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Understanding the Effects of Non&#45;Invasive Transauricular Vagus Nerve Stimulation on EEG and HRV

Several studies have demonstrated promising results of transcutaneous auricular vagus nerve stimulation (taVNS) in treating various disorders; however, no ...

Neurive Co., Ltd.

Korea University Medical Center

The aim of this study was to examine the cytotoxic effect and inflammatory response of human middle ear epithelial cells (HMEECs) induced by urban particles (UP).

Effect of urban particles on human middle ear epithelial cells.

The aim of this study was to evaluate the histologic change of middle ear mucosa and the expression levels of epithelial sodium channel (ENaC) subunits and mucin production genes, after the injection of urban particulate matter (UPM) into the middle ear cavity of rats.

Middle ear inflammation of rat induced by urban particles.

Bone morphogenetic protein 2 (BMP-2) is considered an effective growth factor for bone formation, and is used for making osteo-inductive scaffolds, but the related clinical investigations have shown low success rates. In this study, we genetically manipulated teratoma-derived fibroblast (TDF) cells by simultaneous introduction of BMP-2 and herpes simplex virus-thymidine kinase (HSV-tk) encoding genes. Self-production of BMP-2 in TDF cells strongly enhanced the alkaline phosphatase (ALP) activity, calcium content, and elevated the mRNA expression of osteogenic marker genes during in vitro osteogenesis. The bone formation volume was also remarkably enhanced in calvarial and femoral critical-size defect models. Ganciclovir (GCV) treatment induced apoptosis in TDF cells co-expressing HSV-tk and BMP-2, implying that HSV-tk suicide gene can modulate the side-effects of stem cell therapy, e.g., development of uncontrollable teratoma and tumor formation. Altogether, our findings revealed a safe and highly efficient technique with potential therapeutic applications for bone regeneration.

Engineering functional BMP-2 expressing teratoma-derived fibroblasts for enhancing osteogenesis.

Air-pollutants containing toxic particulate matters (PM) deposit in the respiratory tract and increases microbial infections. However, the mechanism by which this occurs is not well understood. This study evaluated the effect of urban particles (UP) on Streptococcus pneumoniae (pneumococcus) in vitro biofilm formation, colonization of human middle ear epithelium cells (HMEECs) as well as mouse nasal cavity and its transition to the middle ear and lungs. The in vitro biofilms and planktonic growth of S. pneumoniae were evaluated in metal ion free medium in the presence of UP. Biofilms were quantified by crystal violet (CV) microplate assay, colony forming unit (cfu) counts and resazurin staining. Biofilm structures were analyzed using a scanning electron microscope (SEM) and confocal microscopy (CM). Gene expressions of biofilms were evaluated using real time RT-PCR. Effects of UP exposure on S. pneumoniae colonization to HMEECs were evaluated using fluorescent in-situ hybridization (FISH), cell viability was detected using the Ezcyto kit, apoptosis in HMEECs were evaluated using Annexin-V/PI based cytometry analysis and reactive oxygen species (ROS) production were evaluated using the Oxiselect kit. Alteration of HMEECs gene expressions on UP exposure or pneumococci colonization was evaluated using microarray. In vivo colonization of pneumococci in the presence of UP and transition to middle ear and lungs were evaluated using an intranasal mice colonization model. The UP exposure significantly increased (*p < 0.05) pneumococcal in vitro biofilms and planktonic growth. In the presence of UP, pneumococci formed organized biofilms with a matrix, while in absence of UP bacteria were unable to form biofilms. The luxS, ply, lytA, comA, comB and ciaR genes involved in bacterial pathogenesis, biofilm formation and quorum sensing were up-regulated in pneumococci biofilms grown in the presence of UP. The HMEECs viability was significantly decreased (p < 0.05) and bacteria colonization was significantly elevated (p < 0.05) in co-treatment (UP + S. pneumoniae) when compared to single treatment. Similarly, increased apoptosis and ROS production were detected in HMEECs treated with UP + pneumococci. The microarray analysis of HMEECs revealed that the genes involve in apoptosis and cell death, inflammation, and immune response, were up-regulated in co-treatment and were unchanged or expressed in less fold in single treatments of UP or S. pneumoniae. The in vivo study showed an increased pneumococcal colonization of the nasopharynx in the presence of UP and a higher transition of bacteria to the middle ear and lungs in the presence of UP. The UP exposure elevated S. pneumoniae in vitro biofilm and colonization of HMEECs, and in vivo mouse nasopharyngeal colonization, and increased dissemination to mouse middle ear and lungs.

Urban Particles Elevated Streptococcus pneumoniae Biofilms, Colonization of the Human Middle Ear Epithelial Cells, Mouse Nasopharynx and Transit to the Middle Ear and Lungs.

Cannabidiol (CBD) has anti-tumorigenic activity. However, the anti-cancer effect of CBD on head and neck squamous cell carcinoma (HNSCC) remains unclear. The cytotoxicity of CBD on HNSCC was analyzed using cell survival and colony-forming assays in vitro. RNA-seq was used for determining the mechanism underlying CBD-induced cell death. Xenograft mouse models were used to determine CBD's effects in vivo. CBD treatment significantly reduced migration/invasion and viability of HNSCC cells in a dose- and time-dependent manner. HNSCC mouse xenograft models revealed anti-tumor effects of CBD. Furthermore, combinational treatment with CBD enhanced the efficacy of chemotherapy drugs. Apoptosis and autophagy processes were involved in CBD-induced cytotoxicity of HNSCCs. RNA-seq identified decreased expression of genes associated with DNA repair, cell division, and cell proliferation, which were involved in CBD-mediated cytotoxicity toward HNSCCs. We identified CBD as a new potential anti-cancer compound for single or combination therapy of HNSCC.

Cannabidiol enhances cytotoxicity of anti-cancer drugs in human head and neck squamous cell carcinoma.

Human chorion membrane extracts (CME) are known to exhibit osteogenic effects when used for treating human osteoblast-like cells (MG63 cells), but the active compound in CME remains unknown. The aim of this study was to identify the presence of exosomes in CME and to determine the osteogenic effect of CME exosomes on MG63 cells.

Osteogenic effects of exosomes derived from human chorion membrane extracts.

Human mesenchymal stem cells (MSCs) are therapeutic for clinical applications because of their excellent immunomodulatory and multiple lineage differentiation abilities at tissue injury sites. However, insufficient number of cells and lack of regenerative properties during in vitro expansion still limit the clinical applicability of MSC therapies. Here, we demonstrated a preconditioning strategy with trophoblast stem cell-derived extracellular vesicles (TSC-EVs) to boost the proliferation and regenerative capacity of MSCs.

Regenerative capacity of trophoblast stem cell-derived extracellular vesicles on mesenchymal stem cells.

Otitis media is a common disease but can cause severe inner ear inflammation and hearing loss if it persists for more than two weeks. This study elucidates the inflammation-inhibiting efficacy of conditioned medium (CM) and extracellular vesicles (EVs) derived from human trophoblast (TB) cells in lipopolysaccharide (LPS)-induced human middle ear epithelial cells (HMEECs). TB-conditioned medium (TB-CM) reduced the inflammatory response and regulated mucin and epithelial sodium channel genes in LPS-induced HMEECs. The underlying mechanism of cell migration during inflammatory healing in LPS-induced HMEECs treated with TB-CM was determined by RNA-sequencing analysis. Specifically, the NF-κB pathway related to the copper metabolism MURR1 domain protein was studied and verified through siRNA. This elucidation of the anti-inflammatory effect of TB-CM and TB-derived EVs demonstrates their clinical potential to treat chronic inflammation.

Inhibition of lipopolysaccharide-induced inflammation by trophoblast-conditioned medium and trophoblast-derived extracellular vesicles in human middle ear epithelial cells.

Jae-Jun Song

Neurive Co., Ltd.

Understanding the Effects of Non-Invasive Transauricular Vagus Nerve Stimulation on EEG and HRV