and IL-10, hence owing to the dual characteristic of TFH cells and Treg cells. ICOS, expressed on activated CD4+ effector T cells, participates in T cell activation, differentiation, and effector process. The expression of ICOS is highest on TFH and TFR cells, indicating it as a key regulator of humoral immunity. Multiple sclerosis (MS) is a severe autoimmune disease that affects the central nervous system and results in disability, mediated by autoreactive T cells with evolving evidence of a remarkable contribution from humoral responses. This review summarizes recent advances regarding TFH cells, TFR cells, and ICOS, as well as their functional characteristics in relation to MS.
Parkinson's disease (PD) is the second most common neurodegenerative disease in humans. The effect of Krüppel-like factor (KLF) 4 in PD is unknown. In this study, KLF4 was found to be increased in both a time-dependent manner and a dose-dependent manner in response to the incubation with 1-methyl-4-phenylpyridinium (MPP+) in human dopamine neuroblastoma M17 cells, suggesting a potential role in MPP + -induced neurotoxicity. Following experiments showed that overexpression of KLF4 in M17 cells promoted MPP + -induced oxidative stress, embodied by exacerbated reactive oxygen species, 4-hydroxy-2-nonenal, and protein carbonyls. Furthermore, overexpression of KLF4 slowed cell proliferation and promoted lactate dehydrogenase release. Conversely, inhibition of KLF4 in M17 cells attenuated MPP + -induced neurotoxicity. The expression of superoxide dismutase (SOD) 1 in both mRNA and protein levels was found to be decreased by overexpressing KLF4, while increased by knockdown of KLF4. Moreover, promoter luciferase experiments showed that transcriptional activity on SOD1 was inhibited by KLF4. All the results indicated that KLF4 promoted the neurotoxicity of MPP + via inhibiting the transcription of SOD1, suggesting a potential mechanism of increased oxidative stress and cell death in Parkinson's disease.
Objectives To investigate the otoprotective effects of mouse nerve growth factor (mNGF) in A/J mice.Methods The mice at postnatal day 7 (P7) were randomly separated into a mNGF treated group (mNGF group) and a distilled water (for injection) treated group (control group). The mNGF dissolved in distilled water or distilled water alone was given to the mice once every other day from P7 by intramuscular injection in the hips. The otoprotective effects of mNGF in A/J mice were observed in a time course manner. The thresholds of auditory-evoked brainstem response (ABR) were tested from the age of the 3rd to the 8th week. Sections of the inner ears were stained by hematoxylin and eosin, and spiral ganglion neurons (SGNs) were observed at the age of the 3rd, the 6th,and the 8th week. Counts of whole mount outer hair cells (OHCs) in the cochleae were made at the age of 8 weeks. Expression of apoptosis related genes was determined by quantitative real-time polymerase chain reaction and Western blotting.Results ABR thresholds of the mNGF group were significantly lower than those of the control group at the age of the 6th and the 8th week. Moreover, the mNGF preserved OHC and SGN in the mouse cochleae in this period. Further experiments showed that the expression of caspase genes (including caspase-3) was inhibited in the mouse inner ears in the mNGF group.Conclusion The mNGF improves hearing in A/J mice by preserving SGN and OHC in the cochleae.
α-Synuclein (α-syn) aggregation has far-reaching implications in the pathogenesis of Parkinson's disease, and the levels of α-syn protein determine its neurotoxic potential. However, the intrinsic pathway of α-syn accumulation and the mode of α-syn degradation remain contentious. Following a stereotactic infusion of rotenone into the substantia nigra and the ventral tegmental area, the chronic rat model of Parkinson's disease was established successfully. In response to the rotenone, increased intracellular α-syn levels and autophagic flux monitored by LC3 II turnover were induced in dopaminergic neurons (TH-positive) of rat substantia nigra and ventral tegmental area. In the cytoplasm, increased immune response of LC3 colocalized with α-syn on the basis of rotenone-mediated neurotoxicity. The immunoreactivity for p62, an adaptor of the autophagy, was upregulated in the cytoplasm and nucleus. The enhancement of autophagy by valproate acid decreased rotenone-induced α-syn aggregation, whereas the inhibition of autophagy by 3-methyladenine increased α-syn aggregation. In addition, the expression of bcl-2 was reduced in rotenone-induced neurotoxicity, accompanied by the enhancement of autophagy. Small interfering RNA-mediated knockdown of bcl-2 expression facilitated the expression of p62 protein and autophagy. Moreover, the inhibition of bcl-2 increased rotenone-based α-syn aggregation. In short, in rotenone-based models, dowregulation of bcl-2 negatively controlled rotenone-induced autophagy and α-syn aggregation.
Mouse models of Parkinson's disease were established by oral rotenone administration and reproduced some of the features of dopaminergic neuronal degeneration. Roscovitine protects against rotenone-induced parkinsonism.
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