Immunostimulatory Effects of Korean Mineral-Rich Seawaters on Cyclophosphamide-Induced Immunosuppression in Mice.

Deep seawater (DS), obtained from a depth over 200 m, has health benefits due to its rich nutrients and minerals, and intake of DS has shown diverse immunomodulatory effects in allergies and cancer. Therefore, the immunostimulatory effects of Korean mineral-rich seawaters were examined in a cyclophosphamide (CPA)-induced immunosuppression model. Three samples of Korean seawater, namely DS from the East Sea off the coasts of Pohang (PDS) and Uljin (UDS), and seawater from the West Sea off the coast of Boryeong (BS), were collected. The seawaters were abundant in several minerals (calcium, iron, zinc, selenium, etc.). Mice were orally administered the seawaters for 42 days, followed by CPA-induced immunosuppression. The CPA induction reduced the weight of the spleen and lymph nodes; however, the administration of seawaters increased the weight of the lymphoid organs, accompanied by stimulation of natural killer cells' activity and NF-kB-mediated cytokine production (IFNγ, TNFα, IL1ß, IL6, and IL12). The mouse-derived splenocytes showed lymphoproliferation without cytotoxicity in the seawater groups. Histopathological analysis revealed that the seawaters improved the CPA-induced atrophic changes by promoting lymphoproliferation in the spleen and lymph nodes. These results provide useful information for the use of Korean mineral-rich seawaters, particularly PDS and UDS, as alternative immunostimulants under immunosuppressive conditions.

Melosira nummuloides Ethanol Extract Ameliorates Alcohol-Induced Liver Injury by Affecting Metabolic Pathways.

Melosira nummuloides is a microalga with a nutritionally favorable polyunsaturated fatty acid profile. In the present study, M. nummuloides ethanol extract (MNE) was administered to chronic-binge alcohol-fed mice and alcohol-treated HepG2 cells, and its hepatoprotective effects and underlying mechanisms were investigated. MNE administration reduced triglyceride (TG), total cholesterol (T-CHO), and liver injury markers, including aspartate transaminase (AST) and alanine transaminase (ALT), in the serum of chronic-binge alcohol-fed mice. However, MNE administration increased the levels of phosphorylated adenosine monophosphate-activated protein kinase (P-AMPK/AMPK) and PPARα, which was accompanied by a decrease in SREBP-1; this indicates that MNE can inhibit adipogenesis and improve fatty acid oxidation. Moreover, MNE administration upregulated the expression of antioxidant enzymes, including SOD, NAD(P)H quinone dehydrogenase 1, and GPX, and ameliorated alcohol-induced inflammation by repressing the Akt/NFκB/COX-2 pathway. Metabolomic analysis revealed that MNE treatment modulated many lipid metabolites in alcohol-treated HepG2 cells. Our study findings provide evidence for the efficacy and mechanisms of MNE in ameliorating alcohol-induced liver injury.

CDK4/6 inhibitors induce breast cancer senescence with enhanced anti-tumor immunogenic properties compared with DNA-damaging agents.

Since therapy-induced senescence (TIS) can either support or inhibit cancer progression, identifying which types of chemotherapeutic agents can produce the strongest anti-tumor TIS is an important issue. Here, cyclin-dependent kinase4/6 inhibitors (CDK4/6i)-induced senescence was compared to the TIS induced by conventional DNA-damaging agents. Despite both types of agents eliciting a similar degree of senescence, we observed increased expression of the senescence-associated secretory phenotype (SASP) and ligands related to pro-tumor immunity (IL6, CXCL8, TGFß, CD274, and CEACAM1) and angiogenesis (VEGFA) mainly in TIS induced by DNA-damaging agents rather than by CDK4/6i. Additionally, although all agents increased the expression of anti-tumor immunomodulatory proteins related to antigen presentation (MHC-I, B2M) and T cell chemokines (CXCL9, 10, 11), CDK4/6i-induced senescent cells still maintained this expression at a similar or even higher intensity than cells treated with DNA-damaging agents, despite the absence of nuclear factor-kappa-B (NF-κB) and p53 activation. These data suggest that in contrast with DNA-damaging agents, which augment the pro-tumorigenic microenvironment via pro-inflammatory SASP, CDK4/6i can generate TIS only with antitumor immunomodulatory proteins.

Enhancing Supplemental Effects of Acute Natural Antioxidant Derived from Yeast Fermentation and Vitamin C on Sports Performance in Triathlon Athletes: A Randomized, Double-Blinded, Placebo-Controlled, Crossover Trial.

This study investigated the acute effects of natural antioxidants, derived from yeast fermentation containing glutathione and dietary vitamin C supplementation, on metabolic function, skeletal muscle oxygenation, cardiac function, and antioxidant function during submaximal exercise in middle-aged triathlon athletes. Twelve participants (aged 49.42 ± 5.9 years) completed 90 min submaximal cycling trials corresponding to 70% maximal oxygen uptake with either vitamin C and glutathione (VitC+Glu), vitamin C (VitC), glutathione (Glu) supplementation, or placebo. Metabolic function (minute ventilation, oxygen uptake, carbon dioxide output [VCO2], respiratory exchange ratio [RER], oxygen pulse [O2pulse], carbohydrate oxidation, fat oxidation, and energy expenditure), skeletal muscle oxygenation (oxidized hemoglobin and myoglobin in skeletal muscle tissue, total hemoglobin and myoglobin in skeletal muscle tissue [tHb]), cardiac function (heart rate [HR], stroke volume [SV], cardiac output, end-diastolic volume, end-systolic volume, and ejection fraction), and antioxidant function parameters (blood lactate, superoxide dismutase, catalase, glutathione peroxidases, glutathione [GSH], diacron reactive oxygen metabolite [dROM], and biological antioxidant potential [BAP]) were measured during submaximal exercise and recovery. VCO2, RER, HR, blood lactate after exercise, and dROM were significantly lower, and O2pulse, tHb, and BAP were significantly higher for VitC+Glu than for the other trials (p < 0.05). In conclusion, combined vitamin C and glutathione supplementation was more effective in improving metabolic function, skeletal oxygenation, cardiac function, and antioxidant function during prolonged submaximal exercise in middle-aged triathletes.

Toxic effects of sub-acute microplastic (polyamide) exposure on the accumulation, hematological, and antioxidant responses in crucian carp, Carassius carassius.

The purpose of this study is to investigate the impact of microplastics (MPs) on fish and to confirm the toxic effects of MPs on fish, as well as to clarify the standard indicators. MPs are present in a large amount in the aquatic environment and can have various adverse effects on aquatic animals. Crucian carp, Carassius carassius (mean weight, 23.7 ± 1.6 g; mean length, 13.9 ± 1.4 cm), were exposed to PA (Polyamide) concentrations of 0, 4, 8, 16, 32 and 64 mg/L for 2 weeks. The PA accumulation profile in C. carassius decreased from the intestine to the gill to the liver. Hematological parameters such as red blood cell (RBC) counts, hemoglobin (Hb), and hematocrit (Ht) notably decreased at high levels of PA exposure. Plasma components such as calcium, magnesium, glucose, cholesterol, total protein, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) were significantly altered by PA exposure. The activities of superoxide dismutase (SOD), catalase (CAT), glutathione S-transferase (GST) and glutathione (GSH) of liver, gill and intestine significantly increased following PA exposure. The results of this study suggest that MP exposure affects the hematological physiology and antioxidant responses in C. carassius as well as accumulation in specific tissues.

Toxic effects of microplastic (polyethylene) exposure: Bioaccumulation, hematological parameters and antioxidant responses in crucian carp, Carassius carassius.

The purpose of this study was to evaluate the toxic effects of polyethylene microplastics (PE-MPs) by measuring the bioaccumulation, hematological parameters, and antioxidant responses in crucian carp (Carassius Carassius) exposed to waterborne 22-71 µm PE-MPs. C. carassius (mean weight, 24.0 ± 2.1 g; mean length, 13.1 ± 1.2 cm) were exposed to PE-MPs at concentration of 0, 4, 8, 16, 32, and 64 mg/L for 2 weeks. The accumulation of PE-MPs in each tissue of C. carassius was significantly increased in proportion to the PE-MPs concentration; the highest accumulation was observed in the intestine, followed by the gills and liver. Hematological parameters, plasma components and antioxidants responses were significantly affected by PE-MPs in a concentration-dependent manner. Exposure to ≥32 mg/L PE-MPs induced a significant decrease in red blood cells (RBCs), hemoglobin (Hb) content, and hematocrit values. However, exposure to ≥32 mg/L PE-MPs induced oxidative stress in the liver, gill, and intestine of C. carassius, thereby resulting in a significant increase in the levels of superoxide dismutase (SOD), catalase (CAT), and glutathione S-transferase (GST) and a decrease in glutathione (GSH) levels. The effects of interaction between the PE-MPs and exposure periods showed no significant changes in bioaccumulation, hematological parameters, plasma components and antioxidant responses. These finding indicate that the exposure to ≥32 mg/L PE-MPs could cause a significant accumulation in specific tissues of C. carassius, resulting in changes in hematological parameters, plasma components, and antioxidant responses. However, the interaction between PE-MPs and exposure periods had no significant effects, thereby suggesting the lack of toxicological interactions between PE-MPs and exposure periods in C. carassius.

The mercury accumulation and its effects on antioxidant and immune responses in starry flounder, Platichthys stellatus exposed to dietary mercury.

The purpose of this study is to investigate the effect of inorganic mercury (Hg) on fish. Inorganic Hg is less toxic than organic Hg, but it is used more in human daily life, such as manufacturing Hg batteries and fluorescent lamps. For this reason, inorganic Hg was used in this study. Starry flounder, Platichthys stellatus (mean weight 43.9 ± 4.4 g; mean length 14.2 ± 0.4 cm) were exposed for 4 weeks to the different levels of dietary inorganic Hg at concentrations of 0, 4, 8, 12 and 16 mg Hg/kg, and depuration was performed for 2 weeks after exposure. Bioaccumulation of Hg in the tissues was observed to increase significantly, in following order: intestine > head kidney > liver > gills > muscle. Antioxidant responses (superoxide dismutase (SOD), catalase (CAT), glutathione-S-transferase (GST) and glutathione (GSH)) were significantly increased. Immune responses (lysozyme and phagocytosis activity) were substantially decreased. The results of this study suggest that dietary inorganic Hg induces bioaccumulation in specific tissues, increases antioxidant responses and decreases immune responses. After the depuration period for 2 weeks, it was effective to alleviate bioaccumulation in tissues. However, antioxidant and immune responses were limited to be attenuated for recovery.

Helmet-Mounted Real-Time Toxic Gas Monitoring and Prevention System for Workers in Confined Places.

Occupational health and safety hazards associated with confined places are mainly caused by exposure to toxic gases and oxygen deficiency. Lack of awareness, inappropriate monitoring, and improper evacuation methods can lead to worker fatalities. Although previous studies have attempted to develop systems to solve this issue, limited research is available on their application in confined places. In this study, a real-time helmet-mounted system was developed to monitor major toxic gases (methane (CH4), hydrogen sulfide (H2S), ammonia (NH3), and carbon monoxide (CO)), oxygen, temperature, and humidity. Workers outside and inside confined spaces receive alerts every second to immediately initiate the rescue operation in the event of a hazard. The test results of a confined environment (wastewater treatment unit) highlighted that concentrations of CH4 and H2S were predominant (13 ppm). Compared to normal atmosphere, CH4 concentration was 122- and 130-fold higher in the landfill and digestion tanks, respectively, while H2S was 36- and 19-fold higher in the primary and secondary clarifiers, respectively. The oxygen content (18.2%) and humidity (33%) were below the minimum required limits. This study will benefit future research to target appropriate toxic gas monitoring and alert workers by studying the existing issues and associated factors in confined places.

Influence of o,p'-DDT on MUC5AC expression via regulation of NF-κB/AP-1 activation in human lung epithelial cells.

o,p'-Dichlorodiphenyltrichloroethane (o,p'-DDT) is a representative endocrine disruptor, and exposure to o,p'-DDT may produce immune disorders and inflammation, leading to various diseases such as cancer. Chronic airway inflammation is characterized by excessive mucus secretion resulting in chronic obstructive pulmonary disease (COPD). Mucin 5AC  (MUC5AC), one of the mucus genes, plays an important role in mucus secretion and inflammation in the airways. The aim of this study was to examine the effects of o,p'-DDT on the regulation of MUC5AC expression in human lung epithelial A549 cell line. o,p'-DDT increased mRNA levels and the promoter activity of MUC5AC. Transient transfection with mutation promoter constructs of MUC5AC demonstrated that nuclear factor kappa-b (NF-κB) and activator protein 1(AP-1) response elements were essential for the consequences of o,p'-DDT on MUC5AC expression. In addition, o,p'-DDT induced phosphorylation of ERK, JNK, p38, and Akt, which are involved in the regulation of MUC5AC expression. It is noteworthy that inhibitors of NF-κB, AP-1, Akt, and MAPKs blocked enhanced o,p'-DDT-induced MUC5AC mRNA expression. Data indicate that o,p'-DDT increase in NF-κB, and AP-1 transcriptional activation-dependent MUC5AC expression is associated with stimulation of Akt and MAPK signaling pathways in A549 cells.

Impressic Acid Ameliorates Atopic Dermatitis-Like Skin Lesions by Inhibiting ERK1/2-Mediated Phosphorylation of NF-κB and STAT1.

Impressic acid (IPA), a lupane-type triterpenoid from Acanthopanax koreanum, has many pharmacological activities, including the attenuation of vascular endothelium dysfunction, cartilage destruction, and inflammatory diseases, but its influence on atopic dermatitis (AD)-like skin lesions is unknown. Therefore, we investigated the suppressive effect of IPA on 2,4-dinitrochlorobenzene (DNCB)-induced AD-like skin symptoms in mice and the underlying mechanisms in cells. IPA attenuated the DNCB-induced increase in the serum concentrations of IgE and thymic stromal lymphopoietin (TSLP), and in the mRNA levels of thymus and activation regulated chemokine(TARC), macrophage derived chemokine (MDC), interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-13 (IL-13), tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) in mice. Histopathological analysis showed that IPA reduced the epidermal/dermal thickness and inflammatory and mast cell infiltration of ear tissue. In addition, IPA attenuated the phosphorylation of NF-κB and IκBα, and the degradation of IκBα in ear lesions. Furthermore, IPA treatment suppressed TNF-α/IFN-γ-induced TARC expression by inhibiting the NF-κB activation in cells. Phosphorylation of extracellular signalregulated protein kinase (ERK1/2) and the signal transducer and activator of transcription 1 (STAT1), the upstream signaling proteins, was reduced by IPA treatment in HaCaT cells. In conclusion, IPA ameliorated AD-like skin symptoms by regulating cytokine and chemokine production and so has therapeutic potential for AD-like skin lesions.

Impressic Acid Attenuates the Lipopolysaccharide-Induced Inflammatory Response by Activating the AMPK/GSK3ß/Nrf2 Axis in RAW264.7 Macrophages.

Inflammatory diseases are caused by excessive inflammation from pro-inflammatory mediators and cytokines produced by macrophages. The Nrf2 signaling pathway protects against inflammatory diseases by inhibiting excessive inflammation via the regulation of antioxidant enzymes, including HO-1 and NQO1. We investigated the anti-inflammatory effect of impressic acid (IPA) isolated from Acanthopanax koreanum on the lipopolysaccharide (LPS)-induced inflammation and the underlying molecular mechanisms in RAW264.7 cells. IPA attenuated the LPS-induced production of pro-inflammatory cytokines and reactive oxygen species, and the activation of the NF-κB signaling pathway. IPA also increased the protein levels of Nrf2, HO-1, and NQO1 by phosphorylating CaMKKß, AMPK, and GSK3ß. Furthermore, ML385, an Nrf2 inhibitor, reversed the inhibitory effect of IPA on LPS-induced production of pro-inflammatory cytokines in RAW264.7 cells. Therefore, IPA exerts an anti-inflammatory effect via the AMPK/GSK3ß/Nrf2 signaling pathway in macrophages. Taken together, the findings suggest that IPA has preventive potential for inflammation-related diseases.

Immunomodulatory Activity of Lactococcus lactis GCWB1176 in Cyclophosphamide-Induced Immunosuppression Model.

Recently, Lactococcus lactis subsp. lactis has been reported to have immunostimulating properties in an immunosuppressed-animal model. However, the immunological activities of Lactococcus lactis and the molecular mechanisms remain unclear. In this report, we evaluated the immunostimulating activity and associated mechanisms of Lactococcus lactis subsp. lactis GCWB1176 (GCWB1176) in macrophages and cyclophosphamide (CTX)-induced immunosuppressed mice. In a series of safety tests, GCWB1176 was found to have a negative response to hemolysis, as well as susceptibility to antibiotics. Administration of GCWB1176 elevated natural killer (NK) cell activities; concanavalin A-induced T cell proliferation; and serum levels of tumor necrosis factor (TNF)-α, interferon (IFN)-γ, interleukin (IL)-2, IL-4, IL-10 and IL-12 in CTX-induced immunosuppressed mice. In RAW264.7 macrophages, treatment with GCWB1176 induced phagocytic activity and increased the production of nitric oxide (NO) and expression of inducible NO synthase. Simultaneously, GCWB1176 increased the production of TNF-α, IFN-γ, IL-1ß, IL-10 and IL-12 from mouse splenocytes and RAW264.7 cells. In addition, GCWB1176 significantly increased the transcriptional activities of NF-κB and iNOS. Taken together, GCWB1176 improved immune function through the activation of macrophages and NK cells. These findings suggest that dietary supplementation of GCWB1176 may be used to enhance immunity.

Codium fragile Ameliorates High-Fat Diet-Induced Metabolism by Modulating the Gut Microbiota in Mice.

Codium fragile (CF) is a functional seaweed food that has been used for its health effects, including immunostimulatory, anti-inflammatory, anti-obesity and anti-cancer activities, but the effect of CF extracts on obesity via regulation of intestinal microflora is still unknown. This study investigated anti-obesity effects of CF extracts on gut microbiota of diet-induced obese mice. C57BL/6 mice fed a high-fat (HF) diet were given CF extracts intragastrically for 12 weeks. CF extracts significantly decreased animal body weight and the size of adipocytes, while reducing serum levels of cholesterol and glucose. In addition, CF extracts significantly shifted the gut microbiota of mice by increasing the abundance of Bacteroidetes and decreasing the abundance of Verrucomicrobia species, in which the portion of beneficial bacteria (i.e., Ruminococcaceae, Lachnospiraceae and Acetatifactor) were increased. This resulted in shifting predicted intestinal metabolic pathways involved in regulating adipocytes (i.e., mevalonate metabolism), energy harvest (i.e., pyruvate fermentation and glycolysis), appetite (i.e., chorismate biosynthesis) and metabolic disorders (i.e., isoprene biosynthesis, urea metabolism, and peptidoglycan biosynthesis). In conclusion, our study showed that CF extracts ameliorate intestinal metabolism in HF-induced obese mice by modulating the gut microbiota.

Orostachys japonicus ethanol extract inhibits 2,4-dinitrochlorobenzene-induced atopic dermatitis-like skin lesions in NC/Nga mice and TNF-α/IFN-γ-induced TARC expression in HaCaT cells.

The risk of atopic dermatitis (AD)-like skin lesions has increased due to the elevated levels of allergens worldwide. Natural-origin agents, which are effective and safe, show promise for the prevention and treatment of inflammatory conditions. Orostachys japonicus (OJ) A. Berger is an ingredient of traditional herbal medicines for fever, gingivitis, and cancer in Korea, China, and Japan. However, the effect of OJ on AD-like skin lesions is unknown. Therefore, we investigated the effect of OJ ethanol extract (OJEE) on AD-like skin symptoms in mice and cells. OJEE reduced the 2,4-dinitrochlorobenzene-induced AD severity, serum levels of IgE and TARC, and mRNA levels of TARC, TNF-α, and IL-4 in NC/Nga mice. Histopathological analysis showed that OJEE reduced the thickness of the epidermis/dermis and dermal infiltration of inflammatory cells in ear tissue. Furthermore, OJEE suppressed the TNF-α/IFN-γ-increased TARC mRNA level by inhibiting NF-κB and STAT1 activation in HaCaT cells. Taken together, our findings show that OJEE reduced the risk of AD-like skin symptoms by decreasing TARC expression via inhibiting NF-κB and STAT1 activation in skin keratinocytes and thus shows promise as an alternative therapy for AD-like skin lesions.

Polyhexamethylene Guanidine Phosphate Damages Tight Junctions and the F-Actin Architecture by Activating Calpain-1 via the P2RX7/Ca2+ Signaling Pathway.

Polyhexamethylene guanidine phosphate (PHMG-p), a member of the polymeric guanidine family, has strong antimicrobial activity and may increase the risk of inflammation-associated pulmonary fibrosis. However, the effect of PHMG-p on the barrier function of the bronchial epithelium is unknown. Epithelial barrier functioning is maintained by tight junctions (TJs); damage to these TJs is the major cause of epithelial barrier breakdown during lung inflammation. The present study showed that, in BEAS-2B human bronchial epithelial cells, exposure to PHMG-p reduced the number of TJs and the E-cadherin level and impaired the integrity of the F-actin architecture. Furthermore, exposure to PHMG-p stimulated the calcium-dependent protease calpain-1, which breaks down TJs. However, treatment with the calpain-1 inhibitor, ALLN, reversed the PHMG-p-mediated impairment of TJs and the F-actin architecture. Furthermore, exposure to PHMG-p increased the intracellular Ca2+ level via P2X purinoreceptor 7 (P2RX7) and inhibition of P2RX7 abolished the PHMG-p-induced calpain-1 activity and protein degradation and increased the intracellular Ca2+ level. Although exposure to PHMG-p increased the extracellular ATP level, hydrolysis of extracellular ATP by apyrase did not influence its detrimental effect on bronchial epithelial cells. These results implicate the impairment of TJs and the F-actin architecture in the pathogenesis of pulmonary diseases.

Impressic Acid, a Lupane-Type Triterpenoid from Acanthopanax koreanum, Attenuates TNF-α-Induced Endothelial Dysfunction via Activation of eNOS/NO Pathway.

Atherosclerosis is one of the most reported diseases worldwide, and extensive research and trials are focused on the discovery and utilizing for novel therapeutics. Nitric oxide (NO) is produced mainly by endothelial nitric oxide synthase (eNOS) and it plays a key role in regulating vascular function including systemic blood pressure and vascular inflammation in vascular endothelium. In this study hypothesized that Impressic acid (IPA), a component isolated from Acanthopanax koreanum, acts as an enhancer of eNOS activity and NO production. IPA treatment induced eNOS phosphorylation and NO production, which was correlated with eNOS phosphorylation via the activation of JNK1/2, p38 MAPK, AMPK, and CaMKII. In addition, the induction of eNOS phosphorylation by IPA was attenuated by pharmacological inhibitor of MAPKs, AMPK, and CaMKII. Finally, IPA treatment prevented the adhesion of TNF-α-induced monocytes to endothelial cells and suppressed the TNF-α-stimulated ICAM-1 expression via activation of NF-κB, while treatment with L-NAME, the NOS inhibitor, reversed the inhibitory effect of IPA on TNF-α-induced ICAM-1 expression via activation of NF-κB. Taken together, these findings show that IPA protects against TNF-α-induced vascular endothelium dysfunction through attenuation of the NF-κB pathway by activating eNOS/NO pathway in endothelial cells.

WY-14643 Regulates CYP1B1 Expression through Peroxisome Proliferator-Activated Receptor α-Mediated Signaling in Human Breast Cancer Cells.

Human cytochrome P450 1B1 (CYP1B1)-mediated biotransformation of endobiotics and xenobiotics plays an important role in the progression of human breast cancer. In this study, we investigated the effects of WY-14643, a peroxisome proliferator-activated receptor α (PPARα) agonist, on CYP1B1 expression and the related mechanism in MCF7 breast cancer cells. We performed quantitative reverse transcription-polymerase chain reaction, transient transfection, and chromatin immunoprecipitation to evaluate the effects of PPARα on peroxisome proliferator response element (PPRE)-mediated transcription. WY-14643 increased the protein and mRNA levels of CYP1B1, as well as promoter activity, in MCF-7 cells. Moreover, WY-14643 plus GW6471, a PPARα antagonist, significantly inhibited the WY-14643-mediated increase in CYP1B1 expression. PPARα knockdown by a small interfering RNA markedly suppressed the induction of CYP1B1 expression by WY-14643, suggesting that WY-14643 induces CYP1B1 expression via a PPARα-dependent mechanism. Bioinformatics analysis identified putative PPREs (-833/-813) within the promoter region of the CYP1B1 gene. Inactivation of these putative PPREs by deletion mutagenesis suppressed the WY-14643-mediated induction of CYP1B1 promoter activation. Furthermore, WY-14643 induced PPARα to assume a form capable of binding specifically to the PPRE-binding site in the CYP1B1 promoter. Our findings suggest that WY-14643 induces the expression of CYP1B1 through activation of PPARα.

Delta neutrophil index as a predictor of disease severity, surgical outcomes, and mortality rates in gastrointestinal diseases: Rationale for a meta-analysis of diagnostic test accuracy.

BACKGROUND: Delta neutrophil index (DNI) is the ratio of the number of immature granulocytes and the total neutrophil count in peripheral circulation. DNI precedes changes in white blood cell or neutrophil counts due to the course of granular leukocyte differentiation in infectious and inflammatory conditions, beginning with immature granulocyte formation. The role of DNI as a biomarker of various infectious or inflammatory conditions has been reported. However, no studies explored the potential role of DNI as an initial biomarker for predicting disease severity, surgical outcomes, and mortality rates of gastrointestinal diseases with pooled diagnostic test accuracy. This study aims to provide evidence that DNI is a predictor of disease severity, surgical outcomes, and mortality rates in patients with gastrointestinal diseases in emergency medical departments. METHODS: MEDLINE, EMBASE, and the Cochrane Library will be searched using common keywords (inception to July 2019) by 2 independent evaluators. Inclusion criteria will be patients with gastrointestinal diseases, DNI measurements performed in the emergency department, indices of diagnostic performance (sensitivity, specificity, predictive values, and likelihood ratios) of DNI for predicting severity, surgical outcomes, and mortality rate of gastrointestinal diseases. True and false positives and negatives will be calculated based on the diagnostic indices of each study. All types of study designs with full-text literature written in English will be included. Risk of bias will be assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool. Descriptive data synthesis will be conducted and quantitative synthesis (bivariate and hierarchical summary receiver operating characteristic model) will be performed if the included studies are sufficiently homogenous. Meta-regression, sensitivity analysis, publication bias, and Fagan nomogram will be analyzed and described. RESULTS: The pooled synthesis of the diagnostic performance of various gastrointestinal diseases with different cut-off values for DNI may limit the interpretation of uniform diagnostic validity. The authors will contact the corresponding authors for the missing values, requesting the original data in each study. However, if there are no responses from these authors, these studies will be excluded. CONCLUSION: This study will provide diagnostic validity of DNI as an initial marker for the prediction of severity, surgery, and mortality of gastrointestinal diseases.

Automated classification of gastric neoplasms in endoscopic images using a convolutional neural network.

BACKGROUND: Visual inspection, lesion detection, and differentiation between malignant and benign features are key aspects of an endoscopist's role. The use of machine learning for the recognition and differentiation of images has been increasingly adopted in clinical practice. This study aimed to establish convolutional neural network (CNN) models to automatically classify gastric neoplasms based on endoscopic images. METHODS: Endoscopic white-light images of pathologically confirmed gastric lesions were collected and classified into five categories: advanced gastric cancer, early gastric cancer, high grade dysplasia, low grade dysplasia, and non-neoplasm. Three pretrained CNN models were fine-tuned using a training dataset. The classifying performance of the models was evaluated using a test dataset and a prospective validation dataset. RESULTS: A total of 5017 images were collected from 1269 patients, among which 812 images from 212 patients were used as the test dataset. An additional 200 images from 200 patients were collected and used for prospective validation. For the five-category classification, the weighted average accuracy of the Inception-Resnet-v2 model reached 84.6 %. The mean area under the curve (AUC) of the model for differentiating gastric cancer and neoplasm was 0.877 and 0.927, respectively. In prospective validation, the Inception-Resnet-v2 model showed lower performance compared with the endoscopist with the best performance (five-category accuracy 76.4 % vs. 87.6 %; cancer 76.0 % vs. 97.5 %; neoplasm 73.5 % vs. 96.5 %; P  < 0.001). However, there was no statistical difference between the Inception-Resnet-v2 model and the endoscopist with the worst performance in the differentiation of gastric cancer (accuracy 76.0 % vs. 82.0 %) and neoplasm (AUC 0.776 vs. 0.865). CONCLUSION: The evaluated deep-learning models have the potential for clinical application in classifying gastric cancer or neoplasm on endoscopic white-light images.

Alcohol consumption is associated with the risk of developing colorectal neoplasia: Propensity score matching analysis.

Although alcohol intake is known to be associated with the development of colorectal cancer, the effect of alcohol consumption on the development of colorectal neoplasm (CRN) is unclear. We performed a retrospective cohort analysis with 1 to 1 propensity score matching in a single center of Korea. Among 1,448 patients who underwent index and surveillance colonoscopy, 210 matched pairs were analyzed. The 5-year cumulative occurrence of overall CRN after index colonoscopy was higher in the significant alcohol consumption group (defined as alcohol consumption more than 30 g/day in men and 20 g/day in women) (vs. without significant alcohol consumption group) (40% vs. 27.6%, p = 0.004). Significant alcohol consumption increased the development of overall CRN (adjusted hazard ratio [aHR]: 1.86, 95% confidence interval [CI]: 1.28-2.70, p = 0.001) at surveillance colonoscopy. However, this effect was not valid on the development of advanced CRN. In subgroup analysis considering the risk classification of index colonoscopy, significant alcohol consumption increased the overall CRN development at surveillance colonoscopy in the normal group (patients with no detected adenoma in the index colonoscopy) (aHR: 1.90, 95% CI: 1.16-3.13, p = 0.01). Alcohol consumption habits should be considered in optimizing time intervals of surveillance colonoscopy.