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.

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.

Microplastic polyamide toxicity: Neurotoxicity, stress indicators and immune responses in crucian carp, Carassius carassius.

This study aimed to determine the toxicity standard and potential risks and effects of polyamide (PA) exposure on neurotoxicity, stress indicators, and immune responses in juvenile crucian carp Carassius carassius. Numerous microplastics (MPs) exists within aquatic environments, leading to diverse detrimental impacts on aquatic organisms. The C. carassius (mean weight, 23.7 ± 1.6 g; mean length, 13.9 ± 1.4 cm) were exposed to PA concentrations of 0, 4, 8, 16, 32 and 64 mg/L for 2 weeks. Among the neurotransmitters, the acetylcholinesterase (AChE) activity in the liver, gill, and intestine of C. carassius was significantly inhibited by PA exposure. Stress indicators such as cortisol and heat shock protein 70 (HSP70) in the liver, gill, and intestine of C. carassius were significantly increased, while immune responses to lysozyme and immunoglobulin M (IgM) were significantly decreased. Our study demonstrates the toxic effects of MP exposure on crucian carp's neurotoxicity, stress indicators, and immune responses.

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.

The application and future of biofloc technology (BFT) in aquaculture industry: A review.

This review describes the applicability of biofloc technology (BFT) to future aquaculture technologies. BFT is considered an innovative alternative for solving the problems of traditional aquaculture (for example, environmental pollution, high maintenance costs, and low productivity). Extensive research is being conducted to apply BFT to breed and raise many aquatic animal species. In BFT, maintaining an appropriate C:N ratio by adding a carbon source promotes the growth of microorganisms in water and maintains the aquaculture water quality through microbial processes such as nitrification. For the efficient use and sustainability of BFT, various factors such as total suspended solids, water turbidity, temperature, dissolved oxygen, pH, and salinity, stocking density, and light should be considered. The application of the transformative fourth industrial revolution technologies, Information and Communications Technology (ICT) and Internet of Things (IoT), to aquaculture can reduce the risk factors and manual interventions in aquaculture through automation and intelligence. The combination of ICT/IoT with BFT can enable real-time monitoring of the necessary elements of BFT farming using various sensors, which is expected to increase productivity by ensuring the growth and health of the organisms being reared.

Shrimp bacterial and parasitic disease listed in the OIE: A review.

Shrimp aquaculture industry has steadily increased with demand and development of aquaculture technology. In recent years, frequent diseases have become a major risk factor for shrimp aquaculture, such as a drastically reduced the production of shrimp and causing national economic loss. Among them, shrimp bacterial diseases such as hepatopancreatic necrosis disease (AHPND) and necrotizing hepatopancreatitis (NHP-B) and parasitic disease such as Aphanomyces astaci (crayfish plague) are emerging and evolving into new types. OIE (World Organization for Animal Health) regularly updates information on diseases in the Aquatic Code and Aquatic Manual, but in-depth information on the shrimp diseases are lacking. Therefore, the purpose of this review is to provide information necessary for the response and prevention of shrimp diseases by understanding the characteristics and diagnosis of shrimp diseases designated by OIE.

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 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.

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.

Stimulatory effects of platycodin D on osteoblast differentiation.

Previous studies have suggested that platycodin D is implicated in bone biology and ameliorates osteoporosis development. Platycodin D repressed the osteoclast activity and enhanced bone mineral density in the mouse model. However, the effects of platycodin D on osteoblast differentiation have not been elucidated yet. In C3H10T1/2 cells, platycodin D upregulated osteogenic markers including alkaline phosphatase (ALP), bone sialoprotein, and collagen type 1 alpha 1, and transcription factors, such as Runx2 and osterix, subsequently enhancing the bone mineralization. In a molecular mechanism study, platycodin D induced ß-catenin nuclear accumulation by upregulating GSK3ß phosphorylation. Furthermore, platycodin D upregulated the ALP activity and enhanced the mineralization process in osteoblast cells via the sirtuin 1/ß-catenin pathways. Taken together, these results suggested that platycodin D could be an effective therapeutic compound against osteoporosis because of its regulatory effects during the osteoblast differentiation.

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.

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.

Advanced glycation end products promote triple negative breast cancer cells via ERK and NF-κB pathway.

Advanced glycation end products (AGEs) are harmful compounds generated by nonspecific glycation of proteins and lipids. The accumulation of AGEs is associated with various diseases, including breast cancer. AGEs have been shown to promote a breast cancer cell line by enhancing proliferation, invasion and migration. In this study, we investigated the effect and associated mechanism of AGEs on triple negative breast cancer cells. AGEs enhanced the proliferation, tumorigenicity, invasion and migration of primary breast cancer cells. AGEs also enhanced the RNA and protein expression of matrix metalloproteinase (MMP)-9 and its gelatinase activity. Enhanced MMP-9 expression was mediated by extracellular-signal regulated kinase (ERK) and nuclear factor kappa B (NF-κB) pathways. Moreover, inhibitors of ERK and NF-κB signaling attenuated the effect of AGEs on tumorigenicity, invasion and migration of primary breast cancer cells. Taken together, we suggest that AGEs directly promote primary breast cancer cells via the ERK and NF-κB pathway, which may lead to advanced therapeutic modalities of breast cancer.

Pentamidine blocks hepatotoxic injury in mice.

Toxin-induced liver diseases lack effective therapies despite increased understanding of the role factors such as an overactive innate immune response play in the pathogenesis of this form of hepatic injury. Pentamidine is an effective antimicrobial agent against several human pathogens, but studies have also suggested that this drug inhibits inflammation. This potential anti-inflammatory mechanism of action, together with the development of a new oral form of pentamidine isethionate VLX103, led to investigations of the effectiveness of this drug in the prevention and treatment of hepatotoxic liver injury. Pretreatment with a single injection of VLX103 in the d-galactosamine (GalN) and lipopolysaccharide (LPS) model of acute, fulminant liver injury dramatically decreased serum alanine aminotransferase levels, histological injury, the number of terminal deoxynucleotide transferase-mediated deoxyuridine triphosphate nick end-labeling (TUNEL)-positive cells and mortality compared with vehicle-injected controls. VLX103 decreased GalN/LPS induction of tumor necrosis factor (TNF) but had no effect on other proinflammatory cytokines. VLX103 prevented the proinflammatory activation of cultured hepatic macrophages and partially blocked liver injury from GalN/TNF. In GalN/LPS-treated mice, VLX103 decreased activation of both the mitochondrial death pathway and downstream effector caspases 3 and 7, which resulted from reduced c-Jun N-terminal kinase activation and initiator caspase 8 cleavage. Delaying VLX103 treatment for up to 3 hours after GalN/LPS administration was still remarkably effective in blocking liver injury in this model. Oral administration of VLX103 also decreased hepatotoxic injury in a second more chronic model of alcohol-induced liver injury, as demonstrated by decreased serum alanine and aspartate aminotransferase levels and numbers of TUNEL-positive cells. CONCLUSION: VLX103 effectively decreases toxin-induced liver injury in mice and may be an effective therapy for this and other forms of human liver disease. (Hepatology 2017;66:922-935).

Measurement error induced by the power-frequency delay of the light source in optical correlation-domain distributed Brillouin sensors.

Direct current modulation of a semiconductor laser is a key method adopted in most optical correlation-domain distributed Brillouin sensors such as Brillouin optical correlation-domain analysis (BOCDA) and reflectometry (BOCDR) for localizing the sensing position by synthesis of an optical coherence function. We report that distributed measurement of Brillouin frequency by the BOCDA or BOCDR system can suffer significant distortion caused by phase delay between output power and frequency variations of the modulated light source. We calculate characteristics of the distortion by numerical simulations, and compare the results with experimental data obtained by a BOCDA system for confirmation. Our results show that a maximum error of more than 30 MHz can occur in Brillouin frequency measured under ordinary operating conditions with MHz-order direct current modulation.

Layer-by-layer assembled multilayers of charged polyurethane and graphene oxide platelets for flexible and stretchable gas barrier films.

With the advent of the era of consumer-oriented displays and mobile devices, the importance of barrier film coatings for securing devices from oxygen or moisture penetration has become more salient. Recently developed approaches to generate gas barrier films in a combination of polyelectrolyte multilayer matrices and incorporated inorganic nanosheets have shown great potential in outperforming conventional gas barrier films. However, these films have the intrinsic drawback of vulnerability to brittleness and inability to stretch for flexible device applications. To overcome this issue, we present a method in which we prepare multilayered films of complementarily charged polyurethane and graphene oxide platelets using spin-assisted, layer-by-layer self-assembly to obtain well-stacked film structures. As a result, the multilayered, thin films deposited on a poly(ethylene terephthalate) (PET) substrate can exhibit significantly reduced oxygen penetration properties (∼30 cc m-2 day-1 for the oxygen transmission rate) while still demonstrating large bending or stretching deformations. Therefore, the proposed approach in this study is anticipated to be extensively utilized for surface coating and protection of flexible and stretchable devices under various operating conditions.

Platycodin D Inhibits Osteoclastogenesis by Repressing the NFATc1 and MAPK Signaling Pathway.

Platycodon grandiflorum root-derived saponins (Changkil saponins, CKS) are reported to have many pharmacological activities. In our latest research, CKS was proven to have a significant osteogenic effect. However, the detail molecular mechanism of CKS on osteoclastic differentiation has not been fully investigated. Administration of CKS considerably reduced OVX-induced bone loss, and ameliorated the reduction in plasma levels of alkaline phosphatase, calcium, and phosphorus observed in OVX mice. CKS also repressed the deterioration of bone trabecular microarchitecture. Interestingly, platycodin D, the most abundant and major pharmacological constituent of triterpenoid CKS, inhibited receptor activator of NF-κB ligand (RANKL)-induced activation of NF-κB, and ERK and p38 MAPK, ultimately repressing osteoclast differentiation. OVX-induced bone turnover was attenuated by CKS, possibly via repression of osteoclast differentiation by platycodin D, the active component of CKS. Platycodin D can be regarded as an antiosteoporotic candidate for treatment of osteoporosis diseases. J. Cell. Biochem. 118: 860-868, 2017. © 2016 Wiley Periodicals, Inc.

Endosulfan induces COX-2 expression via NADPH oxidase and the ROS, MAPK, and Akt pathways.

Endosulfan (1,4,5,6,7,7-hexachloro-8,9,10-trinorborn-5-en-2,3-ylenebismet-hylene) is correlated with endocrine disruption, reproductive, and immune dysfunctions. Recently, endosulfan was shown to have an effect on inflammatory pathways, but its influence on cyclooxygenase-2(COX-2) expression is unclear. This study investigated the effects of COX-2 and molecular mechanisms by endosulfan in murine macrophage RAW 264.7 cells. Endosulfan significantly induced COX-2 protein and mRNA levels, as well as COX-2 promoter-driven luciferase activity and the production of prostaglandin E2, a major COX-2 metabolite. Transfection experiments with several human COX-2 promoter constructs revealed that endosulfan activated NF-κB, C/EBP, AP-1, and CREB. Moreover, Akt and mitogen-activated protein kinases (MAPK) were significantly activated by endosulfan. Moreover, endosulfan increased production of the ROS and the ROS-producing NAPDH-oxidase (NOX) family oxidases, NOX2, and NOX3. Endosulfan-induced Akt/MAPK pathways and COX-2 expression were attenuated by DPI, a specific NOX inhibitor, and the ROS scavenger N-acetylcysteine. These results demonstrate that endosulfan induces COX-2 expression via NADPH oxidase, ROS, and Akt/MAPK pathways. These findings provide further insight into the signal transduction pathways involved in the inflammatory effects of endosulfan.