Sleep Fragmentation Accelerates Carcinogenesis in a Chemical-Induced Colon Cancer Model.

Aims of this study were to test whether sleep fragmentation (SF) increased carcinogenesis and to investigate the possible mechanisms of carcinogenesis in a chemical-induced colon cancer model. In this study, eight-week-old C57BL/6 mice were divided into Home cage (HC) and SF groups. After the azoxymethane (AOM) injection, the mice in the SF group were subjected to SF for 77 days. SF was accomplished in a sleep fragmentation chamber. In the second protocol, mice were divided into 2% dextran sodium sulfate (DSS)-treated, HC, and SF groups and were exposed to the HC or SF procedures. Immunohistochemical and immunofluorescent stainings were conducted to determine the level of 8-OHdG and reactive oxygen species (ROS), respectively. Quantitative real-time polymerase chain reaction was used to assess the relative expression of inflammatory and ROS-generating genes. The number of tumors and average tumor size were significantly higher in the SF group than in the HC group. The intensity (%) of the 8-OHdG stained area was significantly higher in the SF group than in the HC group. The fluorescence intensity of ROS was significantly higher in the SF group than the HC group. SF accelerated cancer development in a murine AOM/DSS-induced model of colon cancer, and the increased carcinogenesis was associated with ROS- and oxidative stress-induced DNA damage.

A pH-Responsive Glycyrrhetinic-Acid-Modified Small-Molecule Conjugate for NIR Imaging of Hepatocellular Carcinoma (HCC).

We report a glycyrrhetinic-acid (GA)-decorated small-molecule conjugate for pH-triggered near-infrared (NIR) fluorescence imaging of hepatocellular carcinoma (HCC). Our in vitro studies demonstrated that the conjugate, referred to as NIR-GA, was efficiently taken up by liver cancer cell lines such as HepG2 and Huh7 through an endocytic pathway mediated by GA receptors. As suggested by co-localization studies, NIR-GA mainly localized in the lysosome, where the acidic pH results in the activation of the fluorescent dye through H+ -triggered spirolactam ring opening to give strong fluorescence in the NIR region.

Intermittent hypoxia promotes carcinogenesis in azoxymethane and dextran sodium sulfate-induced colon cancer model.

Intermittent hypoxia (IH), a characteristic of obstructive sleep apnea, is known to promote cancer progression and aggressiveness in mouse models. However, little is known regarding the effect of IH on cancer initiation. Here, the effect of IH on carcinogenesis was explored in azoxymethane (AOM) and dextran sodium sulfate (DSS)-induced colon cancer models with three different protocols. In the first protocol, two other application time points (early or late initiation of IH) were applied. In the second protocol, mice were divided into only two groups, and then exposed to either N or IH conditions for 14 days. In the third protocol, a pharmacological inhibition study for anti-inflammation (5-aminosalicylate) or anti-oxidative stress (N-acetylcysteine [NAC]) was performed. The number of tumors was significantly higher in the IH-1 than in the N or IH-2 groups. 8-oxo-2'-deoxyguanosine (8-OHdG) levels were higher in tumors of the IH-1 group than in that of the N and IH-2 groups. Gene expression related to reactive oxygen species production was higher in the IH-1 group than in the N and IH-2 groups, and it showed a positive correlation with 8-OHdG levels. Prior to cancer development 8-OHdG levels were already elevated in colonic epithelial regions in the IH group, possibly due to an imbalance between oxidative stress and antioxidant systems. NAC treatment resulted in a significant reduction in the number of tumors in mice exposed to IH. In conclusion, IH promotes carcinogenesis in a chemically-induced colon cancer model where elevated 8-OHdG may contribute to the increased tumor induction.

Melatonin improves insulin resistance and hepatic steatosis through attenuation of alpha-2-HS-glycoprotein.

Melatonin plays an important role in regulating circadian rhythms. It also acts as a potent antioxidant and regulates glucose and lipid metabolism, although the exact action mechanism is not clear. The α2-HS-glycoprotein gene (AHSG) and its protein, fetuin-A (FETUA), are one of the hepatokines and are known to be associated with insulin resistance and type 2 diabetes. The aim of this study was to determine whether melatonin improves hepatic insulin resistance and hepatic steatosis in a FETUA-dependent manner. In HepG2 cells treated with 300 µmol/L of palmitic acid, phosphorylated AKT expression decreased, and FETUA expression increased, but this effect was inhibited by treatment with 10 µmol/L of melatonin. However, melatonin did not improve insulin resistance in FETUA-overexpressing cells, indicating that improvement in insulin resistance by melatonin was dependent on downregulation of FETUA. Moreover, melatonin decreased palmitic acid-induced ER stress markers, CHOP, Bip, ATF-6, XBP-1, ATF-4, and PERK. In addition, in the high-fat diet (HFD) mice, oral treatment with 100 mg/kg/day melatonin for 10 weeks reduced body weight gain to one-third of that of the HFD group and hepatic steatosis. Insulin sensitivity and glucose intolerance improved with the upregulation of muscle p-AKT protein expression. FETUA expression and ER stress markers in the liver and serum of HFD mice were decreased by melatonin treatment. In conclusion, melatonin can improve hepatic insulin resistance and hepatic steatosis through reduction in ER stress and the resultant AHSG expression.

Low Quality of Life and Depressive Symptoms as an Independent Risk Factor for Erectile Dysfunction in Patients with Obstructive Sleep Apnea.

INTRODUCTION: Accumulating evidence indicates that obstructive sleep apnea (OSA) is associated with a high prevalence of erectile dysfunction (ED), but the factors that predict the risk of ED in OSA patients have yet to be defined clearly. AIMS: The aims of the present study were to investigate the clinical characteristics of OSA patients with ED and to identify plausible predictors of ED. METHODS: The present cross-sectional analysis included 713 male patients who visited Seoul National University Hospital for snoring and/or daytime sleepiness from 2006 to 2014. An in-laboratory polysomnography procedure was conducted to obtain objective recordings of OSA and other sleep parameters. MAIN OUTCOME MEASURES: The demographic data of all patients were obtained, and each patient completed all requirements of the following questionnaires: the Calgary Sleep Apnea Quality of Life Index (SAQLI), the Korean version of the International Index of Erectile Function (KIIEF-5), the Beck Depression Inventory (BDI), and the Epworth Sleepiness Scale (ESS). ED and OSA were defined as a KIIEF-5 < 21 and a respiratory disturbance index (RDI) ≥ 5, respectively. Depressive symptoms were defined as a BDI ≥ 10. RESULTS: The frequency of ED did not differ significantly according to OSA severity. In Spearman's correlation analysis, the BDI and the ESS were inversely correlated with the KIIEF-5, whereas the SAQLI was positively correlated with the KIIEF-5. The RDI and the lowest oxygen saturation (SaO2 ) did not exhibit significant correlations with the KIIEF-5. A multivariate logistic regression analysis adjusted for possible confounding factors showed that ED was independently associated with the SAQLI and depressive symptoms, but there was no significant association of ED with either the RDI or the lowest SaO2 . CONCLUSIONS: The present study demonstrated that depressive symptoms and a low quality of life specific to sleep apnea are independent risk factors for ED in OSA patients.

Non-alcoholic fatty liver disease among sasang constitutional types: a population-based study in Korea.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease and is highly prevalent in populations with metabolic conditions such as obesity and type II diabetes. Specific types of Sasang constitution can act as a risk factor for metabolic diseases, but there are no studies addressing the association between the Sasang constitutional types (SCTs) and NAFLD. METHODS: A total of 1184 individuals (508 males, 676 females) that enrolled in the Korean Genome and Epidemiology Study were included in the present study. Classification of SCTs was done with an integrated diagnostic model. NAFLD was diagnosed when the liver attenuation index (LAI) value was <5 Hounsfield units using computed tomography. Relationships between the SCTs and NAFLD were analyzed using multiple logistic regressions. RESULTS: The average LAI was 13.3±6.0 in the So-eum (SE) type, 12.3±7.0 in the So-yang (SY) type, and 6.5±9.9 in the Tae-eum (TE) type. Prevalence of NAFLD was 4.7% in the SE type, 14.0% in the SY type, and 34% in the TE type. Even after adjusting for possible confounders, the SY and TE types continued to show a 3.90-fold (95% CI, 1.60-9.51; P=0.0028) and 3.36-fold (95% CI, 1.42-7.92; P=0.0057) increase in chance of having NAFLD, respectively, compared with the SE type. In the additional analysis including only non-obese subjects, the odds ratio of NAFLD was 3.27 (95% CI, 1.29-8.29; P=0.0126) in the SY type and 3.53 (95% CI, 1.30-9.58; P=0.0134) in the TE type compared with SE type. In the multivariate analysis to determine which parameter had an independent association with NAFLD, higher body mass index, alanine aminotransferase (ALT), triglyceride (TG), and low high-density lipoprotein cholesterol were independently associated with developing NAFLD in the SY type. In contrast, male sex, alcohol consumption, higher ALT, TG, and fasting glucose were risk factors for NAFLD in the TE type. CONCLUSIONS: These results indicated that the SY and TE types are independent risk factors for NAFLD.

Effects of transglutaminase 2 inhibition on ventilator-induced lung injury.

This study was performed to examine the role of transglutaminase 2 (TG2) in ventilator-induced lung injury (VILI). C57BL/6 mice were divided into six experimental groups: 1) control group; 2) lipopolysaccharide (LPS) group; 3) lung protective ventilation (LPV) group; 4) VILI group; 5) VILI with cystamine, a TG2 inhibitor, pretreatment (Cyst+VILI) group; and 6) LPV with cystamine pretreatment (Cyst+LPV) group. Acute lung injury (ALI) score, TG2 activity and gene expression, inflammatory cytokines, and nuclear factor-κB (NF-κB) activity were measured. TG2 activity and gene expression were significantly increased in the VILI group (P < 0.05). Cystamine pretreatment significantly decreased TG2 activity and gene expression in the Cyst+VILI group (P < 0.05). Inflammatory cytokines were higher in the VILI group than in the LPS and LPV groups (P < 0.05), and significantly lower in the Cyst+VILI group than the VILI group (P < 0.05). NF-κB activity was increased in the VILI group compared with the LPS and LPV groups (P < 0.05), and significantly decreased in the Cyst+VILI group compared to the VILI group (P = 0.029). The ALI score of the Cyst+VILI group was lower than the VILI group, but the difference was not statistically significant (P = 0.105). These results suggest potential roles of TG2 in the pathogenesis of VILI.

Association of insomnia and daytime napping with metabolic syndrome and its components in a Korean population: an analysis of data from the Korean Genome and Epidemiology Study.

OBJECTIVES: We investigated the association between metabolic syndrome (MetS) and the coexistence of insomnia and daytime napping, because limited data have been reported regarding this association. METHODS: The study population was 8,440 participants aged 40-65 years, who were from the Korean Genome and Epidemiology Study. Self-reported information on insomnia symptoms and nap duration was used to define exposure variables. Data on waist circumference (WC), blood pressure (BP), and fasting blood glucose (FBG), triglyceride (TG), and high-density lipoprotein cholesterol levels in blood were used to define MetS. Multivariate logistic regression analysis was performed to obtain odds ratio (OR) and 95% confidence interval (CI). RESULTS: In multivariate logistic regression analysis, the coexistence of insomnia and napping was not significantly associated with MetS. However, the insomnia and non-napping group showed higher ORs of high TG (OR, 1.19; 95% CI, 1.02 to 1.39) and high BP (OR, 1.28; 95% CI, 1.10 to 1.49) than the non-insomnia and non-napping group. The combination of non-insomnia and napping and that of insomnia and napping showed higher ORs of high TG (OR, 1.13; 95% CI, 1.00 to 1.29) and high FBG (OR, 1.59; 95% CI, 1.14 to 2.21), respectively. In analyses of insomnia symptoms, only the combination of difficulty in maintaining sleep (DMS) and non-napping showed a higher OR for MetS (OR, 1.25; 95% CI, 1.03 to 1.52) than the non-DMS and non-napping group. CONCLUSIONS: Individuals with insomnia, particularly those who do not take naps, were disproportionately likely to have MetS components, especially TG or BP. Information on these variables may help predict individuals' vulnerability to specific MetS components.

Melatonin Improves Glucose Homeostasis and Insulin Sensitivity by Mitigating Inflammation and Activating AMPK Signaling in a Mouse Model of Sleep Fragmentation.

Sleep fragmentation (SF) can increase inflammation and production of reactive oxygen species (ROS), leading to metabolic dysfunction. SF is associated with inflammation of adipose tissue and insulin resistance. Several studies have suggested that melatonin may have beneficial metabolic effects due to activating AMP-activated protein kinase (AMPK). However, it is unclear whether melatonin affects the AMPK signaling pathway in SF-induced metabolic dysfunction. Therefore, we hypothesize that SF induces metabolic impairment and inflammation in white adipose tissue (WAT), as well as altered intracellular homeostasis. We further hypothesize that these conditions could be improved by melatonin treatment. We conducted an experiment using adult male C57BL/6 mice, which were divided into three groups: control, SF, and SF with melatonin treatment (SF+Mel). The SF mice were housed in SF chambers, while the SF+Mel mice received daily oral melatonin. After 12 weeks, glucose tolerance tests, insulin tolerance tests, adipose tissue inflammation tests, and AMPK assessments were performed. The SF mice showed increased weight gain, impaired glucose regulation, inflammation, and decreased AMPK in WAT compared to the controls. Melatonin significantly improved these outcomes by mitigating SF-induced metabolic dysfunction, inflammation, and AMPK downregulation in adipose tissue. The therapeutic efficacy of melatonin against cardiometabolic impairments in SF may be due to its ability to restore adipose tissue homeostatic pathways.

Total nasal resistance among Sasang constitutional types: a population-based study in Korea.

BACKGROUND: There have been many attempts to find an objective phenotype by Sasang constitutional types (SCTs) on an anatomical, physiological, and psychological basis, but there has been no research on total nasal resistance (TNR) among SCTs. METHODS: We assessed the value of the TNR in the SCTs classified by an integrated diagnostic model. Included in the study were 1,346 individuals (701 males, 645 females) who participated in the Korean Genome and Epidemiology Study (KoGES). The TNR was measured by active anterior rhinomanometry (AAR) at transnasal pressures of 100 and 150 Pascal (Pa). RESULTS: The average TNR was 0.186 ± 0.004 Pa/cm3/second at 100 Pa in the Tae-eum (TE), 0.193 ± 0.007 in the So-eum (SE), and 0.208 ± 0.005 in the So-yang (SY) types. Under condition of 150 Pa the TE type had a TNR value of 0.217 ± 0.004, the SE type was 0.230 ± 0.008, and the SY type was 0.243 ± 0.005. Higher values of TNR were more likely to be reported in the SY type at 100 Pa and 150 Pa. In the stratified analysis by sex, the SY type in males and females tended to have higher TNR value than the TE and SE types at transnasal pressure of both 100 Pa and 150 Pa. CONCLUSIONS: These results provide new approaches to understand the functional characteristics among the SCTs in terms of nasal physiology. Further studies are required to clarify contributing factors for such a difference.

Oral Administration of Human-Gut-Derived Prevotella histicola Improves Sleep Architecture in Rats.

(1) Background: The human gut microbiome may regulate sleep through the gut-brain axis. However, the sleep-promoting effects of gut microbiota remain unclear. (2) Methods: We obtained sleep-wake profiles from 25 rats receiving P. histicola (P. histicola group), 5 rats receiving P. stercorea (P. stercorea group), 4 rats not receiving bacteria (No administration group), and 8 rats receiving P. histicola extracellular vesicles (EV) (EV group) during the baseline, administration, and withdrawal periods. (3) Results: The P. histicola group showed increased total sleep, rapid eye movement (REM) sleep, and non-rapid eye movement (NREM) sleep time during the administration and withdrawal periods; on the last day of administration, we found significant increases of 52 min for total sleep (p < 0.01), 13 min for REM sleep (p < 0.05), and 39 min for NREM sleep (p < 0.01) over the baseline. EV administration also increased NREM sleep time on Day 3 of administration (p = 0.05). We observed a linear trend in the dose-response relationship for total sleep and NREM sleep in the P. histicola group. However, neither the no-administration group nor the P. stercorea group showed significant findings. (4) Conclusions: Oral administration of probiotic P. histicola may improve sleep and could be a potential sleep aid. Further rigorous evaluations for the safety and efficacy of P. histicola supplementation are warranted.

Surface Active Salivary Metabolites Indicate Oxidative Stress and Inflammation in Obstructive Sleep Apnea.

PURPOSE: Obstructive sleep apnea (OSA), a highly prevalent and potentially serious sleep disorder, requires effective screening tools. Saliva is a useful biological fluid with various metabolites that might also influence upper airway patency by affecting surface tension in the upper airway. However, little is known about the composition and role of salivary metabolites in OSA. Therefore, we investigated the metabolomics signature in saliva from the OSA patients and evaluated the associations between identified metabolites and salivary surface tension. METHODS: We studied 68 subjects who visited sleep clinic due to the symptoms of OSA. All underwent full-night in-lab polysomnography. Patients with apnea-hypopnea index (AHI) < 10 were classified to the control, and those with AHI ≥ 10 were the OSA groups. Saliva samples were collected before and after sleep. The centrifuged saliva samples were analyzed by liquid chromatography with high-resolution mass spectrometry (ultra-performance liquid chromatography-tandem mass spectrometry; UPLC-MS/MS). Differentially expressed salivary metabolites were identified using open source software (XCMS) and Compound Discoverer 2.1. Metabolite set enrichment analysis (MSEA) was performed using MetaboAnalyst 5.0. The surface tension of the saliva samples was determined by the pendant drop method. RESULTS: Three human-derived metabolites (1-palmitoyl-2-[5-hydroxyl-8-oxo-6-octenoyl]-sn-glycerol-3-phosphatidylcholine [PHOOA-PC], 1-palmitoyl-2-[5-keto-8-oxo-6-octenoyl]-sn-glycerol-3-phosphatidylcholine [KPOO-PC], and 9-nitrooleate) were significantly upregulated in the after-sleep salivary samples from the OSA patients compared to the control group samples. Among the candidate metabolites, only PHOOA-PC was correlated with the AHI. In OSA samples, salivary surface tension decreased after sleep. The differences in surface tension were negatively correlated with PHOOA-PC and 9-nitrooleate concentrations. Furthermore, MSEA revealed that arachidonic acid-related metabolism pathways were upregulated in the after-sleep samples from the OSA group. CONCLUSIONS: This study revealed that salivary PHOOA-PC was correlated positively with the AHI and negatively with salivary surface tension in the OSA group. Salivary metabolomic analysis may improve our understanding of upper airway dynamics and provide new insights into novel biomarkers and therapeutic targets in OSA.

Spontaneously healed asymptomatic pulmonary tuberculosis: prevalence of airflow obstruction, and correlation between high-resolution CT findings and pulmonary function tests.

RATIONALE AND OBJECTIVES: We investigated the relationships between spontaneously healed asymptomatic pulmonary tuberculosis (SHAPTB), airflow obstruction (AFO), and high-resolution computed tomography (HRCT) findings. MATERIALS AND METHODS: We selected 82 participants with SHAPTB diagnosed by interferon-γ release assay and 8044 with normal chest radiographs (CXR). We applied a CT scoring system for the extent of tuberculous sequelae to correlate the HRCT findings with pulmonary function test. We compared the AFO prevalence between subjects with and without SHAPTB. RESULTS: The subjects with SHAPTB diagnosed by interferon-γ release assay had a significantly higher prevalence of AFO (13.4% [11/82]) than those with normal CXR (7.4% [595/8044]). The important HRCT findings that correlated with AFO were the number of lung segments with TB sequelae and the CT score for emphysema. CONCLUSION: The subjects with SHAPTB had a higher AFO prevalence than those with normal CXR, and the important HRCT findings correlated with AFO were the extent of tuberculous sequelae and emphysema.

Coexistence of Moderate-to-Severe Obstructive Sleep Apnea and Inflammation Accelerates the Risk of Progression of Arterial Stiffness: A Prospective 6-Year Study.

Both obstructive sleep apnea (OSA) and inflammation have now been recognized as imposing substantial cardiometabolic risk. However, no prospective study has reported whether the coexistence of OSA and inflammation exacerbates the progressive arterial stiffening. Thus, the purpose of this study is to examine whether these conditions increase the risk of the progression of arterial stiffening. A total of 1945 participants were randomly selected for the study. Subjects with elevated inflammation were divided by high-sensitivity C-reactive protein (hsCRP) levels. A polysomnography and brachial-ankle pulse wave velocity (baPWV) were performed. The elevation of the baPWV was defined as the levels in the highest quartile of the baPWV. The percentage of the elevated baPWV and the change in the baPWV (ΔbaPWV) were higher in individuals with OSA and higher hsCRP levels. After adjusting for confounders, the participants with OSA and inflammation in the groups not treated with antihypertensive medication had a higher risk of an elevated ΔbaPWV in contrast to those with neither variable. Particularly, the alteration in the baPWV differed significantly based on the existence of moderate-to-severe OSA and inflammation at the 6-year follow-up. In combination, these conditions are associated with an accelerated risk of a future burden of the progression of the arterial stiffness, suggesting a potential important role in the increased risk of CVD.

A cancer cell-specific benzoxadiazole-based fluorescent probe for hydrogen sulfide detection in mitochondria.

The present work describes the design and biological applications of a novel colorimetric and fluorescence turn-on probe for hydrosulfide detection. The probe was designed to introduce hemicyanine as the fluorescent skeleton and 7-nitro-1,2,3-benzoxadiazole as the recognition site. The optical properties and responses of the probe towards HS-, anions and some biothiols indicate an impressively high selectivity of the probe towards HS- such that it can be effectively used as an indicator for monitoring the level of HS- in living cells. In biological experiments using the probe, the H2S levels are found to be higher in cancer cells than in normal cells. In addition, the probe is shown to specifically and rapidly detect endogenous H2S, which is produced primarily in the mitochondria of cancer cells, as demonstrated by a co-localization experiment using specific trackers for the detection of cellular organelles in pharmacological inhibition or stimulation studies, without any significant cytotoxic effects. Thus, the results of the chemical and biological experiments described herein demonstrate the potential of this novel probe to specifically, safely, and rapidly detect H2S to distinguish cancer cells from normal cells by targeting it specifically in mitochondria.

Exosome and Melatonin Additively Attenuates Inflammation by Transferring miR-34a, miR-124, and miR-135b.

The positive effects of mesenchymal stem cells (MSCs) are primarily activated through molecular secretions known as paracrine activity, which regulates the function of various cell types including immune cells. Accumulating evidence shows that exosomes of soluble factors released from MSCs are potential alternative agents for stem cell-based therapy, although the exact underlying mechanism has not been elucidated. The purpose of this study was to evaluate the potential effects of exosomes produced by adipose-derived MSCs and to examine the changes in anti-inflammatory genes in concurrence with the polarization of M2 macrophages in cellular models ex vivo. Isolated exosomes were used to investigate the inflammatory modulation in pro-inflammatory cytokine-treated fibroblasts and THP-1 cells. The anti-inflammatory mRNA expression associated with M2 macrophages was significantly upregulated after exosome treatment in an interferon gamma and tumor necrosis factor alpha-treated inflammatory environment. Furthermore, melatonin-stimulated exosomes exerted superior anti-inflammatory modulation via exosomal miRNAs miR-34a, miR-124, and miR-135b, compared with exosomes. Our results indicate that melatonin-stimulated exosomes originating from adipose-derived MSCs are safe and efficient tools for regenerative medicine to treat inflammatory diseases.

Inhibition of Renal Stellate Cell Activation Reduces Renal Fibrosis.

Interstitial fibrosis is a common feature of chronic kidney disease, and platelet-derived growth factor receptor-ß (PDGFR-ß)-positive mesenchymal cells are reportedly the major source of scar-producing myofibroblasts. We had previously demonstrated that albumin and its derivative R-III (a retinol-binding protein-albumin domain III fusion protein) inhibited the transdifferentiation/activation of hepatic stellate cells (HSCs) to myofibroblasts and that R-III administration reduced liver fibrosis. In this study, we isolated cells (referred to as renal stellate cells, RSCs) from rat kidney tissues using the HSC isolation protocol and compared their morphological and biochemical characteristics with those of HSCs. RSCs shared many characteristics with HSCs, such as storage of vitamin A-containing lipid droplets and expression of HSC markers as well as pericyte markers. RSCs underwent spontaneous transdifferentiation into myofibroblasts in in vitro culture, which was inhibited by albumin expression or R-III treatment. We also evaluated the therapeutic effects of R-III in unilateral ureteral obstruction (UUO)-induced renal fibrosis in mice. Injected R-III localized predominantly in cytoglobin/stellate cell activation-associated protein (Cygb/STAP)-positive cells in the kidney and reduced renal fibrosis. These findings suggest that RSCs can be recognized as the renal counterparts of HSCs and that RSCs represent an attractive therapeutic target for anti-fibrotic therapy.

Biological effects of melatonin on human adipose­derived mesenchymal stem cells.

Mesenchymal stem cells (MSCs) are capable of differentiating into other cell types and exhibit immunomodulatory effects. MSCs are affected by several intrinsic and extrinsic signaling modulators, including growth factors, cytokines, extracellular matrix and hormones. Melatonin, produced by the pineal gland, is a hormone that regulates sleep cycles. Recent studies have shown that melatonin improves the therapeutic effects of stem cells. The present study aimed to investigate whether melatonin enhances the biological activities of human adipose­derived MSCs. The results demonstrated that treatment with melatonin promoted cell proliferation by inducing SRY­box transcription factor 2 gene expression and preventing replicative senescence. In addition, melatonin exerted anti­adipogenic effects on MSCs. PCR analysis revealed that the expression of the CCAAT enhancer binding protein a gene, a key transcription factor in adipogenesis, was decreased following melatonin treatment, resulting in reduced adipogenic differentiation in an in vitro assay. The present study also examined the effect of melatonin on the immunomodulatory response using a co­culture system of human peripheral blood mononuclear cells and MSCs. Activated T cells were strongly inhibited following melatonin exposure compared with those in the control group. Finally, the favorable effects of melatonin on MSCs were confirmed using luzindole, a selective melatonin receptor antagonist. The proliferation­promoting, anti­inflammatory effects of melatonin suggested that melatonin­treated MSCs may be used for effective cell therapy.

Untargeted metabolomics analysis of rat hippocampus subjected to sleep fragmentation.

Sleep fragmentation (SF) commonly occurs in several pathologic conditions and is especially associated with impairments of hippocampus-dependent neurocognitive functions. Although the effects of SF on hippocampus in terms of protein or gene levels were examined in several studies, the impact of SF at the metabolite level has not been investigated. Thus, in this study, the differentially expressed large-scale metabolite profiles of hippocampus in a rat model of SF were investigated using untargeted metabolomics approaches. Forty-eight rats were divided into the following 4 groups: 4-day SF group, 4-day exercise control (EC) group, 15-day SF group, and 15-day EC group (n = 12, each). SF was accomplished by forced exercise using a walking wheel system with 30-s on/90-s off cycles, and EC condition was set at 10-min on/30-min off. The metabolite profiles of rat hippocampi in the SF and EC groups were analyzed using liquid chromatography/mass spectrometry. Multivariate analysis revealed distinctive metabolic profiles and marker signals between the SF and corresponding EC groups. Metabolic changes were significant only in the 15-day SF group. In the 15-day SF group, L-tryptophan, myristoylcarnitine, and palmitoylcarnitine were significantly increased, while adenosine monophosphate, hypoxanthine, L-glutamate, L-aspartate, L-methionine, and glycerophosphocholine were decreased compared to the EC group. The alanine, aspartate, and glutamate metabolism pathway was observed as the common key pathway in the 15-day SF groups. The results from this untargeted metabolomics study provide a perspective on metabolic impact of SF on the hippocampus.

Environmental Benzopyrene Attenuates Stemness of Placenta-Derived Mesenchymal Stem Cells via Aryl Hydrocarbon Receptor.

The toxic effects of particulate matter have been linked to polycyclic aromatic hydrocarbons (PAHs) such as benzopyrene. PAHs are potent inducers of the aryl hydrocarbon receptor (AhR), which is an expressed nuclear receptor that senses environmental stimuli and modulates gene expression. Even though several studies have shown that the benzopyrene (BP) of chemical pollutants significantly impaired stem cell activity, the exact molecular mechanisms were not clearly elucidated. In the present study, we aimed to investigate the effects of BP on placenta-derived mesenchymal stem cells (PD-MSCs) in vitro. We found that the AhR in PD-MSCs was expressed under the treatment of BP, and its activation markedly disrupted osteogenic differentiation through the alteration of stemness activity of PD-MSCs. Moreover, BP treatment significantly reduced the proliferation activity of PD-MSCs and expression of pluripotent markers through the induction of AhR. Treatment with StemRegenin 1 (SR1), a purine derivative that antagonizes the AhR, effectively prevented BP-induced reduction of the proliferation and differentiation activity of PD-MSCs. In this study, we found that BP treatment in PD-MSCs markedly obstructs PD-MSC stemness through AhR signaling. Noteworthy, SR1-mediated MSC application will contribute to new perspectives on MSC-based therapies for air pollution-related bone diseases.