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Abstract This study aimed to observe the impact of pure Binaural Beats (BB) stimulation in the inaudible frequency range, excluding the influence of sound, on visuospatial memory. Additionally, we investigated whether the brainwave changes induced by BB stimulation directly affect brain activation. The experiment involved 17 participants (12 males with a mean age of 23.2 ± 1.7 and 5 females with a mean age of 21.0 ± 0.7) in their 20s. Each participant received 10 Hz BB stimulation by presenting frequencies of 18,000 Hz and 18,010 Hz to the left and right ears, respectively. The experiment consisted of Rest phase (5 min), Task phase (5 min), and Rest phase (5 min). The Task phase included conditions where participants performed the task either without BB stimulation “Task only” or with BB stimulation “Task + BB”. Visuospatial memory was evaluated using the 3-back task. To observe brain activation, functional Near Infrared Spectroscopy (fNIRS) was employed to measure hemodynamic responses in all phases. The cognitive task performance (Accuracy, Reaction time) and oxyhemoglobin (HbO) concentration during the Task phase were compared between conditions with and without BB stimulation using paired t-tests. Results indicated a significantly shorter Reaction time in the Task + BB condition compared to the Task only condition. Moreover, an increase in HbO concentration was observed in the F1-F3, F2-F4, and P2-P4 regions during the Task + BB condition. In conclusion, the observed increase in HbO concentration suggests a positive influence on task performance. This study is meaningful in objectively demonstrating the impact of inaudible BB stimulation on visuospatial memory, utilizing both behavioral data and direct neural activation reflected in hemodynamic responses.

Abstract Background Stem cell therapy is a promising alternative for inflammatory diseases and tissue injury treatment. Exogenous delivery of mesenchymal stem cells is associated with instant blood-mediated inflammatory reactions, mechanical stress during administration, and replicative senescence or change in phenotype during long-term culture in vitro. In this study, we aimed to mobilize endogenous hematopoietic stem cells (HSCs) using AMD-3100 and provide local immune suppression using FK506, an immunosuppressive drug, for the treatment of inflammatory bowel diseases. Methods Reactive oxygen species (ROS)-responsive FK506-loaded thioketal microspheres were prepared by emulsification solvent-evaporation method. Thioketal vehicle based FK506 microspheres and AMD3100 were co-administered into male C57BL6/J mice with dextran sulfate sodium (DSS) induced colitis. The effect of FK506-loaded thioketal microspheres in colitis mice were evaluated using disease severity index, myeloperoxidase activity, histology, flow cytometry, and gene expression by qRT-PCR. Results The delivery of AMD-3100 enhanced mobilization of HSCs from the bone marrow into the inflamed colon of mice. Furthermore, targeted oral delivery of FK506 in an inflamed colon inhibited the immune activation in the colon. In the DSS-induced colitis mouse model, the combination of AMD-3100 and FK506-loaded thioketal microspheres ameliorated the disease, decreased immune cell infiltration and activation, and improved body weight, colon length, and epithelial healing process. Conclusion This study shows that the significant increase in the percentage of mobilized hematopoietic stem cells in the combination therapy of AMD and oral FK506 microspheres may contribute to a synergistic therapeutic effect. Thus, low-dose local delivery of FK506 combined with AMD3100 could be a promising alternative treatment for inflammatory bowel diseases.

Radiofrequency ablation (RFA) is a local treatment modality for primary liver cancers. Although various input parameters of the RF generator have been adjusted to improve the ablation ranges, the limited ablation ranges remain an obstacle to RFA. This study aimed to compare the ablation ranges and efficacy of sine and square electrical waveforms in a mouse tumor model. An RF generator with an adjustable electrical waveform was developed, and its ablation range in the porcine liver was compared. For all RF parameters, the square electrical waveform ablation range was greater than that of the sine electrical waveform (all p < 0.001) in the porcine liver. The 45 BALB/c nude mice were used to evaluate the efficacy of the two electrical waveforms after the RFA. The mean tumor volume in the square group was significantly lower than that in the sine group (p < 0.001), indicating a higher survival rate (60%). The cellular coagulative necrosis, inflammatory cell infiltration, heat shock proteins, cellular necrosis, and tumor necrosis were significantly greater in square electrical waveform than in sine electrical waveform (all; p < 0.05). RFA with square electrical waveforms has therapeutic potential for tumor management with an enhanced ablation range.

Although stem cells are a promising avenue for harnessing the potential of adipose tissue, conventional two-dimensional (2D) culture methods have limitations. This study explored the use of three-dimensional (3D) cultures to preserve the regenerative potential of adipose-derived stem cells (ADSCs) and investigated their cellular properties. Flow cytometric analysis revealed significant variations in surface marker expressions between the two culture conditions. While 2D cultures showed robust surface marker expressions, 3D cultures exhibited reduced levels of CD44, CD90.2, and CD105. Adipogenic differentiation in 3D organotypic ADSCs faced challenges, with decreased organoid size and limited activation of adipogenesis-related genes. Key adipocyte markers, such as lipoprotein lipase (LPL) and adipoQ, were undetectable in 3D-cultured ADSCs, unlike positive controls in 2D-cultured mesenchymal stem cells (MSCs). Surprisingly, 3D-cultured ADSCs underwent mesenchymal–epithelial transition (MET), evidenced by increased E-cadherin and EpCAM expression and decreased mesenchymal markers. This study highlights successful ADSC organoid formation, notable MSC phenotype changes in 3D culture, adipogenic differentiation challenges, and a distinctive shift toward an epithelial-like state. These findings offer insights into the potential applications of 3D-cultured ADSCs in regenerative medicine, emphasizing the need for further exploration of underlying molecular mechanisms.

Background: In-stent restenosis caused by tissue hyperplasia and tumor growth through the wire meshes of an implanted self-expandable metallic stent (SEMS) remains an unresolved obstacle. This study aimed to investigate the safety and efficacy of SEMS-mediated radiofrequency ablation (RFA) for treating stent-induced tissue hyperplasia in a rat gastric outlet obstruction model.Methods: The ablation zone was investigated using extracted porcine liver according to the ablation time. The optimal RFA parameters were evaluated in the dissected rat gastric outlet. We allocated 40 male rats to four groups of 10 rats as follows: group A, SEMS placement only; group B, SEMS-mediated RFA at 4 weeks; group C, SEMS-mediated RFA at 4 weeks and housed until 8 weeks; and group D, SEMS-mediated RFA at 4 and 8 weeks. Endoscopy and fluoroscopy for in vivo imaging and histological and immunohistochemical analysis were performed to compare experimental groups.Results: Stent placement and SEMS-mediated RFA with an optimized RFA parameter were technically successful in all groups. Granulation tissue formation-related variables were significantly higher in group A than in groups B–D (all p < 0.05). Endoscopic and histological findings confirmed that the degrees of stent-induced tissue hyperplasia in group D were significantly lower than in groups B and C (all p < 0.05). Hsp70 and TUNEL expressions were significantly higher in groups B–D than in group A (all p < 0.001).Conclusion: The implanted SEMS-mediated RFA successfully managed stent-induced tissue hyperplasia, and repeated or periodic RFA seems to be more effective in treating in-stent restenosis in a rat gastric outlet obstruction model.

Abstract Endoluminal radiofrequency (RF) ablation has been widely used as a safe and effective treatment for Barrett’s esophagus. However, inadequate RF ablation may occur due to insufficient contact between the electrode and target tissues. Herein, a stent-based monopolar RF electrode (SE) was developed to evenly deliver RF energy to the inner wall of the rat esophagus. The optimal RF parameters were evaluated in the exposed rat esophagus. The temperature in the rat esophagus reached 70 ℃ in 89 s at 30 W, 59 s at 40 W, and 34 s at 50 W. The technical feasibility and efficacy of RF ablation using SE were evaluated based on changes in histological transformation and immunohistochemical parameters of tissues compared at immediately, 1 and 2 weeks after the procedure. The degrees of inflammatory cell infiltration, fibrotic changes, TUNEL, and HSP70 in the RF-ablated rat esophagus were significantly higher than compared with sham control (all p

Abstract Oxysterols are oxygenated derivatives of cholesterol that contain an additional hydroxy, epoxide, or ketone group in the sterol nucleus and/or a hydroxyl group in the side chain of the cholesterol molecule. 27-Hydroxycholesterol (27HC) is a side-chain oxysterol that is oxygenated at the 27th carbon atom of cholesterol. The oxysterol (27HC) is produced via oxidation by sterol 27-hydroxylase (CYP27A1) and metabolized via oxysterol 7a-hydroxylase (CYP7B1) for bile acid synthesis in the liver. A previous study has demonstrated that treatment with the alternative Estrogen receptor alpha (ERα) ligand 27HC induces ERα-dependent hematopoietic stem cell (HSC) mobilization. In addition, Cyp27a1-deficient mice demonstrate significantly reduced 27HC levels and HSC mobilization. Here, we report that exogenous 27HC treatment leads to a substantial reduction in the hematopoietic stem and progenitor cell (HSPC) population owing to significantly increased reactive oxygen species (ROS) levels and apoptosis in the bone marrow (BM). However, 27HC does not influence the population of mature hematopoietic cells in the BM. Furthermore, exogenous 27HC treatment suppresses cell growth and promotes ROS production and apoptosis in leukemic cells. Moreover, acute myeloid leukemia (AML) patients with high CYP7B1 expression (expected to have inhibition of 27HC) had significantly shorter survival than those with low CYP7B1 expression (expected to have an elevation of 27HC). Single-cell RNA-sequencing (scRNA seq) analysis revealed that the expression of CYP7B1 was significantly increased in AML patients. Thus, our study suggests that 27HC may serve as a potent agent for regulating pools of HSPCs and may have an application as a novel therapeutic target for hematological malignancies. Collectively, pharmacological inhibition of CYP7B1 (expected to have an elevation of 27HC) would potentially have fewer long-term hematological side effects, particularly when used in combination with chemotherapy or radiation for the treatment of leukemia patients.

Abstract Several derivatives derived from the oxime structure have been reported as potential anticancer agents in various cancers. Here, we first tested a novel oxime-containing derivative of 2-((2,4,5-trifluorobenzyl)oxy)benzaldehyde oxime (TFOBO) to evaluate its anticancer effect in myeloid leukemic cells. Compared to (2-((2,4,5-trifluorobenzyl)oxy)phenyl)methanol (TFOPM), the oxime derivative TFOBO suppresses leukemic cell growth by significantly increasing reactive oxygen species (ROS) levels and cell death. Leukemic cells treated with TFOBO displayed apoptotic cell death, as indicated by nuclear condensation, DNA fragmentation, and annexin V staining. TFOBO increases Bax/Bcl2 levels, caspase9, and caspase3/7 activity and decreases mitochondrial membrane potential. ROS production was reduced by N-acetyl-l-cysteine, a ROS scavenger, diphenyleneiodonium chloride, a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor, after exogenous TFOBO treatment. ROS inhibitors protect leukemic cells from TFOBO-induced cell death. Thus, our study findings suggest that TFOBO promotes apoptosis by modulating ROS and regulating NADPH oxidase activity. Collectively, the oxime-containing derivative TFOBO is a novel therapeutic drug for myeloid leukemia.

Abstract Background Microbiome has been shown to substantially contribute to some cancers. However, the diagnostic implications of microbiome in head and neck squamous cell carcinoma (HNSCC) remain unknown. Methods To identify the molecular difference in the microbiome of oral and non-oral HNSCC, primary data was downloaded from the Kraken-TCGA dataset. The molecular differences in the microbiome of oral and non-oral HNSCC were identified using the linear discriminant analysis effect size method. Results In the study, the common microbiomes in oral and non-oral cancers were Fusobacterium, Leptotrichia, Selenomonas and Treponema and Clostridium and Pseudoalteromonas, respectively. We found unique microbial signatures that positively correlated with Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways in oral cancer and positively and negatively correlated KEGG pathways in non-oral cancer. In oral cancer, positively correlated genes were mostly found in prion diseases, Alzheimer disease, Parkinson disease, Salmonella infection, and Pathogenic Escherichia coli infection. In non-oral cancer, positively correlated genes showed Herpes simplex virus 1 infection and Spliceosome and negatively correlated genes showed results from PI3K-Akt signaling pathway, Focal adhesion, Regulation of actin cytoskeleton, ECM-receptor interaction and Dilated cardiomyopathy. Conclusions These results could help in understanding the underlying biological mechanisms of the microbiome of oral and non-oral HNSCC. Microbiome-based oncology diagnostic tool warrants further exploration.

Osteoporosis, which is often associated with increased osteoclast activity due to menopause or aging, was the main focus of this study. We investigated the inhibitory effects of water extract of desalted Salicornia europaea L. (WSE) on osteoclast differentiation and bone loss in ovariectomized mice. Our findings revealed that WSE effectively inhibited RANKL-induced osteoclast differentiation, as demonstrated by TRAP staining, and also suppressed bone resorption and F-actin ring formation in a dose-dependent manner. The expression levels of genes related to osteoclast differentiation, including NFATc1, ACP5, Ctsk, and DCSTAMP, were downregulated by WSE. Oral administration of WSE improved bone density and structural parameters in ovariectomized mice. Dicaffeoylquinic acids (DCQAs) and saponins were detected in WSE, with 3,4-DCQA, 3,5-DCQA, and 4,5-DCQA being isolated and identified. All tested DCQAs, including the aforementioned types, inhibited osteoclast differentiation, bone resorption, and the expression of osteoclast-related genes. Furthermore, WSE and DCQAs reduced ROS production mediated by RANKL. These results indicate the potential of WSE and its components, DCQAs, as preventive or therapeutic agents against osteoporosis and related conditions.

Background: Irreversible electroporation (IRE) has been investigated in the alimentary tract; however, the lack of dedicated electrodes and insufficient tissue responses made its application limited. The aim of this study was to investigate the efficacy and safety of image-guided stent-directed IRE in the rat esophagus.Methods: The bipolar self-expandable electrode (SE) was developed using the braiding technique. A finite element analysis was performed to validate optimal electrical field strength for the rat esophagus. A total of 40 out of 50 rats received stent-directed IRE and were sacrificed at 10 h, 3 days, 7 days, and 28 days of 10 each. The remaining ten rats underwent a sham procedure. The outcomes of stent-directed IRE were assessed by esophagography and histological responses.Results: Stent-directed IRE was technically successful in all rats with mild muscle contraction. The heart rate dropped immediately and gradually recovered at 180 s. TUNEL and caspase-3 with submucosal thickness significantly increased at 10 h and Day 3 compared with those of the sham control (all p < 0.001). The thickness of epithelial layers with collagen deposition significantly decreased at 10 h and Day 3 (all p < 0.001), however, increased at Day 7 compared with that of the sham control (all p < 0.05). The Ki67-positive deposition significantly increased at Day 3 and 7 compared with that of the sham control (all p < 0.001). All variables were similar to those of the sham control at Day 28.Conclusion: Image-guided stent-directed IRE was effective and safe in the rat esophagus. It seems to have effectively and evenly induced cell death and gradually recovered with cellular regeneration.

In retinal pigment epithelial (RPE) cells, transforming growth factor-beta (TGF-β) plays a critical role in epithelial-mesenchymal transition (EMT), which contributes to various fibrotic retinal disorders. In the present study, we investigated the effect of recombinant human cluster of differentiation 82 (rhCD82), a tumor metastasis suppressor, on TGF-β-induced EMT in the human RPE cell line APRE-19. The results show that TGF-β1 significantly enhanced cell migration, invasion and the expression of EMT-mediate factors in ARPE-19 cells. However, rhCD82 markedly inhibited cell mobility and the expression of epithelial marker, zonula occludens-1, as well as increased the expression of mesenchymal markers, such as vimentin and α-smooth muscle actin in TGF-β1-treated APRE-19 cells. In addition, TGF-β1 upregulated the phosphorylation of Smad, extracellular signal regulated kinase (ERK) and glycogen synthase kinase-3β (GSK-3β), but only phosphorylation of Smad was suppressed by rhCD82. Noteworthy, rhCD82 greatly suppressed the expression of TGF-β receptor I (TGFRI), TGFRII and integrins in TGF-β1-treated APRE-19 cells. In particular, the result of molecular docking analysis and structural modeling show that rhCD82 partially interacts with the TGF-β1 binding sites of TGFRI, TGFRII, integrin β1 and integrin αv. Taken together, this finding suggested that rhCD82 suppressed TGF-β1-induced EMT of RPE by blocking of Smad-dependent pathway, which is caused by rhCD82 interaction with TGFRs and integrins, suggesting new insight into CD82 as a potential therapeutic strategy in fibrotic retinal disorders.

Olfactory loss has been considered as the earliest complication for the aging process while underlying mechanisms and therapeutic strategies remain unclear. Given the correlation between microglial activation and olfactory dysfunction, here we investigated whether the immunomodulatory action of mesenchymal stem cells (MSCs) can rescue the olfactory impairment in old mice. The intranasal delivery of MSCs limited microglial activation and neuronal apoptosis in the olfactory bulb (OB), leading to improvement in olfaction. MSCs down-regulated the proportion of CD86+ microglia and prevented the maturation of cathepsin S, one of the inflammatory mediators in olfactory impairment, via the suppression of p38 MAPK signaling. Notably, old astrocytes could not prevent excessive microgliosis because the endogenous production of Galectin-1 (Gal1), one of the key microglia regulators secreted by astrocytes, was not sufficiently upregulated in the aged brain despite the presence of reactive astrogliosis. Considering that Gal1 is known as a potent paracrine factor of MSCs, we investigated whether MSC-derived Gal1 could compensate for defective astrocyte function in terms of microglial regulation. MSCs and their culture supernatant (MSC-CM) could regulate the direction of microglial differentiation by impeding the polarization towards the pro-inflammatory M1 type; notably, a selective Gal1 inhibitor OTX008 could hinder this phenomenon, indicating that Gal1 is involved in immunomodulation exerted by MSCs. Also, acute microglial activation within the OB upon LPS infusion was attenuated by MSC-CM in a Gal1-dependent manner. Our study demonstrates the therapeutic benefit of MSCs on age-related olfactory dysfunction and suggests Gal1 as a key mediator of the anti-inflammatory action of MSCs.

In this article, we report on an optical real-time autocorrelator readout with a 5 Hz refresh rate, equipped with a transimpedance amplified photodetector based on the two-photon absorption (TPA) of semiconductor photodiodes (PDs) for ultrashort (1 < ps) pulse measurement. By replacing the GaP PD of a commercial TPA detector with GaAsP and Si PD elements, we demonstrated that the spectral response based on the TPA of each photodetector followed the linear response of the corresponding semiconductor PD within accessible wavelength regions. The TPA spectral response of the GaAsP detector exhibited a peak at 1200 nm and a long wavelength limit near 1300 nm. The TPA spectral response of the Si detector exhibited a short wavelength limit near 1170 nm and a linear response up to 1300 nm. The two types of PD were compared with the characteristics of the GaP photodiode. These photoconductive detectors are efficient, compact, and robust sensors and can be used to diagnose the pulse characteristics of ultrafast fiber lasers and light sources near IR wavelengths.

The purpose of this study is to analyze the cognitive characteristics that can be induced by vibration stimuli at two intensities, three frequencies, and five presentation periods. The experiment was conducted on 20 right-handed adult males, and a subjective evaluation was performed using a questionnaire. Regression analysis was performed to observe the parameters affecting cognitive characteristics according to changes in intensity, frequency, and stimulation duration. The regression analysis results showed that the cognitive characteristics affected by changes in intensity, frequency, and stimulation duration were “heavy”, “bold”, “thick”, and “light”. The cognitive characteristics affected by two-variable combinations were “deep”, “clear”, “vibrating”, “dense”, “numb”, “blunt”, “shallow”, “fuzzy”, and “soft”. Cognitive characteristics affected by either intensity, frequency, or stimulation duration were “fast”, “pungent”, “skinny”, “thin”, “slow”, “ticklish”, “tingling”, “prickling”, “tap”, and “rugged”. By observing the cognitive characteristics that can be induced by the combination of intensity, frequency, and stimulation duration, we confirmed that in addition to intensity and frequency, the stimulation duration is an important factor that influences the induction of various cognitive characteristics. The results presented in the study can be used to enhance the utility of haptic surfaces for extended reality applications.

This study proposes a method for determining obstruction of the endotracheal tube (ET) and its degree and location. Respiratory signals were acquired using a three sensor (microphone, pressure, and flow) integrated sensor connector. Obstruction classification involved pre-processing and feature extraction. During pre-processing, one cycle of the respiratory signal was extracted using respiratory cycle extraction and phase segmentation. The signal was then divided into three phases: (i) inspiratory phase, (ii) expiratory phase, and (iii) between both the phases, where the intrapulmonary pressure increased, decreased, and remained constant, respectively. In the feature extraction process, the results were quantified using absolute value average and texture analyses. Artificial ET tubes were fabricated to simulate the presence of foreign substances in the ET tube; they had different degrees of obstruction (0%, 20%, 40%, and 50%) and obstruction positions (Sections 1, 2, and 3). The experiment was performed by connecting the sensor connector and artificial ET tube between the ventilator and test lung. Respiratory signals were obtained in 10 cases by cross connecting the artificial ET tubes. The degree and location of obstruction were classified according to the average absolute value and texture analyses of the flow data. The obstruction can be determined through the texture analysis results using the combined microphone and flow sensor data. The proposed method is simple in configuration, can be readily used in existing setups, and can be operated regardless of surrounding noise.

Xerostomia is a pathologic condition of hyposalivation due to salivary gland (SG) dysfunction. Although xerostomia significantly affects the quality of patients’ life, there is no satisfactory treatment for this disease. Importantly, the senior population is more susceptible to xerostomia than younger individuals and the prevalence of the disease is much higher in elderly women than in men. However, the mechanisms underlying these clinical correlations have not yet been elucidated and further studies are required. Given that cell lines exhibiting saliva-producing abilities are not available, the generation and maturation of salivary gland organoids (SGOs) have been spotlighted as a modeling system to investigate the homeostasis of SG stem cells, as well as the pathophysiology of SGs in disease. In this review article, we will review the latest reports dealing with the generation and maturation of SGOs by defining the stem cells in SGs. We will also discuss the recent literature proposing strategies to model disease and regenerate damaged tissues.

Abstract Emerging evidences have reported that periodontitis can be a risk factor for the pathogenesis of various systemic diseases. Porphyromonas gingivalis (Pg), one of the crucial pathogens in chronic periodontitis, has been spotlighted as a potential cause for the promotion and acceleration of periodontitis-associated systemic disorders. To investigate the association between Pg and intestinal disease or homeostasis, we treated Pg-derived lipopolysaccharide (LPS) in murine colitis model or intestinal organoid, respectively. Pg-derived LPS (Pg LPS) was administrated into chemically induced murine colitis model and disease symptoms were monitored compared with the infusion of LPS derived from E. coli (Ec LPS). Organoids isolated and cultured from mouse small intestine were treated with Pg or Ec LPS and further analyzed for the generation and composition of organoids. In vivo observations demonstrated that both Pg and Ec LPS exerted slight protective effects against murine colitis. Pg LPS did not affect the generation and growth of intestinal epithelial organoids. Among subtypes of epithelial cells, markers for stem cells, goblet cells or Paneth cells were changed in response to Pg LPS. Taken together, these results indicate that Pg LPS leads to partial improvement in colitis and that its treatment does not significantly affect the self-organization of intestinal organoids but may regulate the epithelial composition.

The purpose of this study was to observe the effects of audible and inaudible binaural beat stimuli on alpha power elicitation and compare the differences in triggering effects depending on sound perception. Experiments were conducted on healthy male and female subjects (11 males and 10 females, mean age of 24.6 ± 1.8). To induce alpha waves, audible (250 Hz) or non-audible baseline sound frequencies (18,000 Hz) were presented to the left ear, and a frequency 10 Hz higher than the baseline was presented to the right ear. There were two experimental phases: a rest phase (5 min) in which no stimulus was presented and a stimulation phase (5 min) in which the binaural beat stimulus was presented. An electroencephalogram was measured at a sampling rate of 500 Hz, and relative alpha power values were calculated for each phase in each brain area. In the central regions, both baseline frequencies (audible and inaudible) increased the relative alpha power during the stimulation phase compared with the rest phase, and there were no differences between the two baseline frequencies. In the frontal and central regions, there was a greater increase in relative alpha power in the audible case compared with the inaudible case.

This study demonstrates the feasibility of a mid-air means of haptic stimulation at a long distance using the plasma effect induced by laser. We hypothesize that the stress wave generated by laser-induced plasma in the air can propagate through the air to reach the nearby human skin and evoke tactile sensation. To validate this hypothesis, we investigated somatosensory responses in the human brain to laser plasma stimuli by analyzing electroencephalography (EEG) in 14 participants. Three types of stimuli were provided to the index finger: a plasma stimulus induced from the laser, a mechanical stimulus transferred through Styrofoam stick, and a sham stimulus providing only the sound of the plasma and mechanical stimuli at the same time. The event-related desynchronization/synchronization (ERD/S) of sensorimotor rhythms (SMRs) in EEG was analyzed. Every participant verbally reported that they could feel a soft tap on the finger in response to the laser stimulus, but not to the sham stimulus. The spectrogram of EEG evoked by laser stimulation was similar to that evoked by mechanical stimulation; alpha ERD and beta ERS were present over the sensorimotor area in response to laser as well as mechanical stimuli. A decoding analysis revealed that classification error increased when discriminating ERD/S patterns between laser and mechanical stimuli, compared to the case of discriminating between laser and sham, or mechanical and sham stimuli. Our neurophysiological results confirm that tactile sensation can be evoked by the plasma effect induced by laser in the air, which may provide a mid-air haptic stimulation method.

The aim of this study was to observe the effects of oligonol on submandibular gland dysfunction in ovariectomized rats. We randomly divided female Sprague-Dawley rats into sham-operated, ovariectomized, and oligonol-treated ovariectomized groups. Oligonol was intraperitoneally administered at 30 mg/kg daily for six weeks. Lipogenesis increased after the ovariectomy while fatty acid oxidation increased and intracellular triglyceride levels decreased in response to oligonol treatment. Submandibular gland fibrosis characterized by collagen type I accumulation was observed in the ovariectomized group. However, oligonol markedly reduced fibrosis to a level comparable to that observed in the sham group. Aquaporin 1 and glucose transporter 4 were downregulated in the ovariectomized group. Nevertheless, both factors were significantly upregulated by oligonol treatment. However, aquaporin 5 was significantly downregulated in the oligonol treatment group. Our findings indicate that oligonol protects against damage in postmenopausal rat salivary glands.

Post-menopausal dry mouth or xerostomia is caused by reduced salivary secretion. This study aimed to investigate the efficacy of echinochrome A (Ech A) in alleviating submandibular gland dysfunctions in ovariectomized rats that mimic menopause. Female rats that were eight-weeks-old were randomly divided into SHAM-6, -12; OVX-6, -12; and ECH-6, -12 groups (consisting of 6- and 12-weeks post-sham-operated, ovariectomized, and Ech A-treated ovariectomized rats, respectively). The ECH groups had lower body weight than OVX but similar food intake and estradiol or estrogen receptor β expression. However, the ECH groups had lower mRNA expression of sterol-regulatory element binding protein-1c (Srebp-1c), acetyl-CoA carboxylase (Acc), fatty acid synthase (Fasn), cluster of differentiation 36 (Cd36), and lipid vacuole deposition than OVX mice. Moreover, reactive oxygen species (ROS), malondialdehyde (MDA), and iron accumulation were lower in the ECH than in the OVX groups. Fibrosis markers, transforming growth factor β (Tgf-βI and Tgf-βII mRNA) increased in the OVX than SHAM groups but decreased in the ECH groups. Aquaporin (Aqp-1 and Aqp-5 mRNA) and mucin expressions were downregulated in the OVX groups but improved with Ech A. In addition, Ech A prevented post-menopausal salivary gland dysfunction by inhibiting lipogenesis and ferroptosis. These findings suggest Ech A as an effective remedy for treating menopausal dry mouth.

The diverse therapeutic feasibility of the sea urchin-derived naphthoquinone pigment, Echinochrome A (Ech A), has been studied. Simple and noninvasive administration routes should be explored, to obtain the feasibility. Although the therapeutic potential has been proven through several preclinical studies, the biosafety of orally administered Ech A and its direct influence on intestinal cells have not been evaluated. To estimate the bioavailability of Ech A as an oral administration drug, small intestinal and colonic epithelial organoids were developed from mice and humans. The morphology and cellular composition of intestinal organoids were evaluated after Ech A treatment. Ech A treatment significantly increased the expression of LGR5 (~2.38-fold change, p = 0.009) and MUC2 (~1.85-fold change, p = 0.08). Notably, in the presence of oxidative stress, Ech A attenuated oxidative stress up to 1.8-fold (p = 0.04), with a restored gene expression of LGR5 (~4.11-fold change, p = 0.0004), as well as an increased expression of Ly6a (~3.51-fold change, p = 0.005) and CLU (~2.5-fold change, p = 0.01), markers of revival stem cells. In conclusion, Ech A is harmless to intestinal tissues; rather, it promotes the maintenance and regeneration of the intestinal epithelium, suggesting possible beneficial effects on the intestine when used as an oral medication.

Background: Several dietary patterns are reported as risk factors for several chronic diseases including oral diseases. However, thus far, there has been no comprehensive quantitative analysis of nutrition and periodontal diseases. Methods: This systematic review was conducted according to the PRISMA guidelines. Cohort, case–control, and cross-sectional studies were eligible for inclusion in this study. The Newcastle–Ottawa scale was used to qualitatively assess the risk of bias in the included studies. The number of samples was used for odds ratio calculation, followed by the unadjusted value and 95% confidence interval. Results: Nine papers were included for the systematic review and meta-analysis. The results of screening for database search records showed that four diet patterns (western diet, dairy product intake, sugar intake, and vitamin C intake) have enough data for meta-analysis. The risk of periodontal disease in the western-diet group and the lowest dairy product intake group was 1.05 (0.51–2.13) and 1.28 (0.89–1.84), respectively. The risk of periodontal disease in the highest sugar intake group and the lowest vitamin C intake group was 1.52 (0.79–2.91) and 1.15 (1.08–1.23), respectively. Conclusions: With aging of the population globally, the prevalence of periodontal disease increases, and the associated cost also increases. Though this study, we found foods related to the risk of periodontal disease, and we are confident that it will contribute to lowering the incidence of the disease.

Abstract Background Systemic inflammatory response syndrome (SIRS) is common in severe fulminant hepatic failure (FHF) and has a high mortality rate (20–50%) due to irreversible cerebral edema or sepsis. Stem cell-based treatment has emerged as a promising alternative therapeutic strategy to prolong the survival of patients suffering from FHF via the inhibition of SIRS due to their immunomodulatory effects. Methods 3D spheroids of adipose-derived mesenchymal stem cells (3D-ADSC) were prepared by the hanging drop method. The efficacy of the 3D-ADSC to rescue FHF was evaluated in a d-galactosamine/lipopolysaccharide (GalN/LPS)-induced mouse model of FHF via intraportal transplantation of the spheroids. Results Intraportally delivered 3D-ADSC better engrafted and localized into the damaged livers compared to 2D-cultured adipose-derived mesenchymal stem cells (2D-ADSC). Transplantation of 3D-ADSC rescued 50% of mice from FHF-induced lethality, whereas only 20% of mice survived when 2D-ADSC were transplanted. The improved transplantation outcomes correlated with the enhanced immunomodulatory effect of 3D-ADSC in the liver microenvironment. Conclusion The study shows that the transplantation of optimized 3D-ADSC can efficiently ameliorate GalN/LPS-induced FHF due to improved viability, resistance to exogenous ROS, and enhanced immunomodulatory effects of 3D-ADSC.

Objectives Factors predictive of the severity of and recovery from Bell’s palsy remain unclear. This study evaluated the association between neutrophil to lymphocyte ratio (NLR) and the severity of and recovery from Bell’s palsy. Methods This retrospective study included 51 patients who were hospitalized with Bell’s palsy from 2015 to 2017. Degree of paralysis was assessed by House-Brackmann (H-B) grade. Patients with H-B grades 2–4 were classified as having mild to moderate palsy and patients with H-B grade 5 or 6 were classified as having severe palsy. Patients were evaluated for obesity, hypertension and diabetes mellitus, and blood tests were performed to determine NLR and platelet to lymphocyte ratio. Patients were treated with steroids and antiviral agents. H-B grade was assessed 1 week, 1 month, and 3 months after treatment. Results NLR was significantly higher in patients with severe than with mild to moderate palsy (P=0.048). Recovery time was significantly longer in patients with high NLR than low NLR (P=0.045). Conclusion Higher NLR in patients with Bell’s palsy was associated with longer recovery time. NLR may be prognostic of recovery time in patients with Bell’s palsy.

Intramural hematoma of the gastrointestinal tract is a rare disease entity. Pancreatitis-induced intramural gastric hematoma (IGH) is far more seldom reported. Here, we report a rare case of a giant IGH occurring as a delayed complication of pancreatitis in a 51-year-old man. The diagnosis was made using computed tomography (CT) and endoscopic ultrasonography. The patient was conservatively managed, and follow-up abdominal CT showed marked decreases in the size of the IGH.

Abstract Background This study was conducted to measure the effect of different drilling depths on compression forces generated by two commonly used headless compression screws using the two different types of drill bit, the Acutrak® mini (conical type drill bit) and the Synthes 3.0 HCS® (cylindrical type drill bit). Methods A load cell was placed between two Sawbone blocks, which were 12 mm and 40 mm in thickness, respectively. After placing the guide pin into the center of the block, the drilling depth of the Acutrak® mini and Synthes HCS® screws ranged from 16 to 28 mm and 22 to 28 mm, respectively. The 24-mm screws were inserted and the compression force was measured immediately and at 30 min post-insertion. Results The Acutrak® mini generated greater compression force compared to the Synthes 3.0 HCS® when drilled to a depth of less than 24 mm. The compression force of the Acutrak® mini showed a strong inverse correlation with the drilling depth. There was no significant inverse correlation observed between the compression force of the Synthes HCS® and the drilling depth. Conclusions If the screw length and the drill depth are the same, the Synthes 3.0 HCS® (cylindrical type drill bit) is safer and easier to use as it has no change in the compression force even when over-drilling because the compression force of the two screws is similar. As for the Acutrak® mini (conical type drill bit), while it is technically demanding due to varying compression force according to the drill depth, it can be used in certain cases because it can give stronger compression force through under-drilling.

This study was examined the effective connectivity between brain areas activated during driving. Using a driving simulator, the subjects controlled a wheel with both of their hands as well as an accelerator and brake pedal with their right foot. Of the areas activated during driving, three areas from each hemisphere were analyzed for effective connectivity using dynamic causal modeling. In the right hemisphere, bidirectional connectivity was prominent between the inferior temporal gyrus, precuneus, and lingual gyrus, which provided driving input (driving input refers to the area of input among areas connected with effective connectivity). In the left hemisphere, the superior temporal gyrus provided driving input, and bidirectional connectivity was prominent between the superior temporal gyrus, inferior parietal lobule, and inferior frontal gyrus. The visual attention pathway was activated in the right hemisphere, whereas the inhibitory control movement and task-switching pathways, which are responsible for synesthesia, were activated in the left hemisphere. In both of the hemispheres, the visual attention, inhibitory control movement, and episodic memory retrieval pathways were prominent. The activation of these pathways indicates that driving requires multi-domain executive function in addition to vision. Moreover, pathway activation is influenced by the driving experience and familiarity of the driver. This study elucidated the overall effective connectivity between brain areas related to driving.

The therapeutic potential of tonsil-derived mesenchymal stem cells (TMSCs) has been proved in several in vitro and in vivo models based on their antioxidative capacity. Oxidative stress is involved in the formation of vocal fold scars and the aging of vocal folds. However, few studies have examined the direct correlation between oxidative damage and reconstitution of extracellular matrix (ECM) in the vocal fold fibrosis. We, therefore, sought to investigate the impact of oxidative stress on cell survival and ECM production of human vocal fibroblasts (hVFFs) and the protective effects elicited by TMSCs against oxidative damages in hVFFs. hVFFs were exposed to different concentrations of tert-butyl hydroperoxide in the presence or absence of TMSCs. Cell viability and reactive oxygen species (ROS) production were assessed to examine the progression of oxidative stress in vitro. In addition, expression patterns of ECM-associated factors including various collagens were examined by real-time PCR and immunocytochemical analysis. We found that both cell viability and proliferation capacity of hVFFs were decreased following the exposure to tBHP in a dose-dependent manner. Furthermore, tBHP treatment induced the generation of ROS and reactive aldehydes, while it decreased endogenous activity of antioxidant enzymes in hVFF. Importantly, TMSCs could rescue these oxidative stress-associated damages of hVFFs. TMSCs also downregulated tBHP-mediated production of proinflammatory cytokines in hVFFs. In addition, coculture with TMSC could restore the endogenous matrix metalloproteinase (MMP) activity of hVFFs upon tBHP treatment and, in turn, reduce the oxidative stress-induced ECM accumulation in hVFFs. We have, therefore, shown that the changes in hVFF proliferative capacity and ECM gene expression induced by oxidative stress are consistent with in vivo phenotypes observed in aging vocal folds and vocal fold scarring and that TMSCs may function to reduce oxidative stress in aging vocal folds.

Inherited metabolic disease: Restoring motor function by reducing cholesterol An acid secreted by stem cells can reduce the excess cholesterol caused by a genetic metabolic disorder. Niemann–Pick type C disease is a rare, inherited condition that causes defective muscular development and progressive neurological degeneration. A key disease mechanism is the excessive accumulation of cholesterol within cells. Kyung-Sun Kang at Seoul National University, South Korea, and co-workers have demonstrated that a metabolite molecule called 14,15-epoxyeicosatrienoic acid (14,15-EET) derived from stem cells from human umbilical cord blood significantly reduced cholesterol in Neimann-Pick Type C mouse models and human cell samples. The team administered the stem cell therapy non-invasively via the nose, and observed significant improvements in motor function in the mice. Experiments in both animals and cells showed that the treatment resulted in reduced cholesterol levels and the correction of defective signalling within cells.

Aging: Clues in nuclear proteins Abnormal versions of proteins that support the structure and function of the membrane of the cell nucleus are implicated in premature aging disorders, and also in normal aging. Researchers in South Korea led by Kyung-Sun Kang at Seoul National University investigated the protein network known as the nuclear lamina. They studied a specific type of human stem cell that gives rise to bone, cartilage, muscle and fat. They found that altering the levels of proteins produced by specific key genes promotes cell aging, and the alterations led to abnormalities in the proteins of the nuclear lamina. The researchers suggest that their work provides new insights into the molecular and cellular causes of premature and normal aging. Understanding the molecular triggers of aging could lead to treatments to delay both its normal and disease-linked forms.

Stem cell therapy: Finding the best cells Stem cells from some donors have a stronger therapeutic effect than others, and can be identified by genetic markers. Adult or mesenchymal stem cells (MSCs), which can differentiate into many other cell types, show promise to treat many diseases. Kyung-Sun Kang at Seoul National University and co-workers investigated whether MSCs from some donors show better therapeutic efficacy than others. They tested MSCs from several donors in a mouse model simulating a stroke in a hindlimb, and measured regrowth of blood vessels. MSCs from one donor showed higher regenerative efficacy, triggering regrowth of many blood vessels and allowing the limb to be saved. Kang and co-workers used genetic analysis to identify genes that showed higher expression in these MSCs. This gene expression profile could be used to select MSCs with a higher regenerative capacity.

Superoxide dismutase 3 (SOD3), also known as extracellular superoxide dismutase, is an enzyme that scavenges reactive oxygen species (ROS). It has been reported that SOD3 exerts anti-inflammatory abilities in several immune disorders. However, the effect of SOD3 and the underlying mechanism in inflammatory bowel disease (IBD) have not been uncovered. Therefore, in the present study, we investigated whether SOD3 can protect intestinal cells or organoids from inflammation-mediated epithelial damage. Cells or mice were treated with SOD3 protein or SOD3-transduced mesenchymal stem cells (MSCs). Caco-2 cells or intestinal organoids stimulated with pro-inflammatory cytokines were used to evaluate the protective effect of SOD3 on epithelial junctional integrity. Dextran sulfate sodium (DSS)-induced colitis mice received SOD3 or SOD3-transduced MSCs (SOD3-MSCs), and were assessed for severity of disease and junctional protein expression. The activation of the mitogen-activated protein kinase (MAPK) pathway and elevated expression of cytokine-encoding genes decreased in TNF-α-treated Caco-2 cells or DSS-induced colitis mice when treated with SOD3 or SOD3-MSCs. Moreover, the SOD3 supply preserved the expression of tight junction (ZO-1, occludin) or adherence junction (E-cadherin) proteins when inflammation was induced. SOD3 also exerted a protective effect against cytokine- or ROS-mediated damage to intestinal organoids. These results indicate that SOD3 can effectively alleviate enteritis symptoms by maintaining the integrity of epithelial junctions and regulating inflammatory- and oxidative stress.

Blood transfusions hold an indispensable part in the modern healthcare system. Up to date, the blood supply is largely dependent on donations. Unfortunately, collecting the clinical-grade blood products has become a challenging mission due to accelerated population aging, which not only increases the need for blood transfusions but also decreases the number of healthy donors. Moreover, individuals with severe hematological abnormalities or rare blood phenotypes need alternative therapeutic approaches instead of conventional blood transfusion. In these aspects, the concept of in vitro/ex vivo production of blood cells has been emerging and many attempts have been focused on manufacturing mature erythrocytes, so-called red blood cells (RBCs), the most common and important component among the blood derivatives. In this review, we provide a general overview regarding the current strategies for generating RBCs from various stem cell sources including pluripotent stem cells (PSCs) as well as circulating blood stem cells and the remaining challenges that must be overcome prior to their practical application.

Mesenchymal stem cells (MSCs) have been reported to possess regulatory functions on immune cells which make them alternative therapeutics for the treatment of inflammatory and autoimmune diseases. The interaction between MSCs and immune cells through paracrine factors might be crucial for these immunomodulatory effects of MSCs. Extracellular vesicles (EVs) are defined as bilayer membrane structures including exosomes and microvesicles which contain bioactive paracrine molecules affecting the characteristics of target cells. Recently, several studies have revealed that EVs derived from MSCs (MSC-EVs) can reproduce similar therapeutic impacts of parent MSCs; MSC-EVs could regulate proliferation, maturation, polarization, and migration of various immune effector cells and modulate the immune microenvironment depending on the context by delivering inflammatory cytokines, transcription factors, and microRNAs. Therefore, MSC-EVs can be applied as novel and promising tools for the treatment of immune-related disorders to overcome the limitations of conventional cell therapy regarding efficacy and toxicity issues. In this review, we will discuss current insights regarding the major outcomes in the evaluation of MSC-EV function against inflammatory disease models, as well as immune cells.

Benzo[a]pyrene, classified as a Group 1 carcinogen, is metabolized to B[a]P-7,8-dihydrodiol-9,10-epoxide (BPDE), causing DNA mutations and eventually cancer. Quercetin is a dietary flavonoid abundant in fruits and vegetables. After quercetin intake, quercetin’s metabolites isorhamnetin and miquelianin are more highly concentrated than quercetin in the human plasma. In this study, we investigated the molecular mechanisms associated with the cytoprotective effect of quercetin and its metabolites against benzo[a]pyrene from a detoxification perspective. Quercetin and its metabolite isorhamnetin reduced benzo[a]pyrene-induced cytotoxicity, whereas the metabolite miquelianin did not mitigate benzo[a]pyrene-induced cytotoxicity. Moreover, quercetin and isorhamnetin reduced intracellular levels of BPDE-DNA adducts. The formation and elimination of BPDE is mediated by the xenobiotic detoxification process. Quercetin and isorhamnetin increased the gene and protein expression levels of phase I, II, and III enzymes involved in xenobiotic detoxification. Furthermore, quercetin and isorhamnetin induced the translocation of aryl hydrocarbon receptor (AhR) and nuclear factor erythroid 2-related factor 2 (NRF2), which regulate the expression level of phase enzymes. Our results suggest that quercetin and isorhamnetin promote the metabolism, detoxification, and elimination of B[a]P, thereby increasing anti-genotoxic effects and protecting against B[a]P-induced cytotoxicity.

A non-contact tactile stimulation system using a time-varying magnetic field was developed. The system comprises a control unit, power unit, output unit, and actuator. The control unit adjusts stimulation parameters, particularly the signal intensity and frequency. The power unit produces high voltages for generating the magnetic field, whereas the output unit transmits the energy generated according to the signal from the control unit to the actuator. A spiral coil actuator generates the magnetic field. To validate the effectiveness of the system, preliminary experiments on 10 male adults without neurological disorders (23.2 ± 3.05 years) were conducted. Magnetic field stimuli were presented to the right palm of the subjects at three different frequencies (10, 30, and 50 Hz), and corresponding electroencephalogram (EEG) signals were measured simultaneously. Event-related potential (ERP) analysis showed that N100 and P300 components were identified in somatosensory areas. Subjective evaluations revealed that feelings such as “tingling,” “trembling,” “tapping,” and “percussing” were induced. Moreover, as the stimulus frequency changes, differences may occur in induced feeling. The system uses a time-varying magnetic field, which not only induces tactile stimulation without contact but also has trans-object characteristics that can present tactile sensations, even when there is an obstacle between an actuator and skin.

This study aims to use functional magnetic resonance imaging (fMRI) to assess the effective connectivity between the regions of the brain activated when driving and performing a secondary task (addition task). The subjects used an MR-compatible driving simulator ㅊ to manipulate the driving wheel with both hands and control the pedals (accelerator and brake) with their right foot as if they were driving in an actual environment. Effective connectivity analysis was performed for three regions of the right and the left hemispheres with the highest z-scores, and six of the regions of the entire brain (right and left hemisphere) activated during driving by dynamic causal modeling (DCM). In the right hemisphere, a motor control pathway related to movement control for driving performance was discovered; in the left hemisphere, the pathways in the regions related to movement control for driving performance, starting with the region associated with the secondary task, were discovered. In the whole brain, connectivity was discovered in each of the right and left hemispheres. The motor network of declarative memory, which is the connectivity of the right thalamus, left lingual gyrus, and right precentral gyrus, was worth noting. These results seem meaningful, as they demonstrate the connectivity associated with the control of voluntary movement related to memory from human experience, although limited to driving tasks.

Diabetic nephropathy (DN) is one of the most common complications of diabetes mellitus. After development of DN, patients will progress to end-stage renal disease, which is associated with high morbidity and mortality. Here, we developed early-stage diagnostic biomarkers to detect DN as a strategy for DN intervention. For the DN model, Zucker diabetic fatty rats were used for DN phenotyping. The results revealed that DN rats showed significantly increased blood glucose, blood urea nitrogen (BUN), and serum creatinine levels, accompanied by severe kidney injury, fibrosis and microstructural changes. In addition, DN rats showed significantly increased urinary excretion of kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL). Transcriptome analysis revealed that new DN biomarkers, such as complementary component 4b (C4b), complementary factor D (CFD), C-X-C motif chemokine receptor 6 (CXCR6), and leukemia inhibitory factor (LIF) were identified. Furthermore, they were found in the urine of patients with DN. Since these biomarkers were detected in the urine and kidney of DN rats and urine of diabetic patients, the selected markers could be used as early diagnosis biomarkers for chronic diabetic nephropathy.

Mesenchymal stem cells (MSCs) have been developed as cell therapeutics for various immune disorders using their immunoregulatory properties mainly exerted by their paracrine functions. However, variation among cells from different donors, as well as rapid clearance after transplantation have impaired the uniform efficacy of MSCs and limited their application. Recently, several strategies to overcome this limitation have been suggested and proven in pre-clinical settings. Therefore, in this review article, we will update the knowledge on bioengineering strategies to improve the immunomodulatory functions of MSCs, including genetic modification and physical engineering.

Despite endogenous insults such as mechanical stress and danger signals derived from the microbiome, the intestine can maintain its homeostatic condition through continuous self-renewal of the crypt–villus axis. This extraordinarily rapid turnover of intestinal epithelium, known to be 3 to 5 days, can be achieved by dynamic regulation of intestinal stem cells (ISCs). The crypt base-located leucine-rich repeat-containing G-protein-coupled receptor 5-positive (Lgr5+) ISCs maintain intestinal integrity in the steady state. Under severe damage leading to the loss of conventional ISCs, quiescent stem cells and even differentiated cells can be reactivated into stem-cell-like cells with multi-potency and contribute to the reconstruction of the intestinal epithelium. This process requires fine-tuning of the various signaling pathways, including the Hippo–YAP system. In this review, we summarize recent advances in understanding the correlation between Hippo–YAP signaling and intestinal homeostasis, repair, and tumorigenesis, focusing specifically on ISC regulation.

Mesenchymal stem cells (MSCs) have been spotlighted in the field of cell therapies as a promising tool for the treatment of intractable inflammatory diseases. However, their therapeutic potency still shows a gap between preclinical and clinical settings, and distinctive characteristics of specific tissue-derived MSCs and definitive ways to maximize their beneficial functions have not been fully elucidated yet. We previously identified the unique MSCs population from human palatine tonsil (TMSCs) and revealed their superior properties in proliferation and ROS regulation. Based on these findings, we explored further characteristics of TMSCs particularly focused on immunomodulatory function. We found the merit of TMSCs as a therapeutic agent that retains favorable MSCs properties until relatively late passages and revealed that pre-treatment of TNF-α can enhance the immunomodulatory abilities of TMSCs through the upregulation of the PTGS2/PGE2 axis. TMSCs primed with TNF-α effectively restrained the proliferation and differentiation of T lymphocytes and macrophages in vitro, and more interestingly, these TNF-α-licensed TMSCs exhibited significant prophylactic and therapeutic efficacy in a murine model of autoimmune-mediated acute colitis via clinical and histopathological assessment compared to unprimed naïve TMSCs. These findings provide novel insight into the optimization and standardization of MSCs-based anti-inflammatory therapies, especially targeting inflammatory bowel disease (IBD).

The immunoregulatory abilities of mesenchymal stem cells (MSCs) have been investigated in various autoimmune and allergic diseases. However, the therapeutic benefits observed in preclinical settings have not been reproducible in clinical trials. This discrepancy is due to insufficient efficacy of MSCs in harsh microenvironments, as well as batch-dependent variability in potency. Therefore, to achieve more beneficial and uniform outcomes, novel strategies are required to potentiate the therapeutic effect of MSCs. One of simple strategies to augment cellular function is genetic manipulation. Several studies showed that transduction of antioxidant enzyme into cells can increase anti-inflammatory effects. Therefore, we evaluated the immunoregulatory abilities of MSCs introduced with extracellular superoxide dismutase 3 (SOD3) in the present study. SOD3-overexpressed MSCs (SOD3-MSCs) reduced the symptoms of murine model of atopic dermatitis (AD)-like inflammation, as well as the differentiation and activation of various immune cells involved in AD progression. Interestingly, extracellular vesicles (EVs) isolated from SOD3-MSCs delivered SOD3 protein. EVs carrying SOD3 also exerted improved therapeutic efficacy, as observed in their parent cells. These results suggest that MSCs transduced with SOD3, an antioxidant enzyme, as well as EVs isolated from modified cells, might be developed as a promising cell-based therapeutics for inflammatory disorders.

In this study, we measured neuronal activation in the primary somatosensory area (S1) and Brodmann area 3 (BA3) using 3T functional magnetic resonance imaging (fMRI) while presenting a 250-Hz high-frequency vibrational stimulus to each of three phalanges (distal, intermediate, and proximal) of four fingers of the right hand (index, middle, ring, and little). We compared the nerve activation area between each finger and each phalange. Ten healthy male college students (26.6 ± 2.5 years old) participated in this study. One session consisted of three blocks: a rest (30 s), stimulation (30 s), and response phase (9 s). In the rest phase, the vibrational stimulus was not presented. In the stimulation phase, the vibrational stimulation was presented at any one of the three phalanges of the selected finger. In the response phase, subjects were instructed to press a button corresponding to the phalange that they thought had received the vibration. The subtraction method was used to extract the activation area. The activation area in the S1 was the largest when the little finger was stimulated (for the finger comparison), and largest when the second phalange was stimulated (for the phalange comparison). The BA3 showed similar trends, and there was no statistically significant difference.

Adult stem cells have been developed as therapeutics for tissue regeneration and immune regulation due to their self-renewing, differentiating, and paracrine functions. Recently, a variety of adult stem cells from the oral cavity have been discovered, and these dental stem cells mostly exhibit the characteristics of mesenchymal stem cells (MSCs). Dental MSCs can be applied for the replacement of dental and oral tissues against various tissue-damaging conditions including dental caries, periodontitis, and oral cancers, as well as for systemic regulation of excessive inflammation in immune disorders, such as autoimmune diseases and hypersensitivity. Therefore, in this review, we summarized and updated the types of dental stem cells and their functions to exert therapeutic efficacy against diseases.

Benzo[a]pyrene (B[a]P), a group 1 carcinogen, induces mutagenic DNA adducts. Myricetin is present in many natural foods with diverse biological activities, such as anti-oxidative and anti-cancer activities. The aim of this study was to investigate the protective effects of myricetin against B[a]P-induced toxicity. Treatment of B[a]P induced cytotoxicity on HepG2 cells, whereas co-treatment of myricetin with B[a]P reduced the formation of the B[a]P-7,8-dihydrodiol-9,10-epoxide (BPDE)-DNA adduct, which recovered cell viability. Furthermore, we found a protective effect of myricetin against B[a]P-induced genotoxicity in rats, via myricetin-induced inhibition of 8-hydroxy-2′-deoxyguanosine (8-OHdG) and BPDE-DNA adduct formation in the liver, kidney, colon, and stomach tissue. This inhibition was more prominent in the liver than in other tissues. Correspondingly, myricetin regulated the phase I and II enzymes that inhibit B[a]P metabolism and B[a]P metabolites conjugated with DNA by reducing and inducing CYP1A1 and glutathione S-transferase (GST) expression, respectively. Taken together, this showed that myricetin attenuated B[a]P-induced genotoxicity via regulation of phase I and II enzymes. Our results suggest that myricetin is anti-genotoxic, and prevents oxidative DNA damage and BPDE-DNA adduct formation via regulation of phase I and II enzymes.

Mesenchymal stromal cells (MSCs) from various sources exhibit different potential for stemness and therapeutic abilities. Recently, we reported a unique MSCs from human palatine tonsil (TMSCs) and their superior proliferation capacity compared to MSCs from other sources. However, unique characteristics of each MSC are not yet precisely elucidated. We investigated the role of stanniocalcin-1 (STC1), an anti-oxidative hormone, in the functions of TMSCs. We found that STC1 was highly expressed in TMSC compared with MSCs from bone marrow or adipose tissue. The proliferation, senescence and differentiation of TMSCs were assessed after the inhibition of STC1 expression. STC1 inhibition resulted in a significant decrease in the proliferation of TMSCs and did not affect the differentiation potential. To reveal the anti-oxidative ability of STC1 in TMSCs themselves or against other cell types, the generation of mitochondrial reactive oxygen species (ROS) in TMSC or ROS-mediated production of interleukin (IL)-1β from macrophage-like cells were detected. Interestingly, the basal level of ROS generation in TMSCs was significantly elevated after STC1 inhibition. Moreover, down-regulation of STC1 impaired the inhibitory effect of TMSCs on IL-1β production in macrophages. Taken together, these findings indicate that STC1 is highly expressed in TMSCs and plays a critical role in proliferating and ROS-regulatory abilities.