We report a novel mutation (erlong, erl) of the cadherin 23 (Cdh23) gene in a mouse model for DFNB12 characterized by progressive hearing loss beginning from post-natal day 27 (P27). Genetic and sequencing analysis revealed a 208T>C transition causing an amino acid substitution (70S-P). Caspase expression was up-regulated in mutant inner ears. Hearing was preserved (up to 35-dB improvement) in pan-caspase inhibitor Z-VAD-FMK-treated mutants compared to untreated mutants (P < 0.05). Outer hair cell (OHC) loss in the cochleae of Z-VAD-FMK-treated mutants was significantly reduced compared to those of untreated mice. Thus, the erl mutation can lead to hearing loss through apoptosis. This is the first genetic mouse model of hearing loss shown to respond to otoprotective drug therapy. The short interval from initial hearing loss to deafness (P27-P90) makes this model ideal for screening and validating otoprotective drugs.
Streptococcus pneumoniae is the most common pathogen associated with otitis media. To examine the role of Toll-like receptor 2 (TLR2) in host defense against Streptococcus pneumoniae infection in the middle ear, wild-type (WT; C57BL/6) and TLR2-deficient (TLR2 ؊/؊ ) mice were inoculated with Streptococcus pneumoniae (1 ؋ 10 6 CFU) through the tympanic membrane. Nineteen of 37 TLR2 ؊/؊ mice showed bacteremia and died within 3 days after the challenge, compared to only 4 of 32 WT mice that died. Of those that survived, more severe hearing loss in the TLR2 ؊/؊ mice than in the WT mice was indicated by an elevation in auditory-evoked brain stem response thresholds at 3 or 7 days postinoculation. The histological pathology was characterized by effusion and tissue damage in the middle ear, and in the TLR2 ؊/؊ mice, the outcome of infection became more severe at 7 days. At both 3 and 7 days postchallenge, the TLR2 ؊/؊ mice had higher blood bacterial titers than the WT mice (P < 0.05), and typical bacteria were identified in the effusion from both ears of both mouse groups by acridine orange staining. Moreover, by 3 days postchallenge, the mRNA accumulation levels of NF-B, tumor necrosis factor alpha, interleukin 1, MIP1␣, Muc5ac, and Muc5b were significantly lower in the ears of TLR2 ؊/؊ mice than in WT mice. In summary, TLR2 ؊/؊ mice may produce relatively low levels of proinflammatory cytokines following pneumococcal challenge, thus hindering the clearance of bacteria from the middle ear and leading to sepsis and a high mortality rate. This study provides evidence that TLR2 is important in the molecular pathogenesis and host response to otitis media.Streptococcus pneumoniae, a gram-positive bacterium, is one of the two most common pathogens involved in acute middle ear infection, which frequently leads to acquired hearing loss and communication disorders in children (20). The first line of host defense against bacterial infection by the innate immune system is essentially initiated by Toll-like receptors (TLRs), family-pattern-recognition receptors that detect and respond to microbial ligands (3). TLR2 mediates host responses to gram-positive bacterial cell wall components such as peptidoglycan (PGN), lipoteichoic acids (LTA), and lipoproteins (1, 37). TLR2 may function as a regulator of inflammation, and abnormal immune inflammatory responses develop in the absence of TLR2. In humans, one mutation in the TLR2 gene results in an Arg753Gln polymorphism that predisposes individuals to life-threatening bacterial infections (22). TLR2-deficient (TLR2 Ϫ/Ϫ ) mice succumb to Mycobacterium tuberculosis infection (6) and are highly susceptible to Staphylococcus aureus infection (32). TLR2 Ϫ/Ϫ mice show delayed pneumococcal phagocytosis and impaired oxidative killing by granulocytes (17). Studies have also demonstrated that TLR2 participates in the mediation of the immune response in experimental pneumococcal meningitis (16,18) and that mice with a targeted disruption of the TLR2 gene are more susceptible to meningitis-induce...
Glioma is among the ten most common causes of cancer-related death and has no effective treatment for it, so we are trying to find a new target for anticancer treatment. This study investigates the different expression of SRPK1 as a novel protein in glioma, which can influence tumor cells biological characteristics in normoxic and hypoxic environment. The expression levels of SRPK1 protein in glioma cell lines transfected with siSRPK1 or not were examined using immunofluorescence, RT-PCR and Western blot analysis, respectively. The impact of SRPK1 on the biological characteristics of U251 cells was further studied using methylthiazol tetrazolium assays, flow cytometry, and Transwell invasion chamber assays. The results showed that knockdown of SRPK1 inhibited tumor cells growth, invasion and migration in normoxic condition, but portion of the effect could be reversed in hypoxia. SRPK1 expression was induced in glioma cells by DDP treated, but not TMZ, in both normoxia and hypoxia conditions. We propose SRPK1 as a new molecular player contributing to the early treatment of glioma.
Gliomas, the most common primary brain tumors, have low survival rates and poorly defined molecular mechanisms to target for treatment. Serine/arginine SR protein kinases 1 (SRPK1) can highly and specifically phosphorylate the SR protein found in many tumors, which can influence cell proliferation and angiogenesis. However, the roles and regulatory mechanisms of SRPK1 in gliomas are not understood. The aim of this study was to determine the functions and regulation of SRPK1 in gliomas. We found that SRPK1 inhibition induces early apoptosis and significantly inhibits xenograft tumor growth. Our results indicate that SRPK1 affects Akt and eIF4E phosphorylation, Bax and Bcl-2 activation, and HIF-1 and VEGF production in glioma cells. Moreover, transfection of SRPK1 siRNA strongly reduced cell invasion and migration by regulating the expression of MMP2 and MMP9 and significantly decreased the volume of tumors and angiogenesis. We show here that a strong link exists among SRPK1, Akt, eIF4E, HIF-1, and VEGF activity that is functionally involved in apoptosis, metastasis, and angiogenesis of gliomas under normoxic conditions. Thus, SRPK1 may be a potential anticancer target to inhibit glioma progression.
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