ABSTRACT
Cigarette smoking is a major cause of lung cancer. Although tobacco smoking-induced genotoxicity has been well established, there is apparent lack of abundance functional epigenetic effects reported On cigarette smoke-induced lung carcinogenesis. The aim of this study was to determine effects of intratracheal administration of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) utilizing target gene expression DNA methylation patterns in lung tissues of mice following twice weekly for 8 weeks treatment. An unbiased approach where genomic regions was undertaken to assess early methylation changes within mouse pulmonary tissues. A methylated-CpG island recovery assay (MIRA) was performed to map the DNA methylome in lung tissues, with the position of methylated DNA determined using a Genome Analyzer (MIRA-SEQ). Alterations in epigenetic-regulated target genes were confirmed with quantitative reverse transcription-PCR, which revealed 35 differentially hypermethylated genes including Cdkn1C, Hsf4, Hnf1a, Cdx1, and Hoxa5 and 30 differentially hypomethylated genes including Ddx4, Piwi1, Mdm2, and Pce1 in NNK-exposed lung tissue compared with controls. The main pathway of these genes for mediating biological information was analyzed using the Kyoto Encyclopedia of Genes and Genomes database. Among them, Rssf1 and Mdm2 were closely associated with NNK-induced lung carcinogenesis. Taken together, our data provide valuable resources for detecting cigarette smoke-induced lung carcinogenesis.
Subject(s)
Carcinogenesis/chemically induced , Carcinogens/toxicity , Epigenesis, Genetic/drug effects , Lung/drug effects , Nitrosamines/toxicity , Animals , Biomarkers, Tumor/genetics , Carcinogenesis/genetics , Carcinogenesis/metabolism , Carcinogenesis/pathology , Carcinogens/analysis , DNA Methylation/drug effects , Epigenome/drug effects , Gene Expression/drug effects , Lung/metabolism , Lung/pathology , Lung Neoplasms/chemically induced , Lung Neoplasms/genetics , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Mice , Nitrosamines/analysis , Tobacco Smoking/adverse effectsABSTRACT
OBJECTIVES: The aim of this study is to compare the radiologic diagnostic performance of arterial phase, portal phase and combined phase computed tomography (CT) for traumatic abdominal injury. In addition, this study is attempted to decrease lifetime attributable risks (LARs) of cancer due to radiation exposure by using optimal CT protocol. MATERIALS AND METHODS: A total of 114 consecutive patients with a traumatic abdominal injury and an abdominal hematoma on CT were enrolled at a single tertiary regional trauma center between January 2016 and March 2017. Each CT protocol set was independently reviewed by three radiologists, and the diagnostic performance of all three CT phases were compared with regard to the capability to detect active bleeding, contained vascular injuries, and organ injuries. Additionally, LARs for cancer incidence and mortality were calculated using dose-length product values, for each phase of CT. RESULTS: The pooled area under the receiver operating characteristic curves for the diagnosis of active bleeding, contained vascular injuries, and organ injuries ranged from 0.910 to 0.922, 0.643 to 0.723, and 0.948 to 0.915 for arterial, portal, and combined phase CT, respectively. There was no statistically significant difference in the diagnosis of active bleeding and organ injuries for any combination of two phase sets. The mean LARs for cancer incidence was 0.059%, 0.062% and 0.121% during arterial, portal and combined phase CT, respectively. CONCLUSION: Single phase CT could be a potential protocol for abdominal trauma patients. Use of single phase CT could significantly decrease the incidence of radiation-associated cancer in the future.
Subject(s)
Abdominal Injuries/diagnostic imaging , Hemorrhage/diagnostic imaging , Tomography, X-Ray Computed , Wounds, Nonpenetrating/diagnostic imaging , Adult , Aged , Contrast Media , Female , Hemorrhage/etiology , Humans , Male , Middle Aged , ROC Curve , Retrospective Studies , Trauma Centers , Vascular System Injuries/diagnostic imagingABSTRACT
Vimentin, an intermediate filament protein induced during epithelial-to-mesenchymal transition, is known to regulate cell migration and invasion. However, it is still unclear how vimentin controls such behaviors. In this study, we aimed to find a new integrin regulator by investigating the H-Ras-mediated integrin suppression mechanism. Through a proteomic screen using the integrin ß3 cytoplasmic tail protein, we found that vimentin might work as an effector of H-Ras signaling. H-Ras converted filamentous vimentin into aggregates near the nucleus, where no integrin binding can occur. In addition, an increase in the amount of vimentin filaments accessible to the integrin ß3 tail enhanced talin-induced integrin binding to its ligands by inducing integrin clustering. In contrast, the vimentin head domain, which was found to bind directly to the integrin ß3 tail and compete with endogenous vimentin filaments for integrin binding, induced nuclear accumulation of vimentin filaments and reduced the amount of integrin-ligand binding. Finally, we found that expression of the vimentin head domain can reduce cell migration and metastasis. From these data, we suggest that filamentous vimentin underneath the plasma membrane is involved in increasing integrin adhesiveness, and thus regulation of the vimentin-integrin interaction might control cell adhesion.
Subject(s)
Cell Adhesion/genetics , Cytoskeleton/metabolism , Integrin beta3/genetics , Vimentin/genetics , Animals , CHO Cells , Cell Membrane/genetics , Cell Membrane/metabolism , Cell Movement/genetics , Cricetinae , Cricetulus , Cytoskeleton/genetics , Epithelial-Mesenchymal Transition/genetics , Humans , Integrin beta3/metabolism , Ligands , Protein Binding , Protein Interaction Maps , Proteomics , Vimentin/metabolismABSTRACT
In this study, hollow fiber membranes for forward osmosis using cellulose triacetate were prepared using the non-solvent phase separation method, and the water purification properties of the prepared membranes were tested. In order to optimize the membrane morphology, which affects the membrane performance, 1,4-dioxane and lithium chloride were used as additives. Using the forward osmosis process, the properties of the membrane were investigated according to changes in the factors such as the salt type, salt concentration, and solution temperature. In the nanofiltration process, the water flux was found to increase and the salt rejection to decrease with increasing air gaps, regardless of the type of salt. In contrast, in the forward osmosis process, the water flux increased and the solute rejection value increased in a manner similar to the increasing concentration of solute.
ABSTRACT
Integrins are the major cell adhesion molecules responsible for cell attachment to the extracellular matrix. The strength of integrin-mediated adhesion is controlled by the affinity of individual integrins (integrin activation) as well as by the number of integrins involved in such adhesion. The positive correlation between integrin activation and integrin clustering had been suggested previously, but several trials to induce integrin clustering by dimerization of the transmembrane domain or tail region of integrin α subunits failed to demonstrate any change in integrin activation. Here, using platelet integrin αIIbß3 as a model system, we showed that there is intermolecular lateral interaction between integrins through the transmembrane domains, and this interaction can enhance the affinity state of integrins. In addition, when integrin clustering was induced through heteromeric lateral interactions using bimolecular fluorescence complementation, we could observe a significant increase in the number of active integrin molecules. Because the possibility of intermolecular interaction would be increased by a higher local concentration of integrins, we propose that integrin clustering can shift the equilibrium in favor of integrin activation.
Subject(s)
Cell Membrane/metabolism , Platelet Glycoprotein GPIIb-IIIa Complex/chemistry , Platelet Glycoprotein GPIIb-IIIa Complex/metabolism , Animals , Cell Membrane/chemistry , Cell Membrane/genetics , Dimerization , Humans , Platelet Glycoprotein GPIIb-IIIa Complex/genetics , Protein Binding , Protein Structure, TertiaryABSTRACT
Advanced high strength steel (AHSS) is a steel of multi-phase microstructure that is processed under several conditions to meet the current high-performance requirements from the industry. Deep neural network (DNN) has emerged as a promising tool in materials science for the task of estimating the phase volume fraction of these steels. Despite its advantages, one of its major drawbacks is its requirement of a sufficient amount of training data with correct labels to the network. This often comes as a challenge in many areas where obtaining data and labeling it is extremely labor-intensive. To overcome this challenge, an unsupervised way of learning DNN, which does not require any manual labeling, is proposed. Information maximizing generative adversarial network (InfoGAN) is used to learn the underlying probability distribution of each phase and generate realistic sample points with class labels. Then, the generated data is used for training an MLP classifier, which in turn predicts the labels for the original dataset. The result shows a mean relative error of 4.53% at most, while it can be as low as 0.73%, which implies the estimated phase fraction closely matches the true phase fraction. This presents the high feasibility of using the proposed methodology for fast and precise estimation of phase volume fraction in both industry and academia.
ABSTRACT
A convolutional neural network (CNN), which exhibits excellent performance in solving image-based problem, has been widely applied to various industrial problems. In general, the CNN model was applied to defect inspection on the surface of raw materials or final products, and its accuracy also showed better performance compared to human inspection. However, surfaces with heterogeneous and complex backgrounds have difficulties in separating defects region from the background, which is a typical challenge in this field. In this study, the CNN model was applied to detect surface defects on a hierarchical patterned surface, one of the representative complex background surfaces. In order to optimize the CNN structure, the change in inspection performance was analyzed according to the number of layers and kernel size of the model using evaluation metrics. In addition, the change of the CNN's decision criteria according to the change of the model structure was analyzed using a class activation map (CAM) technique, which can highlight the most important region recognized by the CNN in performing classification. As a result, we were able to accurately understand the classification manner of the CNN for the hierarchical pattern surface, and an accuracy of 93.7% was achieved using the optimized model.
ABSTRACT
Purpose: The aim of this study was to compare the diameter and volume of liver metastases on CT images in relation to overall survival and tumor response in patients with gastric cancer liver metastases (GCLM) treated with chemotherapy. Materials and Methods: We recruited 43 patients with GCLM who underwent chemotherapy as a first-line treatment. We performed a three-dimensional quantification of the metastases for each patient. An independent survival analysis using the Response Evaluation Criteria in Solid Tumors (RECIST) was performed and compared to volumetric measurements. Overall survival was evaluated using Kaplan-Meier analysis and compared using Cox proportional hazard ratios following univariate analyses. Results: When patients were classified as responders or non-responders based on volumetric criteria, the median overall survival was 23.6 months [95% confidence interval (CI), 8.63-38.57] and 7.6 months (95% CI, 3.78-11.42), respectively (p = 0.039). The volumetric analysis and RECIST of the non-progressing and progressing groups showed similar results based on the Kaplan-Meier method (p = 0.006) and the Cox proportional hazard model (p = 0.008). Conclusion: Volumetric assessment of liver metastases could be an alternative predictor of overall survival for patients with GCLM treated with chemotherapy.
ABSTRACT
The complexity of interstitial cystitis/bladder pain syndrome (IC/BPS) has led to considerable uncertainty in terms of diagnosis and prevalence of the condition. Here, we try to identify the IC/BPS-associated genes through an integrated analysis of Gene Expression Omnibus (GEO) datasets and confirm experimentally to predict the pathologic diagnosis of IC/BPS. Data mining analysis of GEO datasets (GSE621, GSE11783, GSE28242, and GSE57560) revealed a total of 53 (51 upregulated and two downregulated) common differentially expressed genes (DEGs) in IC/BPS. A protein-protein interaction (PPI) network was then constructed with the 53 common DEGs using Cytoscape v3.7.2, and subsequently, six hub genes (CD5, CD38, ITGAL, IL7R, KLRB1, and IL7R) were identified using cytoHubba v0.1 that were upregulated in IC/BPS. Enrichment analysis of common DEGs revealed that hematopoietic cell lineage, immune system, and T-cell receptor (TCR) signaling in naïve CD4+ T cell signaling pathways were prominently involved with the common 51 upregulated DEGs. The two common downregulated DEGs may enrich linoleic acid metabolism and synthesis of epoxy (EET) and dihydroxyeicosatrienoic acid (DHET) signaling pathways in IC/BPS. Moreover, our RT-PCR data confirmed that the expression of the five hub genes (CD38, ITGAL, IL7R, KLRB1, and IL7R) was significantly augmented in IC/BPS patients' samples when compared with their normal counterparts. In this study, we systematically predict the significant biomarkers and possible signaling pathways involved in IC/BPS, confirming the differential expression of the hub genes in tissue samples from patients with IC/BPS. Thus, the hub genes might be used as potential diagnostic biomarkers of IC/BPS.
ABSTRACT
The world has witnessed unimaginable damage from the coronavirus disease-19 (COVID-19) pandemic. Because the pandemic is growing rapidly, it is important to consider diverse treatment options to effectively treat people worldwide. Since the immune system is at the hub of the infection, it is essential to regulate the dynamic balance in order to prevent the overexaggerated immune responses that subsequently result in multiorgan damage. The use of stem cells as treatment options has gained tremendous momentum in the past decade. The revolutionary measures in science have brought to the world mesenchymal stem cells (MSCs) and MSC-derived exosomes (MSC-Exo) as therapeutic opportunities for various diseases. The MSCs and MSCExos have immunomodulatory functions; they can be used as therapy to strike a balance in the immune cells of patients with COVID-19. In this review, we discuss the basics of the cytokine storm in COVID-19, MSCs, and MSC-derived exosomes and the potential and stem-cell-based ongoing clinical trials for COVID-19. [BMB Reports 2020; 53(8): 400-412].
Subject(s)
Coronavirus Infections/therapy , Exosomes/transplantation , Mesenchymal Stem Cell Transplantation , Pneumonia, Viral/therapy , Betacoronavirus/isolation & purification , COVID-19 , Coronavirus Infections/immunology , Coronavirus Infections/pathology , Coronavirus Infections/virology , Cytokines/metabolism , Humans , Immune System/metabolism , Immunomodulation , Mesenchymal Stem Cells/cytology , Mesenchymal Stem Cells/metabolism , Pandemics , Pneumonia, Viral/immunology , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , SARS-CoV-2ABSTRACT
The availability of autologous adult stem cells is one of the essential prerequisites for human stem cell therapy. Urine-derived stem cells (USCs) are considered as desirable cell sources for cell therapy because donor-specific USCs are easily and non-invasively obtained from urine. Efficient isolation, expansion, and differentiation methods of USCs are necessary to increase their availability. Here, we developed a method for efficient isolation and expansion of USCs using Matrigel, and the rho-associated protein kinase (ROCK) inhibitor, Y-27632. The prepared USCs showed significantly enhanced migration, colony forming capacity, and differentiation into osteogenic or chondrogenic lineage. The USCs were successfully reprogramed into induced pluripotent stem cells (USC-iPSCs) and further differentiated into kidney organoid and hematopoietic progenitor cells (HPCs). Using flavonoid molecules, the isolation efficiency of USCs and the production of HPCs from the USC-iPSCs was increased. Taken together, we present an improved isolation method of USCs utilizing Matrigel, a ROCK inhibitor and flavonoids, and enhanced differentiation of USC-iPSC to HPC by flavonoids. These novel findings could significantly enhance the use of USCs and USC-iPSCs for stem cell research and further application in regenerative stem cell-based therapies.
ABSTRACT
Tetrabromobisphenol A (TBBPA), the most common industrial brominated flame retardant, acts as a cytotoxic, neurotoxic, and immunotoxicant, causing inflammation and tumors. However, the mechanism of TBBPA-induced matrix metalloproteinase-9 (MMP-9) expression in human breast cancer cells is not clear. In human breast cancer MCF-7 cells, treatment with TBBPA significantly induced the expression and promoter activity of MMP-9. Transient transfection with MMP-9 mutation promoter constructs verified that NF-κB and AP-1 response elements are responsible for the effects of TBBPA. Furthermore, TBBPA-induced MMP-9 expression was mediated by NF-κB and AP-1 transcription activation as a result of the phosphorylation of the Akt and MAPK signaling pathways. Moreover, TBBPA-induced activation of Akt/MAPK pathways and MMP-9 expression were attenuated by a specific NADPH oxidase inhibitor, and the ROS scavenger. These results suggest that TBBPA can induce cancer cell metastasis by releasing MMP-9 via ROS-dependent MAPK, and Akt pathways in MCF-7 cells.
ABSTRACT
Toll-like receptor 3 (TLR3) participates in the innate immune response by recognizing viral pathogens. In this study, human brain astrocytes were found to constitutively express TLR3, and this expression was increased by interferon-gamma (IFN-gamma) or double-stranded RNA (dsRNA). Treatment employing dsRNA in astrocytes induced IFN regulatory factor 3 (IRF3) phosphorylation, dimer formation and nuclear translocation followed by STAT1 activation. This treatment also activated nuclear factor-kappaB, p38 and c-Jun N-terminal kinase significantly, while activating extracellular signal-regulated kinase to a lesser extent. Treatment with anti-TLR3 antibody inhibited dsRNA-mediated interleukin-6 (IL-6) production. In the presence of mitogen-activated protein kinase inhibitors, astrocytes failed to secrete IL-6 in response to dsRNA treatment. Therefore, dsRNA-induced IL-6 production is dependent on mitogen-activated protein kinases and type I IFN production is dependent on IRF3 in brain astrocytes. These results suggest that brain inflammation, which produces inflammatory cytokines and type I IFNs, may enhance TLR3 expression in astrocytes. Additionally, upregulated TLR3 might modulate inflammatory processes by producing proinflammatory cytokines.
Subject(s)
Astrocytes/immunology , Brain/immunology , Interferon Regulatory Factor-3/metabolism , Interleukin-6/biosynthesis , Toll-Like Receptor 3/metabolism , Brain/embryology , Cells, Cultured , Dose-Response Relationship, Immunologic , Electrophoretic Mobility Shift Assay/methods , Fetus/immunology , Humans , I-kappa B Proteins/metabolism , Interferon-gamma/immunology , Mitogen-Activated Protein Kinase Kinases/immunology , NF-KappaB Inhibitor alpha , NF-kappa B/metabolism , Polynucleotides/immunology , RNA, Double-Stranded/immunology , Reverse Transcriptase Polymerase Chain Reaction/methods , STAT1 Transcription Factor/metabolism , Up-Regulation/immunologyABSTRACT
Hexokinase type II (HK II) is the key enzyme for maintaining increased glycolysis in cancer cells where it is overexpressed. 3-bromopyruvate (3-BrPA), an inhibitor of HK II, induces cell death in cancer cells. To elucidate the molecular mechanism of 3-BrPA-induced cell death, we used the hepatoma cell lines SNU449 (low expression of HKII) and Hep3B (high expression of HKII). 3-BrPA induced ATP depletion-dependent necrosis and apoptosis in both cell lines. 3-BrPA increased intracellular reactive oxygen species (ROS) leading to mitochondrial dysregulation. NAC (N-acetyl-L: -cysteine), an antioxidant, blocked 3-BrPA-induced ROS production, loss of mitochondrial membrane potential and cell death. 3-BrPA-mediated oxidative stress not only activated poly-ADP-ribose (PAR) but also translocated AIF from the mitochondria to the nucleus. Taken together, 3-BrPA induced ATP depletion-dependent necrosis and apoptosis and mitochondrial dysregulation due to ROS production are involved in 3-BrPA-induced cell death in hepatoma cells.
Subject(s)
Apoptosis/physiology , Carcinoma, Hepatocellular/pathology , Hexokinase/antagonists & inhibitors , Liver Neoplasms/pathology , Mitochondria/metabolism , Mitochondria/pathology , Reactive Oxygen Species/metabolism , Apoptosis/drug effects , Carcinoma, Hepatocellular/metabolism , Cell Line, Tumor , Gene Expression Regulation, Neoplastic , Humans , Liver Neoplasms/metabolism , Pyruvates/pharmacologyABSTRACT
The purpose of this study was to analyze the combined effects of regular exercise and ginseng supplementation on peritoneal exudate ROS (reactive oxygen species), lymphocyte proliferation by splenocytes, and DNA damage following exhaustive exercise stress. Thirty-six female BALB/c mice were randomly divided into control (UT, n = 12), trained (TR, n = 12), and ginseng supplemented and trained (GT, n = 12) groups. Each group was divided into two equal subgroups where mice were studied at rest (UTre, TRre, and GTre) or immediately after exhaustive exercise stress (UTex, TRex, and GTex). Animals were bred in the animal facility, where they were housed at 22-24 degrees C and relative humidity (RH) 50-60% in a controlled environment with a 12-hour photoperiod, and provided food and water ad libitum. The trained mice underwent 10 weeks of endurance swim training (5 times/week) in water at 27-30 degrees C for 60 minutes. The analytical items examined were weight, proliferative activity, the production of ROS from peritoneal exudate cells, and DNA damage following exhaustive exercise stress (2 h exercise stress). Significant level was set at p < 0.05. The results obtained showed that the trained group had a significantly lower mean body weight than the untrained group (p < 0.05). However, there was no significant difference between UT and GT. Swim training increased swim survival time in TRex and GTex, and TRex showed the highest swim survival time. With regard to mitogenic activities of splenocytes in response to exhaustive exercise stress, all groups showed much lower lymphocyte proliferative activity when stimulated with media (Med), concanavalin A (ConA), or lipopolysaccharide (LPS) after exhaustive exercise stress. However, GTex had a higher proliferative activity than the other groups. Trained and ginseng-supplemented groups showed lower peritoneal ROS responses and lymphocyte DNA damage levels after exhaustive exercise. These findings suggest that the combined effect of swim training and ginseng supplementation sustain lymphocyte function in the presence of reduced ROS production and DNA damage following acute exercise stress.
Subject(s)
DNA Damage , Panax , Physical Conditioning, Animal/physiology , Physical Endurance/physiology , Reactive Oxygen Species/metabolism , Animals , B-Lymphocytes/immunology , Exudates and Transudates/drug effects , Exudates and Transudates/physiology , Female , Lymphocyte Activation/drug effects , Male , Mice , Mice, Inbred BALB C , Physical Endurance/drug effects , Swimming/physiology , T-Lymphocytes/immunologyABSTRACT
Hormone replacement therapy (HRT) consists of highly effective prescription medications for treating menopausal symptoms; however, these agents have exhibited side effects including the risk of estrogen-induced carcinogenesis. Therefore, interest in phytotherapy-based materials as a natural source of alternatives to estrogen therapy has increased. However, some of these herbal medicines have been reported to increase the risk of estrogen-induced cancer. Herbal formulations composed of a combination of Cynanchum wilfordii Hemsley (CW), Phlomis umbrosa Turczaninow (PU), and Angelica gigas Nakai (AG) extracts (CPAE) have been used for treating menopausal symptoms. Therefore, in this study, we aimed to examine the safety of CPAE by determining its potential adverse estrogenic activity using the Organization for Economic Cooperation and Development (OECD) test guideline 455 (TG455) in a stably transfected transcriptionally activated human estrogen receptor α (hERα)-HeLa9903 cell model. We found that CPAE did not how any estrogenic activity or stimulate promoters containing estrogen response elements in MCF-7 cells. In addition, CPAE showed no significant selective activity against hERα and hERß, non-selective activity against the ER, or effects on ER target gene expression. Furthermore, CPAE did not significantly induce MCF-7 cell proliferation and uterine weight increase in ovariectomized rats. These results demonstrate that CPAE can be used as beneficial herbal drug for prevention and therapeutic intervention of estrogen carcinogenesis in menopausal women.
ABSTRACT
Cardiovascular disease, which is caused by unregulated platelet aggregation, is one of the main causes of deaths worldwide. Many studies have focused on natural products with antiplatelet effects as a safe alternative therapy to prevent the disease. In this context, an in-house chemical library was screened to find natural products capable of inhibiting the interaction between platelet integrin αIIbß3 and fibrinogen, which is an essential step in platelet aggregation. On the basis of the screening results, indothiazinone, an alkaloid found in microbial cultures, was identified as a potential antiplatelet agent. Specifically, indothiazinone treatment significantly inhibited the binding of fibrinogen to Chinese hamster ovary cells expressing integrin αIIbß3. It also restricted thrombin- and adenosine diphosphate-dependent spreading of human platelets on a fibrinogen matrix. More importantly, surface plasmon resonance and molecular dynamics studies suggested that indothiazinone suppressed talin-induced activation of integrin αIIbß3 presumably by inhibiting talin-integrin interaction. In conclusion, these results suggest that indothiazinone can be used as a lead compound for the development of antiplatelet drugs with a novel mode of action.
Subject(s)
Blood Platelets/drug effects , Indoles/pharmacology , Platelet Aggregation Inhibitors/pharmacology , Thiazoles/pharmacology , Animals , Blood Platelets/cytology , Blood Platelets/metabolism , CHO Cells , Cricetulus , Humans , Indoles/chemistry , Models, Molecular , Platelet Aggregation Inhibitors/chemistry , Platelet Glycoprotein GPIIb-IIIa Complex/metabolism , Talin/metabolism , Thiazoles/chemistryABSTRACT
Platycodon grandiflorum has been healthy effects due to its various nutritious compounds and is considered as a functional food. Platycodon grandiflorum root-derived saponins (CKS) have been reported to show a variety of effects including anti-inflammatory and anti-oxidative activity. Although CKS have been studied on various bioactivities, the inhibitory effect of CKS on non-alcoholic steatohepatitis (NASH) is not examined. In this study, the inhibitory effects on HFD-induced NASH by CKS were determined. CKS suppressed HFD-induced hepatic lipid peroxidation level, collagen deposition, pro-fibrogenic and pro-inflammatory cytokines expression. CKS treatment suppressed HFD-induced COX-2 expression via inhibition of NF-κB p65 nuclear translocation and IκBα degradation. CKS treatment restored HFD-reduced Nrf2-mediated antioxidant enzymes expression. Furthermore, CKS treatment reinstated HFD-reduced peroxisomal proliferator-activated receptor alpha (PPARα)-regulated acyl-coA oxidase and carnitine-palmitoyl-coA transferase-1 expression. These findings suggest that CKS reduces HFD-induced NASH by up-regulation of Nrf2-mediated anti-oxidant enzymes and PPARα-regulated fatty acid oxidation.
Subject(s)
Diet, High-Fat/adverse effects , Non-alcoholic Fatty Liver Disease/drug therapy , Plant Extracts/therapeutic use , Plant Roots , Platycodon , Saponins/therapeutic use , Animals , Anti-Inflammatory Agents/isolation & purification , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Antioxidants/isolation & purification , Antioxidants/pharmacology , Antioxidants/therapeutic use , Dose-Response Relationship, Drug , Lipid Peroxidation/drug effects , Lipid Peroxidation/physiology , Male , Non-alcoholic Fatty Liver Disease/metabolism , Plant Extracts/isolation & purification , Plant Extracts/pharmacology , Rats , Rats, Sprague-Dawley , Saponins/isolation & purification , Saponins/pharmacologyABSTRACT
l-theanine, a water-soluble amino acid isolated from green tea (Camellia sinensis), has anti-inflammatory activity, antioxidative properties, and hepatoprotective effects. However, the anti-allergic effect of l-theanine and its underlying molecular mechanisms have not been elucidated. In this study, we investigated the protective effects of l-theanine on asthmatic responses, particularly airway inflammation and oxidative stress modulation in an ovalbumin (OVA)-induced murine model of asthma. Treatment with l-theanine dramatically attenuated the extensive trafficking of inflammatory cells into bronchoalveolar lavage fluid (BALF). Histological studies revealed that l-theanine significantly inhibited OVA-induced mucus production and inflammatory cell infiltration in the respiratory tract and blood vessels. l-theanine administration also significantly decreased the production of IgE, monocyte chemoattractant protein-1 (MCP-1), interleukin (IL)-4, IL-5, IL-13, tumor necrosis factor-alpha (TNF-α), and interferon-gamma in BALF. The lung weight decreased with l-theanine administration. l-theanine also markedly attenuated the OVA-induced generation of reactive oxygen species and the activation of nuclear factor kappa B (NF-κB) and matrix metalloprotease-9 in BALF. Moreover, l-theanine reduced the TNF-α-induced NF-κB activation in A549 cells. Together, these results suggest that l-theanine alleviates airway inflammation in asthma, which likely occurs via the oxidative stress-responsive NF-κB pathway, highlighting its potential as a useful therapeutic agent for asthma management.
Subject(s)
Anti-Allergic Agents/pharmacology , Anti-Asthmatic Agents/pharmacology , Asthma/drug therapy , Glutamates/pharmacology , Inflammation/drug therapy , Ovalbumin/toxicity , Respiratory System/drug effects , Animals , Anti-Inflammatory Agents/pharmacology , Asthma/chemically induced , Asthma/immunology , Blotting, Western , Cytokines/metabolism , Female , Inflammation/chemically induced , Inflammation/immunology , Mice , Mice, Inbred ICRABSTRACT
Leptin plays a key role in the control of adipocyte formation, as well as in the associated regulation of energy intake and expenditure. The goal of this study was to determine if leptin-induced aromatase enhances estrogen production and induces tumor cell growth stimulation. To this end, breast cancer cells were incubated with leptin in the absence or presence of inhibitor pretreatment, and changes in aromatase and cyclooxygenase-2 (COX-2) expression were evaluated at the mRNA and protein levels. Transient transfection assays were performed to examine the aromatase and COX-2 gene promoter activities and immunoblot analysis was used to examine protein expression. Leptin induced aromatase expression, estradiol production, and promoter activity in breast cancer cells. Protein levels of phospho-STAT3, PKA, Akt, ERK, and JNK were increased by leptin. Leptin also significantly increased cAMP levels, cAMP response element (CRE) activation, and CREB phosphorylation. In addition, leptin induced COX-2 expression, promoter activity, and increased the production of prostaglandin E2. Finally, a COX-2 inhibitor and aromatase inhibitor suppressed leptin-induced cell proliferation in MCF-7 breast cancer cells. Together, our data show that leptin increased aromatase expression in breast cancer cells, which was correlated with COX-2 upregulation, mediated through CRE activation and cooperation among multiple signaling pathways.