Inhibitors of the secretion of cancer exosomes, which promote cancer progression and metastasis, may not only accelerate exosome biology research but also offer therapeutic benefits for cancer ...patients. Here we identify sulfisoxazole (SFX) as an inhibitor of small extracellular vesicles (sEV) secretion from breast cancer cells through interference with endothelin receptor A (ETA). SFX, an FDA-approved oral antibiotic, showed significant anti-tumor and anti-metastatic effects in mouse models of breast cancer xenografts, the reduced expression of proteins involved in biogenesis and secretion of sEV, and triggered co-localization of multivesicular endosomes with lysosomes for degradation. We demonstrate the important role of ETA, as target of SFX, by gain- and loss-of-function studies of the ETA protein, through a direct binding assay, and pharmacological and genetic approaches. These findings may provide a foundation for sEV-targeted cancer therapies and the mechanistic studies on sEV biology.
Sensory discrimination is essential for survival. However, how sensory information is finely controlled in the brain is not well defined. Here, we show that astrocytes control tactile acuity via ...tonic inhibition in the thalamus. Mechanistically, diamine oxidase (DAO) and the subsequent aldehyde dehydrogenase 1a1 (Aldh1a1) convert putrescine into GABA, which is released via Best1. The GABA from astrocytes inhibits synaptically evoked firing at the lemniscal synapses to fine-tune the dynamic range of the stimulation-response relationship, the precision of spike timing, and tactile discrimination. Our findings reveal a novel role of astrocytes in the control of sensory acuity through tonic GABA release.
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•Thalamic astrocytes synthesize GABA via DAO and Aldh1a1 to mediate tonic inhibition•Tonic GABA improves linearity and temporal fidelity of synaptically evoked TC firing•Astrocytic tonic GABA improves tactile discrimination performance
Kwak et al. report that astrocytes synthesize GABA using DAO and Aldh1a1 and release GABA through the Best1 channel to mediate tonic GABA in the thalamus. Astrocytic tonic GABA fine-tunes the dynamic range and precision of stimulation to response of TC firing, thus enhancing the performance of sensory discrimination of mice.
Antiplatelet therapy has shown protective effects against hepatocellular carcinoma (HCC) in preclinical studies. However, it is unclear whether antiplatelet therapy lowers the risk of HCC in patients ...with chronic hepatitis B. A retrospective analysis was conducted of data from 1,674 chronic hepatitis B patients, enrolled between January 2002 and May 2015, whose serum hepatitis B virus DNA levels were suppressed by antivirals to <2,000 IU/mL. The primary and secondary outcomes were development of HCC and bleeding events, respectively. Risk was compared between patients with antiplatelet treatment (aspirin, clopidogrel, or both; antiplatelet group) and patients who were not treated (non‐antiplatelet group) using a time‐varying Cox proportional hazards model for total population and propensity score–matching analysis. The antiplatelet group included 558 patients, and the non‐antiplatelet group had 1,116 patients. During the study period, 63 patients (3.8%) developed HCC. In time‐varying Cox proportional analyses, the antiplatelet group showed a significantly lower risk of HCC (hazard ratio HR, 0.44; 95% confidence interval CI, 0.23–0.85; P = 0.01), regardless of antiplatelet agent. In propensity score–matched pairs, antiplatelet therapy significantly reduced the risk of HCC (HR, 0.34; 95% CI, 0.15‐0.77; P = 0.01). However, the overall risk of bleeding was higher in the antiplatelet group (HR, 3.28; 95% CI, 1.98‐5.42; P < 0.001), particularly for clopidogrel with or without aspirin. Treatment with aspirin alone was not associated with a higher bleeding risk (HR, 1.11; 95% CI, 0.48‐2.54; P = 0.81). Conclusion: Antiplatelet therapy reduces the risk of HCC in chronic hepatitis B patients whose hepatitis B virus is effectively suppressed. However, antiplatelet therapy containing clopidogrel may increase the risk of bleeding. (Hepatology 2017;66:1556–1569)
Photoacoustic spectroscopy has been shown to be a promising tool for non-invasive blood glucose monitoring. However, the repeatability of such a method is susceptible to changes in skin condition, ...which is dependent on hand washing and drying due to the high absorption of infrared excitation light to the skin secretion products or water. In this paper, we present a method to meet the challenges of mid-infrared photoacoustic spectroscopy for non-invasive glucose monitoring. By obtaining the microscopic spatial information of skin during the spectroscopy measurement, the skin region where the infrared spectra is insensitive to skin condition can be locally selected, which enables reliable prediction of the blood glucose level from the photoacoustic spectroscopy signals. Our raster-scan imaging showed that the skin condition for in vivo spectroscopic glucose monitoring had significant inhomogeneities and large variability in the probing area where the signal was acquired. However, the selective localization of the probing led to a reduction in the effects of variability due to the skin secretion product. Looking forward, this technology has broader applications not only in continuous glucose monitoring for diabetic patient care, but in forensic science, the diagnosis of malfunctioning sweat pores, and the discrimination of tumors extracted via biopsy.
Background and Aim
Recent studies suggest that the anti‐inflammatory agent balsalazide (BSZ) and probiotic agent VSL#3 have potential therapeutic benefits for the treatment of patients with ...inflammatory bowel disease. However, their effectiveness in preventing colitis‐associated carcinogenesis (CAC) remains uncertain. The aim of the present study was to determine the chemopreventive effects of BSZ and VSL#3 in the murine azoxymethane (AOM)/dextran sodium sulfate (DSS) model.
Methods
C57B/L6J mice were randomly divided into four groups: CAC group, BSZ group, VSL#3 group, and BSZ + VSL#3 group. After 2 weeks, the AOM/DSS model was induced by AOM injection followed by two cycles of 2% DSS.
Results
During first and second cycles of DSS, the number of F4/80‐positive macrophages was significantly lower in the drug‐treated groups compared with the CAC group (P < 0.05). At the endpoint, the total numbers of tumors in the drug‐treated groups were significantly low compared with the CAC group (P < 0.05), and the drug‐treated groups had significantly lower F4/80‐positive macrophages in the tumor stroma (P < 0.01). The protein production of macrophage inflammatory protein 1 beta, monocyte chemoattractant protein‐1, interleukin (IL)‐6, and IL‐10 in the colon tissues decreased in concordance with the plasma concentrations of the cytokines (P < 0.05). The drug‐treated groups revealed lower expression of p‐STAT3 compared with the CAC group. In addition, BCL2 decreased, and BAX increased markedly in the BSZ + VSL#3 group.
Conclusions
These results revealed that BSZ and VSL#3 have chemopreventive effects against CAC through IL‐6/STAT3 suppression. BSZ and VSL#3 could be suitable options for chemoprevention of colorectal cancer.
Obesity can be caused by microbes producing metabolites; it is thus important to determine the correlation between gut microbes and metabolites. This study aimed to identify gut ...microbiota-metabolomic signatures that change with a high-fat diet and understand the underlying mechanisms. To investigate the profiles of the gut microbiota and metabolites that changed after a 60% fat diet for 8 weeks, 16S rRNA gene amplicon sequencing and gas chromatography-mass spectrometry (GC-MS)-based metabolomic analyses were performed. Mice belonging to the HFD group showed a significant decrease in the relative abundance of Bacteroidetes but an increase in the relative abundance of Firmicutes compared to the control group. The relative abundance of Firmicutes, such as Lactococcus, Blautia, Lachnoclostridium, Oscillibacter, Ruminiclostridium, Harryflintia, Lactobacillus, Oscillospira, and Erysipelatoclostridium, was significantly higher in the HFD group than in the control group. The increased relative abundance of Firmicutes in the HFD group was positively correlated with fecal ribose, hypoxanthine, fructose, glycolic acid, ornithine, serum inositol, tyrosine, and glycine. Metabolic pathways affected by a high fat diet on serum were involved in aminoacyl-tRNA biosynthesis, glycine, serine and threonine metabolism, cysteine and methionine metabolism, glyoxylate and dicarboxylate metabolism, and phenylalanine, tyrosine, and trypto-phan biosynthesis. This study provides insight into the dysbiosis of gut microbiota and metabolites altered by HFD and may help to understand the mechanisms underlying obesity mediated by gut microbiota.
Diethylnitrosamine (DEN) is a potent toxic material that can cause necrosis and subsequent fibrosis in the liver. Based on the previously reported hepatoprotective effect of Limonium tetragonum ...against the proliferation of hepatic stellate cells, we tested the EtOAc soluble fraction of L. tetragonum extract (EALT) in a DEN-induced hepatotoxic rat model. The development of hepatotoxicity including mononuclear cell infiltration and fibrosis induced by intraperitoneal injections of DEN (70 mg/2 mL/kg body weight (b.w.) per week) was observed at 4, 6 and 8 weeks after the first DEN treatment. Administration of EALT (200 mg/kg body weight, per os (p.o.)) induced significant reductions in serum alanine transaminase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma glutamyl transferase (GGT), and triglycerides (TG) in DEN-injected rats. Increased oxidative stress in DEN-induced liver fibrosis rats was diminished by EALT treatment through a decrease in malondialdehyde (MDA) and increase in superoxide dismutase (SOD). Histologic findings that included markedly attenuated mononuclear cell infiltration and fibrosis could be observed in liver samples from the EALT-treated groups. An extract of Hovenia dulcis fruit and Sylimarin were used as positive controls. The present study provides direct experimental evidence for EALT attenuated hepatic injury and fibrosis in DEN-treated mice. The L. tetragonum EtOAc fraction might be useful in treating fibrotic liver diseases.
Abstract
Increasing evidence suggests that obstructive sleep apnea (OSA) is a metabolic syndrome-related disease; however, the association between nonalcoholic fatty liver disease (NAFLD) and OSA is ...not firmly established. In this study, we investigated the relationship between NAFLD and OSA in a general population drawn from a nationwide population-based cohort. Data from the Korean National Health Insurance System between January 2009 and December 2009 were analyzed using Cox proportional hazards model. NAFLD was defined as a fatty liver index (FLI) ≥ 60 in patients without excessive alcohol consumption (who were excluded from the study). Newly diagnosed OSA during follow-up was identified using claims data. Among the 8,116,524 participants, 22.6% had an FLI score of 30–60 and 11.5% had an FLI ≥ 60. During median follow-up of 6.3 years, 45,143 cases of incident OSA occurred. In multivariable analysis, the risk of OSA was significantly higher in the higher FLI groups (adjusted hazard ratio aHR 1.15, 95% confidence interval CI 1.12–1.18 for FLI 30–60 and aHR 1.21, 95% CI 1.17–1.26 for FLI ≥ 60). These findings were consistent regardless of body mass index and presence of abdominal obesity. In conclusion, a high FLI score may help identify individuals with a high risk of OSA. Understanding the association between NAFLD and OSA may have clinical implications for risk-stratification of individuals with NAFLD.
Dioscorea oppositifolia is a well-known edible and traditional medicine for the treatment of gastrointestinal diseases. In our previous study, D. oppositifolia exhibited both pancreatic lipase ...inhibition and an anti-adipogenesis effect in vitro. This study was performed to investigate the anti-obesity effect of D. oppositifolia on high-fat diet-induced obese mice. Female ICR mice were fed a high-fat diet with the 100 mg/kg of D. oppositifolia n-BuOH extract for 8 weeks. The high-fat diet mice received the 15 mg/kg Orlistat orally as a positive control. The body weight, parametrial adipose tissue weight, and the levels of triglyceride (TG), total cholesterol (TC), and low density lipoprotein (LDL)-cholesterol in blood serum of female ICR mice were significantly decreased by feeding a high-fat diet with the n-BuOH extract of D. oppositifolia. An inhibitory effect of D. oppositifolia extract on dietary fat absorption was also clearly shown. The D. oppositifolia sample was found to contain 3,5-dimethoxy-2,7-phenanthrenediol and (3R,5R)-3,5-dihydroxy-1,7-bis(4-hydroxyphenyl)-3,5-heptanediol as main components based on its phytochemical analysis. The present study is the first report of the anti-obesity effect by D. oppositifolia n-BuOH extract using an established disease model. The increase in fecal fat excretion by treatment of D. oppositifolia may be an effective approach for treating obesity and related diseases.
•Microplastic (MP; 10‒90 μm) removal was studied during drinking water treatment.•Sequential coagulation and sand filtration could completely remove MPs ≥ 45 μm.•Some of the MPs < 20 μm passed ...through sand, which were fragmented in UV oxidation.•UV and UV/H2O2 treatments leached out organics, increasing bacterial toxicity.
The effectiveness of traditional drinking water treatment plants for the removal of Microplastics (MPs) in the size range of tens of micrometers is currently uncertain. This study investigated the behavior and removal efficiency of four different sized polystyrene MPs (10−90 μm in diameter) in a simulated cascade of coagulation/sedimentation, sand filtration, and UV-based oxidation over technically relevant time frames. In the coagulation and sand filtration steps, the larger the MP size, the better it was removed. The coagulant type and water characteristics (i.e., pH and the presence of natural organic matter) influenced the coagulation efficiency for MPs. X-ray microcomputed tomography technique and two-site kinetic modeling were used to identify the mechanisms involved in sand filtration. The MPs > 20 μm could be completely retained in sand by straining, while the attachment to the sand surface was likely responsible for the retention of MPs < 20 μm. However, approximately 16% of 10 μm MPs injected passed through the sand, which were further fragmented by UV oxidation. UV/H2O2 treatment promoted the MP fragmentation and chemical leaching more significantly than UV treatment, resulting in a higher toxicity for UV/H2O2-treated water. Our findings pave the way for deeper understanding of how MPs behave and transform in a sequential drinking water treatment process.
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