Activated tissue-resident macrophages contribute to hair cell insults in noise-induced hearing loss in mice.

Macrophages serve as the primary immune cell population and assume a pivotal role in the immune response within the damaged cochleae. Yet, the origin and role of macrophages in response to noise exposure remain controversial. Here, we take advantage of Ccr2RFP/+ Cx3cr1GFP/+ dual-reporter mice to identify the infiltrated and tissue-resident macrophages. After noise exposure, we reveal that activated resident macrophages change in morphology, increase in abundance, and migrate to the region of hair cells, leading to the loss of outer hair cells and the damage of ribbon synapses. Meanwhile, peripheral monocytes are not implicated in the noise-induced hair cell insults. These noise-induced activities of macrophages are abolished by inhibiting TLR4 signaling, resulting in alleviated insults of hair cells and partial recovery of hearing. Our findings indicate cochlear resident macrophages are pro-inflammatory and detrimental players in acoustic trauma and introduce a potential therapeutic target in noise-induced hearing loss.

Intratympanic injection of MSC-derived small extracellular vesicles protects spiral ganglion neurons from degeneration.

Sensorineural hearing loss is one of the most prevalent sensory deficits. Spiral ganglion neurons (SGNs) exhibit very limited regeneration capacity and their degeneration leads to profound hearing loss. Mesenchymal stem cell-derived small extracellular vesicles (MSC-sEV) have been demonstrated to repair tissue damage in various degenerative diseases. However, the effects of MSC-sEV on SGN degeneration remain unclear. In this study, we investigated the efficacy of MSC-sEV for protection against ouabain-induced SGN degeneration. MSC-sEV were derived from rat bone marrow and their components related to neuron growth were determined by proteomic analysis. In primary culture SGNs, MSC-sEV significantly promoted neurite growth and growth cone development. The RNA-Seq analysis of SGNs showed that enriched pathways include neuron development and axon regeneration, consistent with proteomics. In ouabain induced SGN degeneration rat model, MSC-sEV administration via intratympanic injection significantly enhanced SGN survival and mitigated hearing loss. Furthermore, after ouabain treatment, SGNs displayed evident signs of apoptosis, including nuclei condensation and fragmentation, with numerous cells exhibiting TUNEL-positive. However, administration of MSC-sEV effectively decreased the number of TUNEL-positive cells and reduced caspase-3 activation. In conclusion, our findings demonstrate the potential of MSC-sEV in preventing SGN degeneration and promoting neural growth, suggesting intratympanic injection of MSC-sEV is a specific and efficient strategy for neural hearing loss.

Integrative bioinformatics and validation studies reveal KDM6B and its associated molecules as crucial modulators in Idiopathic Pulmonary Fibrosis.

Background: Idiopathic Pulmonary Fibrosis (IPF) can be described as a debilitating lung disease that is characterized by the complex interactions between various immune cell types and signaling pathways. Chromatin-modifying enzymes are significantly involved in regulating gene expression during immune cell development, yet their role in IPF is not well understood. Methods: In this study, differential gene expression analysis and chromatin-modifying enzyme-related gene data were conducted to identify hub genes, common pathways, immune cell infiltration, and potential drug targets for IPF. Additionally, a murine model was employed for investigating the expression levels of candidate hub genes and determining the infiltration of different immune cells in IPF. Results: We identified 33 differentially expressed genes associated with chromatin-modifying enzymes. Enrichment analyses of these genes demonstrated a strong association with histone lysine demethylation, Sin3-type complexes, and protein demethylase activity. Protein-protein interaction network analysis further highlighted six hub genes, specifically KDM6B, KDM5A, SETD7, SUZ12, HDAC2, and CHD4. Notably, KDM6B expression was significantly increased in the lungs of bleomycin-induced pulmonary fibrosis mice, showing a positive correlation with fibronectin and α-SMA, two essential indicators of pulmonary fibrosis. Moreover, we established a diagnostic model for IPF focusing on KDM6B and we also identified 10 potential therapeutic drugs targeting KDM6B for IPF treatment. Conclusion: Our findings suggest that molecules related to chromatin-modifying enzymes, primarily KDM6B, play a critical role in the pathogenesis and progression of IPF.

Zwitterionic Polymer/Polydopamine Coating of Electrode Arrays Reduces Fibrosis and Residual Hearing Loss after Cochlear Implantation.

Since the first surgery 50 years ago, cochlear implantation (CI) is the major treatment for patients with severe sensorineural hearing loss. However, unexpected foreign body reactions (FBRs) after surgery are reported in 90% of CI recipients, resulting in the formation of fibrosis in the cochlea and progressive residual hearing loss. Zwitterion modification is universally used to reduce bio-fouling and suppress FBRs but never for CI. In the present study, a zwitterionic coating is developed, which is composed of poly sulfobetaine methacrylate (PSB) and polydopamine (PDA) for cochlear implants. The PSB-PDA coating shows a series of characters for an ideal anti-FBRs material, including super-hydrophilicity, low protein and cell adsorption, long-term stability, and high biocompatibility. Compared to the uncoated controls, PSB-PDA coating inhibits the activation of macrophages and reduces the release of inflammatory factors (TNF-α, IL-1ß, NO) and fibrosis-related factors (TGF-ß1, α-SMA, collagen I). PSB-PDA coated electrode arrays suppress fibrosis completely and preserve residual hearing significantly in rat CI models. These results suggest that PSB-PDA coating is a novel strategy for anti-fibrosis to improve the outcomes of CI.

Nomograms predict survival benefits of radical prostatectomy and chemotherapy for prostate cancer with bone metastases: A SEER-based study.

Purpose: This study aimed to identify independent prognosis-associated factors of bone-metastatic prostate cancer. The nomograms were further developed to obtain indicators for the prognostic evaluation. Methods: A total of 7315 bone-metastatic prostate cancer (PCa) patients from 2010 to 2016 were retrospectively collected from the Surveillance, Epidemiology, and End Results (SEER) database. Patients were randomly divided into the training cohort (n=5,120) and test cohort (n=2,195) in a ratio of 7:3. Univariate and multivariate Cox regression models were applied to evaluate potential risk factors. A 1:1 propensity score matching (PSM) was further performed to decrease the confounding effect and re-evaluate the influence of radical prostatectomy and chemotherapy on prognosis. Combining these potential prognosis factors, the nomograms of cancer-specific survival (CSS) and overall survival (OS) at different times were established. C-indexes, calibration curves, and decision curves were developed to evaluate the discrimination, calibration, and clinical benefit of the nomograms. Results: Eleven independent prognosis factors for CSS and twelve for OS were utilized to conduct the nomograms respectively. The C-indexes of nomograms for CSS and OS were 0.712 and 0.702, respectively. A favorable consistency between the predicted and actual survival probabilities was demonstrated by adopting calibration curves. Decision curves also exhibited a positive clinical benefit of the nomograms. Conclusions: Nomograms were formulated successfully to predict 3-year and 5-year CSS and OS for bone-metastatic PCa patients. Radical prostatectomy and chemotherapy were strongly associated with the bone-metastatic PCa prognosis.

Bioinformatics and systems-biology analysis to determine the effects of Coronavirus disease 2019 on patients with allergic asthma.

Background: The coronavirus disease (COVID-19) pandemic has posed a significant challenge for global health systems. Increasing evidence shows that asthma phenotypes and comorbidities are major risk factors for COVID-19 symptom severity. However, the molecular mechanisms underlying the association between COVID-19 and asthma are poorly understood. Therefore, we conducted bioinformatics and systems biology analysis to identify common pathways and molecular biomarkers in patients with COVID-19 and asthma, as well as potential molecular mechanisms and candidate drugs for treating patients with both COVID-19 and asthma. Methods: Two sets of differentially expressed genes (DEGs) from the GSE171110 and GSE143192 datasets were intersected to identify common hub genes, shared pathways, and candidate drugs. In addition, murine models were utilized to explore the expression levels and associations of the hub genes in asthma and lung inflammation/injury. Results: We discovered 157 common DEGs between the asthma and COVID-19 datasets. A protein-protein-interaction network was built using various combinatorial statistical approaches and bioinformatics tools, which revealed several hub genes and critical modules. Six of the hub genes were markedly elevated in murine asthmatic lungs and were positively associated with IL-5, IL-13 and MUC5AC, which are the key mediators of allergic asthma. Gene Ontology and pathway analysis revealed common associations between asthma and COVID-19 progression. Finally, we identified transcription factor-gene interactions, DEG-microRNA coregulatory networks, and potential drug and chemical-compound interactions using the hub genes. Conclusion: We identified the top 15 hub genes that can be used as novel biomarkers of COVID-19 and asthma and discovered several promising candidate drugs that might be helpful for treating patients with COVID-19 and asthma.

In vitro and vivo study of tranilast protects from acute respiratory distress syndrome and early pulmonary fibrosis induced by smoke inhalation.

BACKGROUND: Tranilast (N-[3＇,4＇-dimethoxycinnamoyl]-anthranilic acid) is an analog of a tryptophan metabolite. It was identified with anti-inflammatory and antifibrotic activities, and used in the treatment of a variety of diseases, such as anti - allergy, bronchial asthma, and hypertrophic scars. As a drug with few adverse reactions, tranilast has attracted great attention, but its application is limited due to the uncertainty of dosages and mechanisms. In this study, the protection effects of different doses of tranilast on smoke inhalation mediated lung injury on rats, and on the damage of three kinds of lung cells in vitro were investigated. METHOD: In vivo, Sprague-Dawley rats were randomly divided into sham group, smoke group (rats were exposed to pine sawdust smoke three times, each time for 5 min), different doses of tranilast treatment group (doses were 100 mg/kg, 200 mg/kg and 300 mg/kg, ip.) and placebo group. After 1, 3 and 7 days, pulmonary function, pathologic injury by HE staining, cytokines and oxidative stress level by kits were determined. At 7days, lung fibrosis was assessed by Masson's trichrome staining and the level of hydroxyproline (HYP). In vitro, three kinds of lung cells from normal rats were isolated: type II alveolar epithelial cells (AT-II), pulmonary microvascular endothelial cells (PMVECs) and pulmonary fibroblasts (PFs). To investigate the potential effects of tranilast on cell proliferation, cell cycle and cytokine production of three kinds of lung cells exposed to smoke. RESULTS: Compared with smoke group and placebo group, tranilast treatment significantly reduced histopathological changes (such as pulmonary hemorrhage, edema and inflammatory cell infiltration, etc.), significantly reduced histopathological score (p < 0.05), increased arterial oxygen partial pressure, and decreased the levels of IL-1ß, TNF-α, TGF-ß1 (p < 0.05), oxidative stress and the expression of nuclear transcription factor κB (NF-κB) smoke exposed rats (p < 0.01). In particular, the effect of 200 mg/kg dose was more prominent. In vitro, smoke induced AT-II and PMVECs apoptosis, improved PFs proliferation (p < 0.01), activity of SOD and decreased the content of MDA (p < 0.01). However, tranilast seems to be turning this trend well. The inflammatory factor IL-11ß, TNF-α and TGF-ß1, and the expression of NF-κB were significantly lower in the tranilast treatment than in the smoke group (p < 0.01). CONCLUSION: This study indicates that tranilast had a protective effect on acute respiratory distress syndrome and early pulmonary fibrosis of rats in vivo. In addition, tranilast promotes proliferation of AT-II and PMVECs but inhibits PFs proliferation, down-regulates secretion of inflammatory cytokines and alleviates oxidative stress of AT-II, PMVECs and PFs after smoke stimuli in vitro.

Long-Term Release of Dexamethasone With a Polycaprolactone-Coated Electrode Alleviates Fibrosis in Cochlear Implantation.

Cochlear implantation (CI) is the major treatment for severe sensorineural hearing loss. However, the fibrotic tissue forming around the electrodes reduces the treatment effectiveness of CI. Dexamethasone (DEX) is usually applied routinely in perioperative treatment of cochlear implantation (CI), but its diffusion in the inner ear after systemic administration is limited. In the present study, an electrode coated with polycaprolactone (PCL) loaded with dexamethasone was developed with a simple preparation process to maintain the stability of the electrode itself. The DEX-loaded PCL coating has good biocompatibility and does not change the smoothness, flexibility, or compliance of the implant electrode. Stable and effective DEX concentrations were maintained for more than 9 months. Compared with the pristine electrode, decreasing intracochlear fibrosis, protection of hair cells and spiral ganglion cells, and better residual hearing were observed 5 weeks after PCL-DEX electrode implantation. The PCL-DEX electrode has great potential in preventing hearing loss and fibrosis by regulating macrophages and inhibiting the expression of the fibrosis-related factors IL-1ß, TNF-α, IL-4, and TGF-ß1. In conclusion, the PCL-DEX electrode coating shows promising application in CI surgery.

Uniportal video-assisted thoracoscopic lung sparing tracheo-bronchial and carinal sleeve resections.

Pathology arising from the intrathoracic portion of the trachea (distal trachea), the carina and the main bronchi is usually neoplastic and is mainly treated with surgery. Resection of the intrathoracic portion of the trachea, the carina and the main bronchi for neoplastic lesions does not necessitate lung resection and is traditionally being conducted via open surgery. Video-assisted thoracic surgery (VATS) is witnessing an exponential growth and is the treatment of choice for early-stage non-small cell lung cancer (NSCLC). The experience accumulated over the past two decades along with the introduction of reliable and ergonomic technology, has led to the expansion of its indications. In this article we provide a detailed description of lung sparing distal tracheal, carinal and main bronchi resection for primary neoplasms of the airway, without involvement of the lung, with the uniportal video-assisted technique. The chest is entered through the fourth intercostal space, mid-axillary line. Dissection of the paratracheal space anteriorly, the tracheoesophageal groove posteriorly and the subcarinal space and division of the azygos arch are essential to mobilize the distal trachea and carina. Lateral dissection should be avoided beyond the points of division of the airway, as it may hinder the blood supply to the anastomosis. Any tension to the anastomosis should be relieved by release maneuvers. Ventilation is achieved through an endobronchial catheter, inserted into the left main bronchus through which a high-frequency jet ventilation catheter can be also inserted through it. The rationale of applying a minimally invasive technique for the conduction of tracheal and carinal resections, is to exploit its advantages, namely less pain, earlier mobilization and lower morbidity. Uniportal video-assisted resections of the distal trachea, carina and the main bronchi, are safe when conducted by experienced surgical and anesthetic teams.

CCNB2, NUSAP1 and TK1 are associated with the prognosis and progression of hepatocellular carcinoma, as revealed by co-expression analysis.

The mortality rate associated with hepatocellular carcinoma (HCC) is the third highest among all digestive system tumors. However, the causes of HCC development and the underlying mechanisms have remained to be fully elucidated. In the present bioinformatics study, genetic markers were identified and their association with HCC was determined. The mRNA expression datasets GSE87630, GSE74656 and GSE76427 were downloaded from the Gene Expression Omnibus (GEO) database. A total of 96 differentially expressed genes (DEGs) were screened from the 3 GEO datasets, including 25 upregulated and 71 downregulated genes. DEGs were uploaded to the database for Annotation, Visualization and Integrated Discovery to screen for enriched Gene Ontology terms in various categories and the Search Tool for the Retrieval of Interacting Genes/Proteins was used to identify the interactions and functions of the DEGs. A total of 3 genetic markers were identified in a stepwise pathway and functional analysis in a previous study. The association of the genetic markers with prognosis was analysed using the UALCAN online analysis tool. Regression analysis was also performed to identify the relationship between HCC grade and disease recurrence and the expression of genetic markers using The Cancer Genome Atlas HCC dataset. In addition, the expression of the 3 genetic markers in HCC tissues was determined using reverse transcription-quantitative PCR, the Oncomine database and the Human Protein Atlas database. The expression levels of the 3 genetic markers cyclin B2 (CCNB2), nucleolar and spindle-associated protein 1 (NUSAP1) and thymidine kinase 1 (TK1) were significantly correlated with each other and high mRNA expression of CCNB2 was significantly associated with poor overall survival of patients with HCC. Receiver operating characteristic curve analysis indicated that NUSAP1 and TK1 were capable of distinguishing between recurrent and non-recurrent HCC. Furthermore, CCNB2, NUSAP1 and TK1 were highly correlated with the HCC grade. It was also indicated that the mRNA expression of CCNB2, NUSAPA and TK1 was increased in primary HCC tissues when compared with that in adjacent tissues. The present study identified that the CCNB2, NUSAP1 and TK1 genes may serve as prognostic markers for HCC, and may be of value from the perspectives of basic research and clinical treatment of HCC.

Exogenous regucalcin negatively regulates the progression of cervical adenocarcinoma.

Cervical adenocarcinoma (CA) is a type of cervical cancer, and in previous decades its incidence has steadily increased. The upregulation of regucalcin (RGN) in various tumor cell types inhibits the progression of cancer. To understand the role of RGN in CA, RGN expression in human cervical cancer compared with normal tissues was analyzed using The Cancer Genome Atlas database (TCGA). Subsequently, transfection of lentivirus-mediated RGN into HeLa cells was conducted to study its function in tumor proliferation and metastasis. The expression of RGN and proteins associated with the Wnt/ß-catenin signaling pathway and epithelial-mesenchymal transition (EMT) were determined using reverse transcription-quantitative polymerase chain reaction and western blotting. Cell migration and invasion were evaluated using Transwell assays. Furthermore, cell proliferation, colony formation and cell cycle were assessed using the Cell Counting Kit-8, colony formation assay and flow cytometry, respectively. Lentivirus-mediated RGN effectively upregulated RGN expression, inhibited cell proliferation, retarded cellular invasion and promoted cell cycle arrest at the G2/M phase in HeLa cells. In addition, the expression levels of ß-catenin, p-glycogen synthase kinase (GSK)-3ß, matrix metalloproteinase (MMP)-3, MMP-7 and MMP-9 were effectively decreased, whilst those of E-cadherin and GSK-3ß were increased. The results suggest that RGN may be an inhibitory factor in tumorigenesis, and its mechanism of inhibiting tumor proliferation and metastasis may be associated with Wnt/ß-catenin signaling and EMT.