Publications by authors named "Wenxue Tang"

44 Publications

High Genetic Heterogeneity in Chinese Patients With Waardenburg Syndrome Revealed by Next-Generation Sequencing.

Front Genet 2021 4;12:643546. Epub 2021 Jun 4.

Precision Medicine Center, Academy of Medical Science, Zhengzhou University, Zhengzhou, China.

Objective: This study aimed to explore the genetic causes of probands who were diagnosed with Waardenburg syndrome (WS) or congenital sensorineural hearing loss.

Methods: A detailed physical and audiological examinations were carried out to make an accurate diagnosis of 14 patients from seven unrelated families. We performed whole-exome sequencing in probands to detect the potential genetic causes and further validated them by Sanger sequencing in the probands and their family members.

Results: The genetic causes for all 14 patients with WS or congenital sensorineural hearing loss were identified. A total of seven heterozygous variants including c.1459C > T, c.123del, and c.959-409_1173+3402del of gene (NM_181459.4), c.198_262del and c.529_556del of gene (NM_006941.4), and c.731G > A and c.970dup of gene (NM_000248.3) were found for the first time. Of these mutations, we had confirmed two (c.1459C > T and c.970dup) are by Sanger sequencing of variants in the probands and their parents.

Conclusion: We revealed a total of seven novel mutations in , , and , which underlie the pathogenesis of WS. The clinical and genetic characterization of these families with WS elucidated high heterogeneity in Chinese patients with WS. This study expands the database of , , and mutations and improves our understanding of the causes of WS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fgene.2021.643546DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8212959PMC
June 2021

Neuroprotective effect of stroke pretreated MSCs against cerebral ischemia/reperfusion injury in rats.

World Neurosurg 2021 May 3. Epub 2021 May 3.

Department of General Medicine, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, China. Electronic address:

Background: Mesenchymal stem cells (MSCs) have been shown to enhance neurological recovery after stroke. In this study, a middle cerebral artery occlusion (MCAO) rat model was designed to assess the neuroprotective effects of stroke pretreated MSCs on cerebral ischemia/reperfusion (I/R) injury.

Method: The MSCs were isolated and cultured in medium with 10% FBS, normal control serum (NS), or stroke serum (SS). Then these MSCs were injected into each group rats (n=6) 1 day after MCAO and continue feeding for 28 days. A battery of behavioral tests, TTC staining, hematoxylin and eosin staining, ELISA, and TUNEL assay were used to assess neural injury. Moreover, in order to detected the enhancement of neuronal regeneration and angiogenesis, immunofluorescence and western blotting were performed to assess the expression of trophic factor and growth factor.

Result: After treatment, the behaviour was improvement significantly. And the infarct area, brain lesion, and apoptosis cells were significantly decreased in the SS-MSCs group than others. It also modulated the inflammation by attenuating inflammatory cytokines. In addition, the number of neurogenesis positive cells, the expression of trophic factors and growth factors were significantly higher in the SS-MSCs group than others. At the same time, FBS-MSCs and NS-MSCs showed differences in the expression of trophic factors and growth factors, but the results were not as well as SS-MSCs.

Conclusion: SS-MSCs administration after the reperfusion led to neuroprotection by improving pathological changes, behavioral improvement, neurogenesis, suppression of apoptosis and inflammatory as well as angiogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.wneu.2021.04.114DOI Listing
May 2021

Dynamics of binding ability prediction between spike protein and human ACE2 reveals the adaptive strategy of SARS-CoV-2 in humans.

Sci Rep 2021 02 4;11(1):3187. Epub 2021 Feb 4.

The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China.

SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is a novel coronavirus causing the COVID-19 pandemic in 2020. High adaptive plasticity on the spike protein of SASR-CoV-2 enables it to transmit across different host species. In the present study, we collected 2092 high-quality genome sequences of SARS-CoV-2 from 160 regions in over 50 countries and reconstructed their phylogeny. We also analyzed the polymorphic interaction between spike protein and human ACE2 (hACE2). Phylogenetic analysis of SARS-CoV-2 suggests that SARS-CoV-2 is probably originated from a recombination event on the spike protein between a bat coronavirus and a pangolin coronavirus that endows it humans infectivity. Compared with other regions in the S gene of SARS-CoV-2, the direct-binding sites of the receptor-binding domain (RBD) is more conserved. We focused on 3,860 amino acid mutations in spike protein RBD (T333-C525) of SARS-CoV-2 and simulated their differential stability and binding affinity to hACE2 (S19-D615). The results indicate no preference for SARS-CoV-2 infectivity on people of different ethnic groups. The variants in the spike protein of SARS-CoV-2 may also be a good indicator demonstrating the transmission route of SARS-CoV-2 from its natural reservoir to human hosts.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-021-82938-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862608PMC
February 2021

Auditory Neuropathy Spectrum Disorder (ANSD)-Clinical Characteristics and Pathogenic Variant Analysis of Three Nonsyndromic Deafness Families.

Biomed Res Int 2020 21;2020:8843539. Epub 2020 Dec 21.

Department of Otorhinolaryngology, Head and Neck Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.

Objective: To analyze the phenotypic features and pathogenic variants of three unrelated families presenting with nonsyndromic auditory neuropathy spectrum disorder (ANSD).

Methods: Three recruited families that were affected by congenital deafness were clinically evaluated, including a detailed family history and audiological and radiological examination. The peripheral blood of all patients and their parents was collected for DNA extraction, and then, the exonic and flanking regions were enriched and sequenced using targeted capture and high-throughput sequencing technology. Bioinformatics analyses and the Sanger sequencing were carried out to screen and validate candidate pathogenic variants. The pathogenicity of candidate variants was evaluated by an approach that was based on the standards and guidelines for interpreting genetic variants as proposed by the American College of Medical Genetics and Genomics (ACMG).

Results: Four patients in three families were diagnosed as nonsyndromic ANSD, and all exhibited gene mutations. Among them, two individuals in family 1 (i.e., fam 1-II-2 and fam 1-II-3) carried homozygous variants c.[2688del];[2688del] (NM_194248.3). Two individuals from family 2 (fam 2-II-1) and family 3 (fam 3-II-4) carried compound heterozygous variants c.[4960G>A];[1469C>G] and c.[2675A>G];[2977_2978del], respectively.

Conclusions: Three unrelated pedigrees with ANSD were caused by pathogenic variants in the gene. Five mutations were found and included c.2688del, c.2675A>G, c.2977_2978del, c.4960G>A, and c.1469C>G, of which the first two are novel and expanded mutational spectrum of the gene, thus having important implications for genetic counseling of the family.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2020/8843539DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772035PMC
May 2021

Treacher Collins syndrome: Clinical report and retrospective analysis of Chinese patients.

Mol Genet Genomic Med 2021 02 17;9(2):e1573. Epub 2020 Dec 17.

Department of Otorhinolaryngology, Head and Neck Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.

Background: Treacher Collins syndrome-1 (TCS1; OMIM# 154500) is a rare autosomal dominant disease that is defined by congenital craniofacial dysplasia. Here, we report four sporadic and one familial case of TCS1 in Chinese patients with clinical features presenting as hypoplasia of the zygomatic complex and mandible, downslanting palpebral fissures, coloboma of the lower eyelids, and conductive hearing loss.

Materials And Methods: Audiological, radiological, and physical examinations were performed. Targeted next-generation sequencing (NGS) was performed to examine the genetics of this disease in five probands, and Sanger sequencing was used to confirm the identified variants. A literature review discusses the pathogenesis, treatment, and prevention of TCS1.

Results: We identified a novel insertion of c.939_940insA (p.Gly314Argfs*35; NM_001135243.1), a novel deletion of c.1766delC (p.Pro589Leufs*7), two previously reported insertions of c.1999_2000insC (p.Arg667Profs*31) and c.4218_4219insG (p.Ser1407Valfs*23), and one previously reported deletion of c.4369_4373delAAGAA (p.Lys1457Glufs*12) in the TCOF1 gene. All five cases exhibited a degree of interfamilial and intrafamilial phenotypic variability. A review of the literature revealed no clear evidence of a genotype-phenotype correlation in TCS1.

Conclusion: Our results expand the variant spectrum of TCOF1 and highlight that NGS is essential for the diagnosis of TCS and that genetic counseling is beneficial for guiding prevention.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mgg3.1573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8077114PMC
February 2021

Early truncation of the N-terminal variable region of EYA4 gene causes dominant hearing loss without cardiac phenotype.

Mol Genet Genomic Med 2021 01 10;9(1):e1569. Epub 2020 Dec 10.

Precision Medicine Center, Academy of Medical Science, Zhengzhou University, Zhengzhou, China.

Background: Autosomal dominant hearing loss (ADHL) accounts for about 20% of all hereditary non-syndromic HL. Truncating mutations of the EYA4 gene can cause either non-syndromic ADHL or syndromic ADHL with cardiac abnormalities. It has been proposed that truncations of the C-terminal Eya domain lead to non-syndromic HL, whereas early truncations of the N-terminal variable region cause syndromic HL with cardiac phenotype.

Methods: The proband and all the other hearing impaired members of the family underwent a thorough clinical and audiological evaluation. The cardiac phenotype was examined by ECG and echocardiography. Their DNA was subjected to target exome sequencing of 129 known deafness genes. The sequencing data were analyzed and the candidate variants were interpreted following the ACMG guidelines for clinical sequence interpretation. The effect of candidate variant on EYA4 gene expression was assessed by quantitative PCR and western blot of gene production in blood.

Results: We report a Chinese family cosegregating post-lingual onset, progressive ADHL with a novel nonsense mutation NM_004100.4:c.543C>G (p.Tyr181Ter) of EYA4. Two affected members show no cardiac abnormalities at least until now revealed by electrocardiography and echocardiography. The overall expression level of the EYA4 gene in the proband was lower than that in his unaffected relative.

Conclusion: This report expands the mutational spectrum of the EYA4 gene and highlights the fact that more data are needed to elucidate the complex genotype-phenotype correlation of EYA4 mutations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mgg3.1569DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7963430PMC
January 2021

Development of MOF "Armor-Plated" Phycocyanin and Synergistic Inhibition of Cellular Respiration for Hypoxic Photodynamic Therapy in Patient-Derived Xenograft Models.

Adv Healthc Mater 2021 02 4;10(3):e2001577. Epub 2020 Dec 4.

Department of Radiation Oncology, the Second Clinical Medical College of Jinan University, 1st Affiliated Hospital of Southern University of Science and Technology, Shenzhen People's Hospital, Shenzhen, 518020, China.

Significant progress has been made in the use of phycocyanin (PC) as a photosensitizer (PS) agent for photodynamic therapy (PDT). The clinical use of PC, however, has been limited by its poor stability, unfavorable pharmacokinetics, limited tumor cell uptake, and the hypoxic nature of the tumor microenvironment. In this study, a novel biomimetic mineralization approach is described for encapsulating PC using zeolitic imidazolate framework-8 (ZIF-8), after which MPEG -COOH is further utilized as an anchor on the ZIF/PC complex in order to yield MPEG -ZIF/PC composites (PMs). These PMs are then used as a stable reinforced PS for PDT, effectively improving the intracellular delivery of this protein PS. In contrast to prior studies that have sought to overcome intratumoral hypoxia via increasing oxygen delivery to the tumor site, the mitochondrial complex I inhibitor papaverine (PPV) is instead utilized to reduce intratumor oxygen consumption in an effort to augment the PDT efficacy of the PMs. It is found that this combination treatment strategy markedly improves the antitumor properties of these PMs both in vitro and in patient-derived xenograft (PDX) models without inducing significant side effects. It is therefore proposed that the "armor-plating" of protein PS agents with ZIF-8 in combination with PPV may be a promising approach to precision medicine-mediated tumor treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/adhm.202001577DOI Listing
February 2021

Development of a novel oxidative stress-amplifying nanocomposite capable of supplying intratumoral HO and O for enhanced chemodynamic therapy and radiotherapy in patient-derived xenograft (PDX) models.

Nanoscale 2020 Nov;12(45):23259-23265

Department of Molecular pathology, Application Center for Precision Medicine, the Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China.

Radiotherapy (RT) is a potent approach to cancer treatment, but the tumor microenvironment (TME) in solid tumors is often highly hypoxic and contains high levels of antioxidant enzymes, thereby reducing the RT efficacy. In this study, we developed an oxidative stress amplifier (termed CFM) capable of self-sufficient H2O2 and O2 delivery that can be used in concert with RT and chemodynamic therapy (CDT) to treat tumors in patient-derived xenograft (PDX) model systems. Upon exposure to the hypoxic and acidic TME, CFM undergoes rapid degradation that results in the release of Fe3+, Ca2+, O2, and H2O2. Glutathione can subsequently reduce Fe3+ to Fe2+, which is then able to react with H2O2via the Fenton reaction to yield high levels of hydroxyl radicals which subsequently damage mitochondria. CaO2-derived O2 also modulates intratumoral hypoxia, while excessive Ca2+ levels within mitochondria result in apoptotic cell death. Altogether, these properties sensitize PDX tumors to RT. Importantly, the Fe, Zn, and Ca generated by CFM degradation are essential elements in humans. Altogether, these properties make this approach to oxidative stress amplification a promising means of amplifying oxidative stress within tumors while overcoming hypoxia-related resistance to RT, thereby providing a framework for the design of potent radiosensitizing therapeutic approaches.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/d0nr06594cDOI Listing
November 2020

Thymosin alpha-1 blocks the accumulation of myeloid suppressor cells in NSCLC by inhibiting VEGF production.

Biomed Pharmacother 2020 Nov 14;131:110740. Epub 2020 Sep 14.

Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China. Electronic address:

Background: Thymosin alpha-1 (TA) has been reported to inhibit tumor growth as an immunomodulator. However, its mechanism of action in immunosuppressive cells is unclear. The purpose of this study was to investigate whether TA can reshape the immune microenvironment by inhibiting the function of myeloid-derived suppressor cells (MDSCs) in non-small cell lung carcinoma (NSCLC).

Methods: The effects of TA on peripheral blood monocytic MDSCs (M-MDSCs) in patients with NSCLC and on the apoptosis and migration of M-MDSCs were studied. A mouse subcutaneous xenograft tumor model was constructed, and the effect of TA on M-MDSC migration was evaluated. Quantitative real-time PCR, Western blotting, flow cytometry and immunohistochemistry were used to examine the mechanism by which TA affects M-MDSCs.

Results: TA not only promoted the apoptosis of M-MDSCs by reducing the Bcl-2/BAX ratio but also and more importantly inhibited the migration of MDSCs to the tumor microenvironment by suppressing the production of vascular endothelial growth factor (VEGF) through the downregulation of hypoxia-inducible factor (HIF)-1α in tumor cells.

Conclusions: TA may have a novel antitumor effect mediated by decreasing M-MDSC accumulation in the tumor microenvironment through reduced VEGF production.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.biopha.2020.110740DOI Listing
November 2020

Perrault syndrome: Clinical report and retrospective analysis.

Mol Genet Genomic Med 2020 10 7;8(10):e1445. Epub 2020 Aug 7.

Department of Otorhinolaryngology, Head and Neck Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.

Background: Perrault syndrome (PRLTS4; OMIM# 615300) is a rare autosomal recessive disorder and only a few cases have been reported worldwide. We report a Chinese female characterized by sensorineural hearing loss and premature ovarian insufficiency.

Methods: We evaluated audiological, endocrine, and ultrasound examinations and examined the genetic causes using whole-exome sequencing. We reviewed the literature to discuss the pathogenesis, genotype-phenotype correlation, treatment, and prevention of PRLTS4.

Results: Bioinformatic analysis revealed compound heterozygous mutations in the LARS2 gene, c.880G>A (p.Glu294Lys), and c.2108T>C (p.Ile703Thr) which is a novel missense mutation, co-segregated in this family. Taken together, the patient was clinically diagnosed as PRLTS4. The literature review showed that the phenotype for PRLTS4 varies widely, but the sensorineural hearing loss, increased gonadotropin levels, and amenorrhea occurred frequently. All reported mutations are highly conserved in mammals based on conservation analysis, and there is a mutation hotspot for PRLTS4.

Conclusion: This study expanded the mutation spectrum of LARS2 and is the first report of PRLTS4 in a Chinese family. Genetic testing plays an important role in early diagnosis of syndromic deafness and clinical genetic evaluation is essential to guide prevention.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mgg3.1445DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7549576PMC
October 2020

Mechanisms of hearing loss and cell death in the cochlea of connexin mutant mice.

Am J Physiol Cell Physiol 2020 09 5;319(3):C569-C578. Epub 2020 Aug 5.

Center for Precision Medicine of Zhengzhou University, Zhengzhou, China.

Mutations in connexin 30 (Cx30) are known to cause severe congenital hearing impairment; however, the mechanism by which Cx30 mediates homeostasis of endocochlear gap junctions is unclear. We used a gene deletion mouse model to explore the mechanisms of Cx30 in preventing hearing loss. Our results suggest that despite severe loss of the auditory brain-stem response and endocochlear potential at , Cx30 mice only show sporadic loss of the outer hair cells. This inconsistency in the time course and severity of hearing and hair cell losses in Cx30 mice might be explained, in part, by an increase in reactive oxygen species generation beginning at . The expression of oxidative stress genes was increased in Cx30 mice in the stria vascularis, spiral ligament, and organ of Corti. Furthermore, Cx30 deficiency caused mitochondrial dysfunction at , as assessed by decreased ATP levels and decreased expression of mitochondrial complex I proteins, especially in the stria vascularis. Proteomic analysis further identified 444 proteins that were dysregulated in Cx30 mice, including several that are involved in mitochondria electron transport, ATP synthesis, or ion transport. Additionally, proapoptotic proteins, including Bax, Bad, and caspase-3, were upregulated at , providing a molecular basis to explain the loss of hearing that occurs before hair cell loss. Therefore, our results are consistent with an environment of oxidative stress and mitochondrial damage in the cochlea of Cx30 mice that is coincident with hearing loss but precedes hair cell loss.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1152/ajpcell.00483.2019DOI Listing
September 2020

Multi-faceted epigenetic dysregulation of gene expression promotes esophageal squamous cell carcinoma.

Nat Commun 2020 07 22;11(1):3675. Epub 2020 Jul 22.

Department of Medicine, University of California San Francisco, San Francisco, CA, USA.

Epigenetic landscapes can shape physiologic and disease phenotypes. We used integrative, high resolution multi-omics methods to delineate the methylome landscape and characterize the oncogenic drivers of esophageal squamous cell carcinoma (ESCC). We found 98% of CpGs are hypomethylated across the ESCC genome. Hypo-methylated regions are enriched in areas with heterochromatin binding markers (H3K9me3, H3K27me3), while hyper-methylated regions are enriched in polycomb repressive complex (EZH2/SUZ12) recognizing regions. Altered methylation in promoters, enhancers, and gene bodies, as well as in polycomb repressive complex occupancy and CTCF binding sites are associated with cancer-specific gene dysregulation. Epigenetic-mediated activation of non-canonical WNT/β-catenin/MMP signaling and a YY1/lncRNA ESCCAL-1/ribosomal protein network are uncovered and validated as potential novel ESCC driver alterations. This study advances our understanding of how epigenetic landscapes shape cancer pathogenesis and provides a resource for biomarker and target discovery.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-020-17227-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7376194PMC
July 2020

Roles of HMGB1 in regulating myeloid-derived suppressor cells in the tumor microenvironment.

Biomark Res 2020 16;8:21. Epub 2020 Jun 16.

Department of Oncology, the First Affiliated Hospital of Zhengzhou University, NO.1 Eastern Jianshe Road, Zhengzhou, 450052 Henan China.

Myeloid-derived suppressor cells (MDSCs) are notable contributors to the immunosuppressive tumor microenvironment (TME) and are closely associated with tumor progression; in addition, MDSCs are present in most patients with cancer. However, the molecular mechanisms that regulate MDSCs in the etiopathogenesis of human tumor immunity remain unclear. The secreted alarmin high mobility group box 1 (HMGB1) is a proinflammatory factor and inducer of many inflammatory molecules during MDSC development. In this review, we detail the currently reported characteristics of MDSCs in tumor immune escape and the regulatory role of secreted HMGB1 in MDSC differentiation, proliferation, activity and survival. Notably, different posttranslational modifications of HMGB1 may have various effects on MDSCs, and these effects need further identification. Moreover, exosome-derived HMGB1 is speculated to exert a regulatory effect on MDSCs, but no report has confirmed this hypothesis. Therefore, the effects of HMGB1 on MDSCs need more research attention, and additional investigations should be conducted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s40364-020-00201-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7298841PMC
June 2020

Nanoscale dual-enzyme cascade metal-organic frameworks through biomimetic mineralization as ROS generators for synergistic cancer therapy.

J Mater Chem B 2020 06 6;8(21):4620-4626. Epub 2020 May 6.

Department of Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.

Chemodynamic therapy (CDT) has been critically challenged by insufficient HO in cancer tissues and inefficient reactive oxygen species (ROS) production. Herein, we have reported the facile synthesis of an efficient ROS generator ([email protected]@ZIF-8) that exerts synergistic anticancer activity by blocking glucose metabolism and producing ROS. Glucose oxidase (GOx) and palladium (Pd) cube nanozymes were incorporated in zeolitic imidazolate framework-8 (ZIF-8) by biomimetic mineralization. Systematic characterization indicated the successful entrapment and embedding of GOx and Pd during ZIF-8 crystal growth. The [email protected]@ZIF-8 composite showed favorable catalytic glucose activity and stable ROS production. In vitro experiments showed that the [email protected]@ZIF-8 composite effectively inhibited cancer cell proliferation, invasion, and migration and promoted apoptosis through the ROS-mediated signaling pathway, which was further confirmed by bioinformatics analyses of RNA-seq data obtained from in vitro experiments. Furthermore, the [email protected]@ZIF-8 composite inhibited tumor growth with few to no side effects on other tissues in vivo. This work provides a novel antitumor strategy involving the construction of a stable and highly active ROS generator that shows promise for the treatment of solid cancers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/d0tb00357cDOI Listing
June 2020

Involvement of Glutathione Depletion in Selective Cytotoxicity of Oridonin to p53-Mutant Esophageal Squamous Carcinoma Cells.

Front Oncol 2019 15;9:1525. Epub 2020 Jan 15.

Key Laboratory of Technology of Drug Preparation, Ministry of Education of China, Zhengzhou, China.

Oridonin, a diterpenoid compound isolated from traditional Chinese medicine Rabdosia rubescens, has shown antitumor effects to esophageal cancer. However, its molecular mechanism is not fully understood, which limits its clinical application. In the present study, we used RNA-seq analysis to check the transcriptome changes after oridonin treatment and we found genes controlling the GSH-ROS system were up-regulated, namely , and . Furthermore, our data suggest that oridonin significantly increased the production of ROS in EC109 and TE1 cells, which can be inhibited by NAC. Interestingly, oridonin can dramatically reduce intracellular GSH levels in TE1 cells in a concentration and time-dependent manner. In addition, cell death caused by oridonin was strongly inhibited by GSH (1 mM), while GSSG (1 mM) had little effect. At the same time, we also found that oridonin showed selective cytotoxicity to esophageal squamous carcinoma cell with p53 mutation since mut-p53 cells had lower expression, a component of the cystine/glutamate antiporter. We also found that γ-glutamyl cysteine synthetase inhibitor (BSO) synergizes with oridonin to strongly inhibit EC109 cells at a low dose. These results suggested that the antitumor effects of oridonin are based on its -SH reactivity and glutathione depletion. Esophageal squamous carcinoma cells with p53-mutation showed hypersensitivity to oridonin because of the suppression of SLC7A11 expression by p53 mutation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fonc.2019.01525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6974803PMC
January 2020

Myeloid-derived suppressor cells-new and exciting players in lung cancer.

J Hematol Oncol 2020 01 31;13(1):10. Epub 2020 Jan 31.

Department of Oncology, The First Affiliated Hospital of Zhengzhou University, NO.1 Eastern Jianshe Road, Zhengzhou, 450052, Henan, China.

Lung cancer (LC) is the leading cause of cancer-related death worldwide due to its late diagnosis and poor outcomes. As has been found for other types of tumors, there is increasing evidence that myeloid-derived suppressor cells (MDSCs) play important roles in the promotion and progression of LC. Here, we briefly introduce the definition of MDSCs and their immunosuppressive functions. We next specifically discuss the multiple roles of MDSCs in the lung tumor microenvironment, including those in tumor growth and progression mediated by inhibiting antitumor immunity, and the associations of MDSCs with a poor prognosis and increased resistance to chemotherapy and immunotherapy. Finally, we also discuss preclinical and clinical treatment strategies targeting MDSCs, which may have the potential to enhance the efficacy of immunotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13045-020-0843-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6995114PMC
January 2020

Expression pattern of Connexin 26 and Connexin 30 in mature cochlea of the monkey.

Biochem Biophys Res Commun 2019 10 14;518(2):357-361. Epub 2019 Aug 14.

Department of Otolaryngology, Yerkes National Primate Research Center,Emory University School of Medicine, 615 Michael Street, Atlanta, GA, 30322-3030, USA. Electronic address:

Connexin26 (Cx26) and Cx30 are the predominant connexin subtypes found in the cochlea. They play an essential role in the cochlear functions. However, most studies use mice and the data on the cochlear expression profiles of the two Cxs in higher animals (e.g., humans) are scarce. Studies using the cochleae from non-human primate other than mice may provide information needed to narrow this gap. Here we studied cellular distributions of Cx26 and Cx30 in the adult monkey and guinea pig cochleae by immunofluorescent labeling and confocal microscopy observations. We detected Cx26 and Cx30 expressions in the type I, II& V fibrocytes in the spiral ligament, fibrocytes of the spiral limbus, in the supporting cells of organ of Corti, inner and outer sulcus cells, and in the basal cells of the stria vascularis. Both Cx26 and Cx30 were not detected in hair cells, in mesenchymal cells under the basilar membrane and cells lining the scala vestibule. Cells of the Reissner's membrane and spiral ganglion neurons are also negative. These findings demonstrate that cochlear expressions of Cx26 and Cx30 in the adult mouse, guinea pig and non-human primate have a common cellular pattern.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbrc.2019.08.063DOI Listing
October 2019

Localization of Glucose Transporter 10 to Hair Cells' Cuticular Plate in the Mouse Inner Ear.

Biomed Res Int 2018 14;2018:7817453. Epub 2018 Jun 14.

Department of Otology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, Henan, China.

This study aimed to investigate the localization pattern of glucose transporters (Gluts) in mouse cochlea. Genome-wide gene expression analysis using CodeLink™ bioarrays indicated that Glut1 and Glut10 were highly expressed (~10-fold) in mouse cochlea compared with the other members of glucose transporters (Glut2-6, Glut8, and Glut9). Semiquantitative RT-PCR and western blotting confirmed that Glut10 expression in mouse cochlea was high throughout the embryogenesis and postnatal development. Immunofluorescent staining showed that Glut10 protein was localized in the cuticular plate of the outer and inner cochlear hair cells and in the ampullary crest of the vestibular system. Based on these results, it was supposed that Glut10 may contribute to glucose transport from the endolymph to the hair cells across the cuticular plate.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2018/7817453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6022331PMC
January 2019

Inhibition of cyclooxygenase-2 by NS398 attenuates noise-induced hearing loss in mice.

Sci Rep 2016 Mar 3;6:22573. Epub 2016 Mar 3.

Department of Otolaryngology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou 450014, PR China.

Noise-induced hearing loss (NIHL) is an important occupational disorder. However, the molecular mechanisms underlying NIHL have not been fully clarified; therefore, the condition lacks effective therapeutic methods. Cyclooxygenase-2 (Cox-2) is an inducible enzyme involved in the synthesis of prostaglandins, and has been implicated in many pathophysiological events, such as oxidative stress and inflammation. In this study, we investigated the possible role of Cox-2 in the mechanisms of NIHL and the therapeutic effect of the Cox-2 inhibitor NS398 on NIHL using a mouse model. We demonstrated that Cox-2 is constitutively expressed in the mouse cochlea, and its expression could be dramatically up-regulated by high levels of noise exposure. Furthermore, we demonstrated that pre-treatment with the Cox-2 inhibitor NS398 could inhibit Cox-2 expression during noise overstimulation; and could attenuate noise-induced hearing loss and hair cell damage. Our results suggest that Cox-2 is involved in the pathogenesis of NIHL; and pharmacological inhibition of Cox-2 has considerable therapeutic potential in NIHL.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/srep22573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4776277PMC
March 2016

Timed conditional null of connexin26 in mice reveals temporary requirements of connexin26 in key cochlear developmental events before the onset of hearing.

Neurobiol Dis 2015 Jan 22;73:418-27. Epub 2014 Sep 22.

Department of Otolaryngology, Emory University School of Medicine, 615 Michael Street, Atlanta, GA 30322-3030, USA; Department of Cell Biology, Emory University School of Medicine, 615 Michael Street, Atlanta, GA 30322-3030, USA.

Mutations in the Gjb2 gene, which encodes a gap junction protein connexin26 (Cx26), are the most prevalent form of hereditary deafness in humans and represent about half of non-syndromic congenital deafness cases in many ethnic populations. Cochlear potassium (K+) recycling in mature cochlea is required for normal hearing. It is thought that gap junctions are essential for K+ recycling and that Gjb2 mutations cause Gjb2-associated deafness by disrupting K+ recycling in mature cochlea. Here we present evidence showing that Gjb2 is required for normal development of the neonatal organ of Corti prior to the onset of the hearing in mice. In the conditional Gjb2 null (cCx26 null) mice, ribbon synapses in inner hair cells remained poorly developed, the afferent type I fibers failed to finish the refinement process to form convergent innervation to individual inner hair cells. The spontaneous depolarizing activities in the supporting cells, which normally diminish in the wild type cochleae after postnatal day 8 (P8), remained strong in the cochlea after P8 in the mutant mice. Furthermore, the deafness phenotype was readily generated only if the Cx26 expression in the organ of Corti was significantly reduced before P6. Similar amount of Cx26 reduction in more mature cochleae had a much weaker effect in damaging the hearing sensitivity. Our findings indicated that Cx26 plays essential roles in the maturation process of the organ of Corti prior to the establishment of high K+ in the endolymph and the onset of hearing. These results suggest that successful treatment of Cx26 deafness requires early intervention before the cochlea fully matures.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.nbd.2014.09.005DOI Listing
January 2015

Resveratrol decreases noise-induced cyclooxygenase-2 expression in the rat cochlea.

Otolaryngol Head Neck Surg 2013 May 4;148(5):827-33. Epub 2013 Feb 4.

Department of Otolaryngology-Head & Neck Surgery, Henry Ford Health System, Detroit, Michigan 48322, USA.

Objective: Our previous studies have demonstrated the efficacy of resveratrol, a grape constituent noted for its antioxidant and anti-inflammatory properties, in reducing temporary threshold shifts and decreasing cochlear hair cell damage following noise exposure. This study was designed to identify the potential protective mechanism of resveratrol by measuring its effect on cyclooxygenase-2 (COX-2) protein expression and reactive oxygen species (ROS) formation following noise exposure.

Study Design: Controlled animal intervention study.

Setting: Otology Laboratory, Henry Ford Health System.

Subjects And Methods: Twenty-two healthy male Fischer 344 rats (2-3 months old) were exposed to acoustic trauma of variable duration with or without intervention. An additional 20 healthy male rats were used to study COX-2 expression at different time points during and following treatment of 24 hours of noise exposure. Cochlear harvest was performed at various time intervals for measurement of COX-2 protein expression via Western blot analysis and immunostaining. Peripheral blood was also obtained for ROS analysis using flow cytometry.

Results: Acoustic trauma exposure resulted in a progressive up-regulation of COX-2 protein expression, commencing at 8 hours and peaking at 32 hours. Similarly, ROS production increased after noise exposure. However, treatment with resveratrol reduced noise-induced COX-2 expression as well as ROS formation in the blood as compared with the controls.

Conclusion: COX-2 levels are induced dramatically following noise exposure. This increased expression may be a potential mechanism of noise-induced hearing loss (NIHL) and a possible mechanism of resveratrol's ability to mitigate NIHL by its ability to reduce COX-2 expression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/0194599813475777DOI Listing
May 2013

A low-cost exon capture method suitable for large-scale screening of genetic deafness by the massively-parallel sequencing approach.

Genet Test Mol Biomarkers 2012 Jun 5;16(6):536-42. Epub 2012 Apr 5.

Department of Otolaryngology, Emory University School of Medicine, Atlanta, Georgia 30322, USA.

Current major barriers for using next-generation sequencing (NGS) technologies in genetic mutation screening on an epidemiological scale appear to be the high accuracy demanded by clinical applications and high per-sample cost. How to achieve high efficiency in enriching targeted disease genes while keeping a low cost/sample is a key technical hurdle to overcome. We validated a cDNA-probe-based approach for capturing exons of a group of genes known to cause deafness. Polymerase chain reaction amplicons were made from cDNA clones of the targeted genes and used as bait probes in hybridization for capturing human genomic DNA (gDNA) fragments. The cDNA library containing the clones of targeted genes provided a readily available, low-cost, and regenerable source for producing capture probes with standard molecular biology equipment. Captured gDNA fragments by our method were sequenced by the Illumina NGS platform. Results demonstrated that targeted exons captured by our approach achieved specificity, multiplexicity, uniformity, and depth of coverage suitable for accurate sequencing applications by the NGS systems. Reliable genotype calls for various homozygous and heterozygous mutations were achieved. The results were confirmed independently by conventional Sanger sequencing. The method validated here could be readily expanded to include all-known deafness genes for applications such as genetic hearing screening in newborns. The high coverage depth and cost benefits of the cDNA-probe-based exon capture approach may also facilitate widespread applications in clinical practices beyond screening mutations in deafness genes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/gtmb.2011.0187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3378026PMC
June 2012

Applications of targeted gene capture and next-generation sequencing technologies in studies of human deafness and other genetic disabilities.

Hear Res 2012 Jun 14;288(1-2):67-76. Epub 2012 Jan 14.

Department of Otolaryngology, Emory University School of Medicine, 615 Michael Street, Atlanta, GA 30322-3030, USA.

The goal of sequencing the entire human genome for $1000 is almost in sight. However, the total costs including DNA sequencing, data management, and analysis to yield a clear data interpretation are unlikely to be lowered significantly any time soon to make studies on a population scale and daily clinical uses feasible. Alternatively, the targeted enrichment of specific groups of disease and biological pathway-focused genes and the capture of up to an entire human exome (~1% of the genome) allowing an unbiased investigation of the complete protein-coding regions in the genome are now routine. Targeted gene capture followed by sequencing with massively parallel next-generation sequencing (NGS) has the advantages of 1) significant cost saving, 2) higher sequencing accuracy because of deeper achievable coverage, 3) a significantly shorter turnaround time, and 4) a more feasible data set for a bioinformatic analysis outcome that is functionally interpretable. Gene capture combined with NGS has allowed a much greater number of samples to be examined than is currently practical with whole-genome sequencing. Such an approach promises to bring a paradigm shift to biomedical research of Mendelian disorders and their clinical diagnoses, ultimately enabling personalized medicine based on one's genetic profile. In this review, we describe major methodologies currently used for gene capture and detection of genetic variations by NGS. We will highlight applications of this technology in studies of genetic disorders and discuss issues pertaining to applications of this powerful technology in genetic screening and the discovery of genes implicated in syndromic and non-syndromic hearing loss.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.heares.2012.01.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3881369PMC
June 2012

Early developmental expression of connexin26 in the cochlea contributes to its dominate functional role in the cochlear gap junctions.

Biochem Biophys Res Commun 2012 Jan 28;417(1):245-50. Epub 2011 Nov 28.

Department of Ear Nose & Throat, Third Hospital and Bethune International Peace Hospital of Hebei Medical University, Shijiazhuang, Hebei, People's Republic of China.

Mutations in Gjb2 and Gjb6 genes, coding for connexin26 (Cx26) and Cx30 proteins, respectively, are linked to about half of all cases of human autosomal non-syndromic prelingual deafness. Molecular mechanisms of the hearing impairments, however, are unclear. Most cochlear gap junctions (GJs) are co-assembled from Cx26 and Cx30 and deletion of either one of them causes deafness. Our previous studies have shown that normal hearing is possible in the absence of the Cx30 gene when Cx26 is over-expressed. To further test unique functional requirements for various types of connexins in the hearing, we investigated whether the hearing in the conditional Cx26 (cCx26) null mice could be rescued by genetically over-expressing Cx30. Multiple lines of control and experimental mouse models were used. Auditory brainstem response (ABR) measurements showed normal hearing in targeted gene deletion mice when the deleted Cx26 or Cx30 was transgenically expressed from integrated bacterial artificial chromosome (BAC), demonstrating the effectiveness of the BAC rescue approach. In contrast, severe hearing loss was found in cCx26 null mice in which Cx30 was over-expressed. Morphology observations were consistent with the ABR data. Cochleae of cCx26 null mice with and without the transgenic over-expression of Cx30 both showed the typical immature feature of postnatal cochlear development-the closed tunnel of Corti. Immunolabeling data and Western blot quantification indicated that the Cx26 protein expression preceded that of Cx30 during the early postnatal period in the cochlea. Null expression of Cx26 may therefore uniquely result in a transient period when a total elimination of GJs in functionally-important regions of the developing cochlea is possible. We conclude that Cx26 plays an essential role in the development of the auditory sensory epithelium and its unique developmental functions required for normal hearing is not replaceable by Cx30.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbrc.2011.11.093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3259187PMC
January 2012

Deoxygedunin, a natural product with potent neurotrophic activity in mice.

PLoS One 2010 Jul 13;5(7):e11528. Epub 2010 Jul 13.

Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.

Gedunin, a family of natural products from the Indian neem tree, possess a variety of biological activities. Here we report the discovery of deoxygedunin, which activates the mouse TrkB receptor and its downstream signaling cascades. Deoxygedunin is orally available and activates TrkB in mouse brain in a BDNF-independent way. Strikingly, it prevents the degeneration of vestibular ganglion in BDNF -/- pups. Moreover, deoxygedunin robustly protects rat neurons from cell death in a TrkB-dependent manner. Further, administration of deoxygedunin into mice displays potent neuroprotective, anti-depressant and learning enhancement effects, all of which are mediated by the TrkB receptor. Hence, deoxygedunin imitates BDNF's biological activities through activating TrkB, providing a powerful therapeutic tool for treatment of various neurological diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0011528PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2903477PMC
July 2010

Connexin30 null and conditional connexin26 null mice display distinct pattern and time course of cellular degeneration in the cochlea.

J Comp Neurol 2009 Oct;516(6):569-79

Department of Otolaryngology, Emory University School of Medicine, Atlanta, GA 30322-3030, USA.

Mutations in connexin26 (Cx26) and Cx30 are the most common cause of nonsyndromic inherited deafness in humans. To understand the underlying molecular mechanisms, we investigated the pattern and time course of cellular degeneration in the cochlea of conditional Cx26 (cCx26) null and Cx30 null mice. In cCx26 null mice, initial degeneration was observed around postnatal day 14 in outer hair cells (OHCs) and supporting cells surrounding the OHCs. All cells in the middle turn organ of Corti were lost 1 month after birth, and degeneration gradually spread to the basal and apical turns. Most spiral ganglion (SG) neurons in the middle and basal turns disappeared in the first 3 months, whereas significant amounts of apical SG neurons survived. In the cochlea of Cx30 null mice, survival of most inner HCs, supporting cells, and SG neurons was observed for up to 18 months. The most severe degeneration was found in apical SG neurons and OHCs. OHC loss followed a slow time course and a base to apex gradient. Gross structures of the endolymphatic space and stria vascularis observed at the light microscope level were unchanged in either Cx null mouse models. This study revealed that cellular degeneration in the cochlea of cCx26 null mice was dramatically more rapid and widespread than that observed in Cx30 null mice. The radically different pathogenesis processes displayed by cCx26 and Cx30 null mice suggest heterogeneous underlying deafness mechanisms, despite co-assembly of Cx26 and Cx30 in forming gap junctions in the cochlea.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cne.22117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2846422PMC
October 2009

Targeted connexin26 ablation arrests postnatal development of the organ of Corti.

Biochem Biophys Res Commun 2009 Jul 9;385(1):33-7. Epub 2009 May 9.

Department of Otolaryngology, Emory University School of Medicine, 615 Michael Street, Atlanta, GA 30322-3030, USA.

Mutations in the gene coding for connexin26 (Cx26) is the most common cause of human nonsyndromic hereditary deafness. To investigate deafness mechanisms underlying Cx26 null mutations, we generated three independent lines of conditional Cx26 null mice. Cell differentiation and gross cochlear morphology at birth seemed normal. However, postnatal development of the organ of Corti was stalled as the tunnel of Corti and the Nuel's space were never opened. Cell degeneration was first observed in the Claudius cells around P8. Outer hair cell loss was initially observed around P13 at middle turn when inner hair cells were still intact. Massive cell death occurred in the middle turn thereafter and gradually spread to the basal turn, resulting in secondary degeneration of spiral ganglion neurons in the corresponding cochlear locations. These results demonstrated that Cx26 plays essential roles in postnatal maturation and homoeostasis of the organ of Corti before the onset of hearing.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbrc.2009.05.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2713729PMC
July 2009

Diverse deafness mechanisms of connexin mutations revealed by studies using in vitro approaches and mouse models.

Brain Res 2009 Jun 20;1277:52-69. Epub 2009 Feb 20.

Department of Otolaryngology, Emory University School of Medicine, 615 Michael Street, Atlanta, GA 30322-3030, USA.

Mutations in connexins (Cxs), the constitutive protein subunits of gap junction (GJ) intercellular channels, are one of the most common human genetic defects that cause severe prelingual non-syndromic hearing impairments. Many subtypes of Cxs (e.g., Cxs 26, 29, 30, 31, 43) and pannexins (Panxs) are expressed in the cochlea where they contribute to the formation of a GJ-based intercellular communication network. Cx26 and Cx30 are the predominant cochlear Cxs and they co-assemble in most GJ plaques to form hybrid GJs. The cellular localization of specific Cx subtypes provides a basis for understanding the molecular structure of GJs and hemichannels in the cochlea. Information about the interactions among the various co-assembled Cx partners is critical to appreciate the functional consequences of various types of genetic mutations. In vitro studies of reconstituted GJs in cell lines have yielded surprisingly heterogeneous mechanisms of dysfunction caused by various Cx mutations. Availability of multiple lines of Cx-mutant mouse models has provided some insight into the pathogenesis processes in the cochlea of deaf mice. Here we summarize recent advances in understanding the structure and function of cochlear GJs and give a critical review of current findings obtained from both in vitro studies and mouse models on the mechanisms of Cx mutations that lead to cell death in the cochlea and hearing loss.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.brainres.2009.02.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2755050PMC
June 2009

Anti-intercellular adhesion molecule-1 antibody's effect on noise damage.

Laryngoscope 2009 Apr;119(4):707-12

Department of Otolaryngology, Henry Ford Health System, Detroit, Michigan 48323, USA.

Objectives/hypothesis: The purpose of this study was to investigate possible preventive effects of anti-intercellular adhesion molecule-1 antibody (anti-ICAM-1 Ab) on noise-induced cochlear damage as assessed by changes in auditory thresholds and cochlear blood flow.

Study Design: A controlled animal study. Pretreated rats with anti-ICAM-1 Ab or saline control, followed with exposure to 72 continuous hours of broad band noise (107 dB SPL), and 24 hours after noise exposure treated again with anti-ICAM-1 Ab or saline.

Methods: Eighteen healthy male Fischer rats (200-250 g) were used. Sixteen were randomly selected to study noise-induced temporary threshold shifts. The remaining two rats were used to study cochlear blood flow (CBF), using laser Doppler flowmetry and blood pressure measurements.

Results: Rats treated with anti-ICAM-1 Ab (1.875 mg/kg, intravenously) showed attenuated temporary threshold shifts (TTS) compared to controls. Both groups showed a partial threshold recovery 72 hours following noise exposure, normal for this noise exposure paradigm. Comparisons of baseline and post-treatment measurements of CBF and mean arterial blood pressure revealed no significant changes. Anti-ICAM-1 Ab animals displayed significantly lower mean auditory threshold shifts at all five test frequencies (P < .05) when compared to control.

Conclusions: Blocking the cascade of reactive oxygen species (ROS) generation by using anti-ICAM-Ab protects against noise-induced hearing loss.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/lary.20109DOI Listing
April 2009

Functional studies reveal new mechanisms for deafness caused by connexin mutations.

Otol Neurotol 2009 Feb;30(2):237-40

Department of Otolaryngology, Emory University School of Medicine, Atlanta, Georgia 30322, USA.

Objective: Connexin26 (Cx26) and Cx30 are the major protein subunits forming gap junction (GJ) intercellular channels in the cochlea. Mutations in these 2 Cxs are the major cause of nonsyndromic early childhood deafness in humans. The underlying mechanism for cochlear abnormality is unclear. Here, we used targeted Cx30 gene deletion (Cx30-/-) mice to investigate molecular mechanisms responsible for Cx mutation-linked deafness. Our hypothesis is that specific loss of GJ-mediated biochemical coupling in the cochlea is sufficient to cause deafness.

Study Design: We compared: (1) expression of major cochlear GJ protein subunits, Cx26 and Cx30; and (2) biochemical coupling among cochlear supporting cells in the cochleae of wild type and Cx30-/- mice.

Methods: Immunolabeling was used to examine the expression of the remaining Cx protein expression in the cochlea of Cx30-/- mice. We also used a fluorescent dye diffusion assay performed on a novel flattened cochlear preparation to examine GJ-mediated metabolite transfer among cochlear supporting cells.

Results: Estimation of the residual ionic conductance indicated that considerable intercellular ionic coupling remained in the cochlea of Cx30-/- mice. Direct measurement of GJ-mediated biochemical coupling showed that the transfer of metabolites among cochlear supporting cells in Cx30-/- mice was severely reduced.

Conclusion: Our data support that deficiency in GJ-mediated biochemical coupling is sufficient to cause Cx mutation-linked deafness.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MAO.0b013e318194f774DOI Listing
February 2009