Search

PDF - 430K, Inhibitory effects of various ALK5 inhibitors on TGF−beta1-induced EMT in MCF10A cells. MCF10A cells were treated with TGF−beta1 (2 ng/ml) for 96 h in serum-reduced media (1% heat inactivated-horse serum (HI-HS)) in the presence or absence of the indicated ALK5 inhibitors. Medium was replaced every other day. Cell morphology was observed by phase-contrast microscopy (total magnification: x 100, scale bar: 100 microm).

Advanced tumors produce an excessive amount of transforming growth factor β (TGFβ), which promotes tumor progression at late stages of malignancy. The purpose of this study was to develop anti-TGFβ therapeutics for cancer. We synthesized a novel small-molecule TGFβ receptor I kinase (activin receptor–like kinase 5) inhibitor termed N-[[4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl]methyl]-2-fluoroaniline (EW-7197), and we investigated its potential antimetastatic efficacy in mouse mammary tumor virus (MMTV)/c-Neu mice and 4T1 orthotopic–grafted mice. EW-7197 inhibited Smad/TGFβ signaling, cell migration, invasion, and lung metastasis in MMTV/c-Neu mice and 4T1 orthotopic–grafted mice. EW-7197 also inhibited the epithelial-to-mesenchymal transition (EMT) in both TGFβ-treated breast cancer cells and 4T1 orthotopic–grafted mice. Furthermore, EW-7197 enhanced cytotoxic T lymphocyte activity in 4T1 orthotopic–grafted mice and increased the survival time of 4T1-Luc and 4T1 breast tumor–bearing mice. In summary, EW-7197 showed potent in vivo antimetastatic activity, indicating its potential for use as an anticancer therapy. Mol Cancer Ther; 13(7); 1704–16. ©2014 AACR.

PDF - 80K, (A, B) Breast cancer model #6 (described in the Material and Methods). (A) Inhibition of lung metastasis by EW-7197 was evaluated by analysis of luciferase activity in lungs of 4T1-luc orthotropic xenograft mice. Statistical significance was defined using one-way ANOVA with Dunnett's multiple comparison test. * indicates significance at p

PDF - 191K, Supplementary materials and methods and supplementary figure legends. Supplementary Table 1. Antibodies for Western blot analysis. Supplementary Table 2. Primers for qRT-PCR or RT-PCR. Supplementary Table 3. Radiometric protein kinase assay.

PDF - 150K, Inhibitory effects of various ALK5 inhibitors on TGFbeta1-induced EMT in MCF10A cells. MCF10A cells were treated with TGFbeta1 (2 ng/ml) for 96 h in serum-reduced media (1% HI-HS) in the presence or absence of the indicated ALK5 inhibitors. Medium was replaced every other day. The protein levels of E-CADHERIN and N-CADHERIN were analyzed by western blotting as described in the Material and Methods. beta-ACTIN was used as endogenous control.

PDF - 120K, (A) Blockade of Smad2 phosphorylation by various ALK5 inhibitors. 4T1 cells starved in 0.2% HI-FBS medium for 24 h, and were treated with the indicated chemicals for 2 h with or without TGF-beta1 (2 ng/ml) in 0.2% HI-FBS medium. (B, C) Blockade of Smad2 phosphorylation by EW-7197. NMUMG (B) and MDA-MB-231 (C) cells were incubated with 0.2% HI-FBS medium for 24 h, and treated with TGF-beta1 (2 ng/ml) in the presence or absence of ALK5 inhibitors in 0.2% HI-FBS medium for 2 h. Lysates from the cells were analyzed by Western blotting. EW, SB, LY, IN indicate EW-7197, SB-505124, LY-2157299, and IN-1130, respectively.

PDF - 356K, (A~C) Breast cancer model #1, described in the Material and Methods. (A) Effect of EW-7197 on lung metastasis of breast cancer in MMTV-c/Neu mice. Representative images of H&E stained lungs (total magnification: x 12.5 or 100, scale bar: 800 μm or 100 μm). Total tumor volume (B) and body weight (C) in MMTV/c-Neu mice. Data represent the mean (plus or minus) SE (Veh: n=7, EW: n=10). (D and E) Body weight in breast cancer model #2 (D) and in breast cancer model #3 (E) (described in the Material and Methods). Data represent the mean (plus or minus) SE (n=10/group in Model #2 or n=6~8/group in Model #3). Veh, LY and EW indicate artificial gastric fluid, LY-2157299 and EW-7197, respectively. (F) In breast cancer model #3 (described in the Material and Methods), on day 28, two mice of each group were selected and treated with the indicated concentration of EW-7197. One mouse from each group was injected with TGF-beta1 (50 ng/mouse) through i.v. after 30 min and another was not injected. 90 min after TGF-beta1 injection, mice were sacrificed and lysates from primary mammary tumors were analyzed by western blotting as described in the Material and Methods.

Personalized production has emerged as a result of the increasing customer demand for more personalized products. Personalized production systems carry a greater amount of uncertainty and variability when compared with traditional manufacturing systems. In this paper, we present a smart manufacturing system using a multi-agent system and reinforcement learning, which is characterized by machines with intelligent agents to enable a system to have autonomy of decision making, sociability to interact with other systems, and intelligence to learn dynamically changing environments. In the proposed system, machines with intelligent agents evaluate the priorities of jobs and distribute them through negotiation. In addition, we propose methods for machines with intelligent agents to learn to make better decisions. The performance of the proposed system and the dispatching rule is demonstrated by comparing the results of the scheduling problem with early completion, productivity, and delay. The obtained results show that the manufacturing system with distributed artificial intelligence is competitive in a dynamic environment.

Among abiotic stresses in plants, drought and chilling stresses reduce the supply of moisture to plant tissues, inhibit photosynthesis, and severely reduce plant growth and yield. Thus, the application of water stress-tolerant agents can be a useful strategy to maintain plant growth under abiotic stresses. This study assessed the effect of exogenous bio-based 2,3-butanediol (BDO) application on drought and chilling response in tomato and turfgrass, and expression levels of several plant signaling pathway-related gene transcripts. Bio-based 2,3-BDOs were formulated to levo-2,3-BDO 0.9% soluble concentrate (levo 0.9% SL) and meso-2,3-BDO 9% SL (meso 9% SL). Under drought and chilling stress conditions, the application of levo 0.9% SL in creeping bentgrass and meso 9% SL in tomato plants significantly reduced the deleterious effects of abiotic stresses. Interestingly, pretreatment with levo-2,3-BDO in creeping bentgrass and meso-2,3-BDO in tomato plants enhanced JA and SA signaling pathway-related gene transcript expression levels in different ways. In addition, all tomato plants treated with acibenzolar

Histone deacetylase (HDAC) inhibitors represent a novel class of anticancer agents, which can be used to inhibit cell proliferation and induce apoptosis in several types of cancer cells. In this study, we investigated the anticancer activity of MHY4381, a newly synthesized HDAC inhibitor, against human prostate cancer cell lines and compared its efficacy with that of suberoylanilide hydroxamic acid (SAHA), a well-known HDAC inhibitor. We assessed cell viability, apoptosis, cell cycle regulation, and other biological effects in the prostate cancer cells. We also evaluated a possible mechanism of MHY4381 on the apoptotic cell death pathway. The IC50 value of MHY4381 was lower in DU145 cells (IC50=0.31 μM) than in LNCaP (IC50=0.85 μM) and PC-3 cells (IC50=5.23 μM). In addition, the IC50 values of MHY4381 measured in this assay were significantly lower than those of SAHA against prostate cancer cell lines. MHY4381 increased the levels of acetylated histones H3 and H4 and reduced the expression of HDAC proteins in the prostate cancer cell lines. MHY4381 increased G2/M phase arrest in DU145 cells, and G1 arrest in LNCaP cells. It also activated reactive oxygen species (ROS) generation, which induced apoptosis in the DU145 and LNCaP cells by increasing the ratio of Bax/Bcl-2 and releasing cytochrome c into the cytoplasm. Our results indicated that MHY4381 preferentially results in antitumor effects in DU145 and LNCaP cells via mitochondria-mediated apoptosis and ROS-facilitated cell death pathway, and therefore can be used as a promising prostate cancer therapeutic.

Recently, manufacturing concepts, such as personalized production and distributed manufacturing, have attracted attention owing to the ongoing revolution in industrial technology. Connected micro s...

Purpose In this paper, a three-dimensional (3D) printer-based manufacturing line and supporting system, which supports personalized/customized manufacturing for individual businesses or start-up companies, was studied to evaluate the practicality of using additive manufacturing for personalization/mass customization. Design/methodology/approach First, factory-as-a-service (FaaS) system, which provides factory as a service to customers, was proposed and designed to manufacture various products within a distributed manufacturing environment. This system includes 3D printer-based material extrusion processes, vapor machine/computer numerical control machines as post-processes and assembly and inspection processes with an automated material handling robot in the factory. Second, a virtualization module for the FaaS factory was developed using a simulation model interfaced with a cloud-based order and production-planning system and an internet-of-things-based control and monitoring system. This is part of the system for manufacturing operations, which is capable of dynamic scheduling in a distributed manufacturing environment. In addition, simulation-based virtual production was conducted to verify and evaluate the FaaS factory for the target production scenario. Main information of the simulation also has been identified and included in the virtualization module. Finally, the established system was applied in a sample production scenario to evaluate its practicality and efficiency. Findings Additive manufacturing is a reliable, feasible and applicable technology, and it can be a core element in smart manufacturing and the realization of personalization/mass customization. Originality/value Various studies on additive manufacturing have been conducted with regard to replacing the existing manufacturing methods or integrating with them, but these studies mostly focused on materials or types of additive manufacturing, with few advanced or applied studies on the establishment of a new manufacturing environment for personalization/mass customization.

Background Oncolytic viro-therapeutics is a promising treatment for cancer. Among the different strains of oncolytic viruses currently being developed, potent cytolytic activity, manageable safety profiles, large genomic capacity for addition of transgenes and available advanced manufacture processes make adenovirus (Ad) a great choice.1 However, the delivery of Ad for clinical application is limited due to 1) neutralization by pre-existing neutralizing antibodies (nAb) in bloodstream and 2) receptor restricted tumor-cellular entry.2 To overcome these limitations, we developed a novel proprietary polymer nanoparticle delivery system, so called Stability Enhanced Nano Shells (SENS™) for the delivery of Virus (vSENS). Methods SENS™ employs proprietary an ionizable cationic lipid and biodegradable and biocompatible polymers. Following complexation with replication-incompetent adenovirus serotype 5 (Ad-vSENS) or replication-competent oncolytic adenovirus serotype 5 (OAd-vSENS), the physicochemical properties of the complexes were characterized by dynamic light scattering (DLS) and electron microscopy. The benefit of vSENS in coxsackievirus and adenovirus receptor (CAR) restricted cellular transduction of adenovirus was evaluated with Ad-vSENS in CAR negative cancer cells. Pharmacokinetic profile of OAd-vSENS was examined in mice following systemic administration to assess the protective effect of vSENS in the presence of pre-existing immunity to Adenoviral proteins. Anti-tumor efficacy was evaluated in syngeneic subcutaneous tumor mice models. The serum level of alanine aminotransferase (ALT) in mice was evaluated by blood chemistry analyzer. Results Ad-vSENS effectively infected cancer cells in CAR-independent manner, where cancer cell-killing effects of OAd-vSENS were significantly enhanced in CAR negative cancer cells compare with those of naked OAd. When vSENS is complexed with an adenovirus, it encapsulates the virus like a shell shielding the adenovirus. Consistently, in syngeneic tumor bearing mice with pre-existing Ad immunity, longer virus blood half-life and longer survival of the mice were observed when administered with OAd-vSENS compared to naked OAd. The hepatotoxicity of OAd was greatly reduced by vSENS formulation as evidenced by the absence of acute spike in serum ALT levels typically seen after systemic administration of OAd. Conclusions The results show the potential of vSENS as a novel platform technology for delivery of Ad to overcome challenges adeno-virotherapies face in the clinic. vSENS platform is expected to expand the efficacy of the virus from cancer patients with high CAR expression to patients with limited CAR expression often associated as the cancer progresses. The platform is likely to facilitate treatment in patients with high levels of antibodies to adenovirus by shielding the virus from neutralization and increasing the bioavailability. Ethics Approval The study was approved by Samyang Biopharmaceuticals Institution’s Ethics Board, approval number SYAU2009. References Twumasi-Boateng K, Pettigrew JL, Kwok YYE, Bell JC, Nelson BH, Oncolytic viruses as engineering platforms for combination immunotherapy. Nat Rev Cancer 2018;18:419–322. Zheng M, Huang J, Tong A, Yang H, Oncolytic viruses for cancer therapy: barriers and recent advances. Mol Ther Oncolytics 2019;15:234–247.

BACKGROUND/AIM The study focused on identifying the mechanisms or drugs that could sensitize P-glycoprotein (P-gp)-overexpressing resistant KBV20C cancer cells to halaven (HAL) or vincristine (VIC) treatment. MATERIALS AND METHODS Based on the relatively low dose or IC50 values for sensitizing anti-mitotic drug-resistant KBV20C cells, the aging-related drugs donepezil (DON) and sildenafil citrate (SID) were selected. Fluorescence-activated cell sorting (FACS), western blotting, and annexin V analyses were performed to investigate the mechanism of action of DON and SID in HAL-treated KBV20C cells. RESULTS DON or SID reduced cell viability, increased G2 arrest, and up-regulated the expression of the DNA damaging protein pH2AX when used as co-treatment with HAL. DON and SID induced both early and late apoptosis in KBV20C cells in response to HAL treatment, without increasing autophagy. VIC-DON and VIC-SID co-treatments increased sensitization of KBV20C cells, suggesting that DON and SID can be combined with other anti-mitotic drugs for sensitizing resistant cancer cells. When the sensitization efficacies of DON and SID were compared to that of the anti-psychotic repositioned drug fluphenazine (FLU), HAL-SID or HAL-FLU co-treatments were found to have better sensitization effects than HAL-DON suggesting that HAL-SID sensitization mechanism is different from that of HAL-DON. In addition, DON was found to have higher P-gp inhibitory activity than FLU or SID. CONCLUSION These results suggest that HAL-FLU or HAL-SID sensitization in KBV20C cells involves both cytotoxic and P-gp inhibitory effects, whereas HAL-DON sensitization may involve only P-gp inhibitory activity of DON.

Robot technology is one of the key technologies in the 4th industry revolution along with AI (Artificial Intelligent) and IoT (Internet of Things) technology, and robots that can collaborate with humans are drawing attention at industrial sites in particular. If only humans work on manufacturing sites without robots' help, a flexibility that can respond to a variety of variables can be increased, but productivity can be decreased. In the case of fully automated lines without human participation, productivity increases but lacks flexibility. In addition, it is very expensive to produce fully automated facilities that can be used in various product production processes. Therefore, a proper collaboration between humans and robots is a very important factor in ensuring productivity and flexibility. On the other hand, looking at future manufacturing trends, customer requirements for products are expected to be diversified and change rapidly in the future, which requires a flexible diversified small-quantity production environment, in which factories can produce a wide variety of products in a short period of time. In this paper, manufacturing facilities that can support various product production and precision assembly processes through collaboration between humans and robots, have been developed, and the developed facilities have been applied to two testbed lines respectively and functions are verified through actual product production.

Recently, with the development of artificial intelligence technology, robots have been utilized not only in manufacturing but also in many industrial fields. The needs of customers have been diversified and the trend of future manufacturing has been changing from the conventional mass production to the multiproduct small volume production system. In a smart factory environment for custom manufacturing, the robot must be manually programmed for each work instruction every time, especially when a production product is changed. Robot programming takes a lot of time and effort of people. In this paper, we propose a method to automatically measure the product information(color, size) automatically which are 3D printed out based on HSV (hue, saturation, value) Color Space and to control the auto grasping of robots. Also, we applied this control system to the FaaS(Factory As a Service) testbed for functional verification.

Chronic exposure to cadmium (Cd) causes remarkable damage to the kidneys, a target organ of accumulated Cd after oral administration. The aim of the present study was to investigate the protective effect of curcumin against Cd-induced nephrotoxicity. Sprague–Dawley male rats were divided into the following four treatment groups: control, curcumin (50 mg/kg, oral), CdCl2, (25 mg/kg, oral), and pre-treatment with curcumin (50 mg/kg) 1 h prior to the administration of CdCl2 (25 mg/kg, oral) for 7 days. At 24 h after the final treatment, the animals were killed, and the biomarkers associated with nephrotoxicity were measured. Our data indicated that blood urea nitrogen (BUN) and serum creatinine (sCr) levels were significantly reduced by curcumin pre-treatment in CdCl2-treated animals. Histopathological studies showed hydropic swelling and hypertrophy of the proximal tubular cells in the renal cortex after Cd treatment. Pretreatment with curcumin ameliorated the histological alterations induced by Cd. The urinary excretion of kidney injury molecule-1 (Kim-1), osteopontin (OPN), tissue inhibitor of metalloproteinases 1 (TIMP-1), neutrophil gelatinase-associated lipocalin (NGAL), and netrin-1 significantly reduced by curcumin treatment compared to that in the CdCl2-treated group. The administration of curcumin provided a significant protective effect against Cd-induced nephrotoxicity.

Triclosan (TCS), a common antimicrobial ingredient, is present in many consumer products, including soaps, shampoos, and toothpaste. Owing to its widespread use, potential adverse effects on animals and humans may arise from lifetime exposure, but data on chronic prepubertal exposure of TCS are still lacking. The aim of the present study was to investigate the influence of subchronic TCS exposure (0.25, 25, 250, or 750 mg/kg) on target organ toxicity in prepubertal male rats. After daily administration of TCS to rats by oral gavage for 60 d, a significant reduction in body weight and relative weights of liver, kidneys, testes, and adrenal glands was observed in the 750-mg/kg (high dose) group. Serum alanine aminotransferase and aspartate aminotransferase activities as well as levels of blood urea nitrogen, and creatinine were significantly increased at 750 mg/kg TCS. Further, TCS (750 mg/kg) elevated the protein expressions of hepatic CYP2B1, RXR/PPAR, and levels of malondialdehyde. High-dose TCS exposure induced histological changes as evidenced by reduction of Bowman's space, occlusion of the tubular lumen, and degeneration of tubular epithelial cells in the kidney. Tubular necrosis was confirmed as evidenced by a rise in expression of high mobility group box 1 renal protein. Daily sperm production was significantly diminished by high doses of TCS with marked inhibition of androgen receptor protein expression. Our results indicated that subchronic exposure to excessively high concentrations of 750 mg/kg TCS induced hepatorenal and reproductive toxicities in prepubertal male rats; however, the biological relevance of these findings is questionable as these drug levels are not encountered in the environment.

We propose a simple and robust HSV color-space-based algorithm that can automatically extract object position information without human intervention or prior knowledge. In manufacturing sites with high variability, it is difficult to recognize products through robot machine vision, especially in terms of extracting object information accurately, owing to various environmental factors such as the noise around objects, shadows, light reflections, and illumination interferences. The proposed algorithm, which does not require users to reset the HSV color threshold value whenever a product is changed, uses ROI referencing method to solve this problem. The algorithm automatically identifies the object’s location by using the HSV color-space-based ROI random sampling, ROI similarity comparison, and ROI merging. The proposed system utilizes an IoT device with several modules for the detection, analysis, control, and management of object data. The experimental results show that the proposed algorithm is very useful for industrial automation applications under complex and highly variable manufacturing environments.

Benzo[a]pyrene (BaP) is a well-known carcinogen formed during the cooking process. Although BaP exposure has been implicated as one of the risk factors for lung cancer in animals and humans, there are only limited data on BaP-induced gastrointestinal cancer. Therefore, this study investigated the protective effects of curcumin on BaP-induced DNA damage in rat stomach tissues. BaP (20 mg/kg/day) and curcumin (50, 100, or 200 mg/kg) were administered daily to Sprague-Dawley rats by oral gavage over 30 days. Curcumin was pre-administered before BaP exposure. All rats were euthanized, and liver, kidney, and stomach tissues were removed at 24 h after the last treatment. We observed that aspartate aminotransferase (AST), alanine aminotransferase (ALT), and glucose levels were significantly reduced in rats treated with high dose co-administration of curcumin (200 mg/kg) compared to BaP alone. The expression levels of cytochrome P450 (CYP) 1A1 and CYP1B1 were significantly increased in the liver of rats treated with BaP. However, co-administration of curcumin (200 mg/kg) with BaP markedly reduced CYP1A1 expression in a dose-dependent manner. Furthermore, plasma levels of BaP-diolepoxide (BPDE) and BaP metabolites were significantly reduced by co-administration of curcumin (200 mg/kg). Additionally, co-administration of curcumin (200 mg/kg) with BaP significantly reduced the formation of BPDE-I-DNA and 8-hydroxydeoxy guanosine (8-OHdG) adducts in the liver, kidney, and stomach tissues. The inhibition of these adduct formations were more prominent in the stomach tissues than in the liver. Overall, our observations suggest that curcumin might inhibit BaP-induced gastrointestinal tumorigenesis and shows promise as a chemopreventive agent.

High-fat diet (HFD)-induced obesity is implicated in diabetic nephropathy (DN). EX-527, a selective Sirtuin 1 (SIRT1) inhibitor, has multiple biological functions; however, its protective effect against DN is yet to be properly understood. This study was aimed to explore the protective effect of EX-527 against DN in HFD-induced diabetic Zucker (ZDF) rats. After 21 weeks of continually feeding HFD to the rats, the apparent characteristics of progressive DN were observed, which included an increase in kidney weight (~160%), hyperglycemia, oxidative stress, and inflammatory cytokines, and subsequent renal cell damage. However, the administration of EX-527 for 10 weeks significantly reduced the blood glucose concentration and kidney weight (~59%). Furthermore, EX-527 significantly reduced the serum concentration of transforming growth factor-β1 (49%), interleukin (IL)-1β (52%), and IL-6 in the HFD-fed rats. Overall, the antioxidant activities significantly increased, and oxidative damage to lipids or DNA was suppressed. Particularly, EX-527 significantly reduced blood urea nitrogen (81%), serum creatinine (71%), microalbumin (43%), and urinary excretion of protein-based biomarkers. Histopathological examination revealed expansion of the extracellular mesangial matrix and suppression of glomerulosclerosis following EX-527 administration. EX-527 downregulated the expression of α-SMA (~64%), TGF-β (25%), vimentin, α-tubulin, fibronectin, and collagen-1 in the kidneys of the HFD-fed rats. Additionally, EX-527 substantially reduced claudin-1 and SIRT1 expression, but increased the expression of SIRT3 in the kidneys of the HFD-fed rats. EX-527 also inhibited the growth factor receptors, including EGFR, PDGFR-β, and STAT3, which are responsible for the anti-fibrotic effect of SIRT-1. Therefore, the administration of EX-527 protects against HFD-induced DN.

Hepatic fibrosis is characterized by persistent deposition of extracellular matrix proteins and occurs in chronic liver diseases. The aim of the present study is to investigate whether estrogen deficiency (ED) potentiates hepatic fibrosis in a thioacetamide (TAA)-treated rat model. Fibrosis was induced via intraperitoneal injection (i.p.) of TAA (150 mg/kg/day) for four weeks in ovariectomized (OVX) female, sham-operated female, or male rats. In TAA-treated OVX rats, the activities of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and &gamma, glutamyl transferase (GGT) were significantly increased compared to those in TAA-treated sham-operated OVX rats or TAA-treated male rats. Furthermore, &alpha, smooth muscle actin (&alpha, SMA) expression was significantly increased compared to that in TAA-treated sham-operated rats. This was accompanied by the appearance of fibrosis biomarkers including vimentin, collagen-I, and hydroxyproline, in the liver of TAA-treated OVX rats. In addition, ED markedly reduced total glutathione (GSH) levels, as well as catalase (CAT) and superoxide dismutase (SOD) activity in TAA-treated OVX rats. In contrast, hepatic malondialdehyde (MDA) levels were elevated in TAA-treated OVX rats. Apoptosis significantly increased in TAA-treated OVX rats, as reflected by elevated p53, Bcl-2, and cleaved caspase 3 levels. Significant increases in interleukin-6 (IL-6) and tumor necrosis factor-&alpha, (TNF-&alpha, ) concentrations were exhibited in TAA-treated OVX rats, and this further aggravated fibrosis through the transforming growth factor-&beta, (TGF-&beta, )/Smad pathway. Our data suggest that ED potentiates TAA-induced oxidative damage in the liver, suggesting that ED may enhance the severity of hepatic fibrosis in menopausal women.

Identifying novel biomarkers to detect nephrotoxicity is clinically important. Here, we attempted to identify new biomarkers for mercury-induced nephrotoxicity and compared their sensitivity to that of traditional biomarkers in animal models. Comparative proteomics analysis was performed in kidney tissues of Sprague–Dawley rats after oral treatment with HgCl2 (0.1, 1, or 5 mg/kg/day) for 21 days. Kidney cortex tissues were analyzed by two-dimensional gel electrophoresis/matrix-assisted laser desorption/ionization, and differentially expressed proteins were identified. The corresponding spots were quantitated by RT-PCR. Selenium-binding protein 1 (SBP1) was found to be the most markedly upregulated protein in the kidney cortex of rats after HgCl2 administration. However, blood urea nitrogen, serum creatinine, and glucose levels increased significantly only in the 1 or 5 mg/kg HgCl2-treated groups. A number of urinary excretion proteins, including kidney injury molecule-1, clusterin, monocyte chemoattractant protein-1, and β-microglobulin, increased dose-dependently. Histopathological examination revealed severe proximal tubular damage in high-dose (5 mg/kg) HgCl2-exposed groups. In addition, urinary excretion of SBP1 significantly increased in a dose-dependent manner. To confirm the critical role of SBP1 as a biomarker for nephrotoxicity, normal kidney proximal tubular cells were treated with HgCl2, CdCl2, or cisplatin for 24 h. SBP1 levels significantly increased in conditioned media exposed to nephrotoxicants, but decreased in cell lysates. Our investigations suggest that SBP1 may play a critical role in the pathological processes underlying chemical-induced nephrotoxicity. Thus, urinary excretion of SBP1 might be a sensitive and specific biomarker to detect early stages of kidney injury.

Today, the manufacturing industry is aiming to improve competitiveness through the convergence with cutting-edge ICT technologies in order to secure a new growth engine. Smart Manufacturing, which is the fourth revolution in the manufacturing industry and is also considered as a new paradigm, is the collection of cutting-edge technologies that support effective and accurate engineering decision-making in real time through the introduction of various ICT technologies and the convergence with the existing manufacturing technologies. This paper surveyed and analyzed various articles related to Smart Manufacturing, identified the past and present levels, and predicted the future. For these purposes, 1) the major key technologies related to Smart Manufacturing were identified through the analysis of the policies and technology roadmaps of Germany, the U.S., and Korea that have government-driven leading movements for Smart Manufacturing, 2) the related articles on the overall Smart Manufacturing concept, the key system structure, or each key technology were investigated, and, finally, 3) the Smart Manufacturing-related trends were identified and the future was predicted by conducting various analyses on the application areas and technology development levels that have been addressed in each article.

The aquatic extract of Dendropanax morbifera (DP) is typically consumed as a beverage in Korea and China and is also used in various traditional medicines. However, the functional role of DP on diabetes-induced renal fibrosis is unclear. Here, the protective effects of DP extract against diabetes-induced renal fibrosis were evaluated. Streptozotocin (STZ, 60 mg/kg) was injected intraperitoneally in rats to induce diabetes. After 5 days, DP extract (25 mg/kg/day) and metformin (50 mg/kg/day) were administered orally to diabetic rats for 28 days. DP administration protected both body and organ weight loss in STZ-treated diabetic rats. Significant improvements in serum blood urea nitrogen (BUN), creatinine, and oxidative stress parameters were observed in diabetic rats by DP administration. DP extract markedly protected diabetic-induced histopathological damages in the kidney and pancreas. A significant reduction was observed in microalbumin, kidney injury molecule-1 (KIM-1), selenium binding protein-1 (SBP1), and pyruvate kinase muscle isozyme M2 (PKM2) levels in the urinary excretion of diabetic rats after the administration of DP extract. The expression of pro-inflammatory cytokines and fibrosis marker levels were significantly reduced in the kidney of diabetic rats. Our results strongly indicate that DP extract exhibits protective activity against diabetes-induced renal fibrosis through ameliorating oxidative stress and inflammation. Therefore, we suggest that DP extract can be used as a preventive agent on the progression of diabetic nephropathy and renal fibrosis.

Clinically relevant sirtuin (SIRT) inhibitors may possess antitumor activities. A previous study indicated that 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) exhibited potent anticancer activity by SIRT1 inhibition. Therefore, the aim of the present study was to investigate whether its derivatives (J11-C1 and J19) exhibited anticancer activity against ovarian cancer SKOV3 cells. Cell viability was determined using an MTT assay. Cell cycle arrest, apoptosis and autophagy were determined using flow cytometry or western blot analysis. J11-Cl and J19 were less cytotoxic to SKOV3 cells compared with 15d-PGJ2. Molecular docking studies supported the interactions of 15d-PGJ2, J11-Cl and J19 with various amino acids in SIRT1 proteins. Similar to 15d-PGJ2, J11-C1 and J19 inhibited SIRT1 enzymatic activity and decreased SIRT1 expression levels in a concentration-dependent manner. J11-C1 induced apoptotic cell death more effectively compared with J19, which was associated with markedly decreased expression of the anti-apoptotic molecule B-cell lymphoma 2 (Bcl-2). Furthermore, the levels of light chain 3-II (LC3-II) and beclin-1 were clearly induced in SKOV3 cells treated with J11-Cl. Thus, 15d-PGJ2 and its derivatives exhibited anticancer activity possibly by inducing apoptotic or autophagic cell death pathways. Collectively, the results of the present study suggest that 15d-PGJ2 and its derivatives exerted antitumor activity by selectively modulating the expression of genes associated with cell cycle arrest, apoptosis and autophagy. Notably, J11-C1 is a novel candidate SIRT1 inhibitor with anticancer activity.

We previously found a novel a new sirtuin (SIRT) inhibitor MHY2256 that exerts anticancer activity through p53 acetylation in MCF-7 human breast cancer cells. Here, we investigated the anticancer activity of MHY2256 against hormone-related cancer, which is an endometrial cancer with poor prognosis. We found that MHY2256 markedly reduced cellular proliferation at low concentrations against Ishikawa endometrial cancer cells. The IC50 values of MHY2256 were much lower than that of salermide. Furthermore, MHY2256 significantly reduced the protein expression and activities of SIRT1, 2, and 3 with similar effects as salermide, a well-known SIRT inhibitor. Particularly, MHY2256 markedly inhibited tumor growth in a tumor xenograft mouse model of Ishikawa cancer cells. During the experimental period, there was no significant change in the body weight of mice treated with MHY2256. Detailed analysis of the sensitization mechanisms of Ishikawa cells revealed that late apoptosis was largely increased by MHY2256. Additionally, MHY2256 increased G1 arrest and reduced cell cyclic-related proteins, suggesting that apoptosis by MHY2256 was achieved by cellular arrest. Particularly, p21 was greatly increased by MHY225656, suggesting that cell cycle arrest by p21 is a major factor in MHY2256 sensitization in Ishikawa cells. We also detected a significant increase in acetylated p53, a target protein of SIRT1, in Ishikawa cells after MHY2256 treatment. In a mouse xenograft model, MHY2256 significantly reduced tumor growth and weight without apparent side effects. These results suggest that MHY2256 exerts its anticancer activity through p53 acetylation in endometrial cancer and can be used for targeting hormone-related cancers.

Plumbagin (5-hydroxy-2-methyl-1,4-naphthaquinone) has displayed antitumor activity in vitro and in animal models; however, the underlying molecular mechanisms have not been fully explored. The aim of this study was to investigate the anticancer effects of plumbagin isolated from Nepenthes alata against MCF-7 breast cancer cells. We examined the cytotoxicity, cell cycle regulation, apoptotic cell death, and generation of intracellular reactive oxygen species (ROS) in MCF-7 cells. Plumbagin exhibited potent cytotoxicity in MCF-7 cells (wild-type p53) compared to that in SK-OV-3 (null-type) human epithelial ovarian cancer cells. Specifically, plumbagin upregulated the expression of p21CIP1/WAF1 in MCF-7 cells, causing cell cycle arrest in the G2/M phase through inhibition of cyclin B1 levels. Plumbagin also significantly increased the ratio of Bax/Bcl-2 and release of cytochrome c, resulting in apoptotic cell death in MCF-7 cells. Furthermore, plumbagin dramatically increased the intracellular ROS level, whereas pretreatment with the ROS scavenger N-acetyl cysteine protected against plumbagin-induced cytotoxicity, suggesting that ROS formation plays a pivotal role in antitumor activity in MCF-7 cells. In mice bearing MCF-7 cell xenografts, plumbagin significantly reduced tumor growth and weight without apparent side effects. We therefore concluded that plumbagin exerts anticancer activity against MCF-7 cells through the generation of intracellular ROS, resulting in the induction of apoptosis via a p53-dependent pathway. This study thus identifies a new anticancer mechanism of plumbagin against p53-dependent breast cancer cells and suggests a novel strategy for overcoming of breast cancer therapy.