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Fludioxonil, an antifungal agent used as a pesticide, leaves a measurable residue in fruits and vegetables. It has been identified to cause endocrine disruption, interrupt normal development, and cause various diseases such as cancers. In this study, fludioxonil was examined for its effects on the development and metastasis of breast cancer cells. On fludioxonil exposure (10−5 M) for 72 h, mutant p53 (mutp53) MDA-MB-231 triple-negative breast cancer (TNBC) cells significantly inhibited cell viability and developed into polyploid giant cancer cells (PGCCs), with an increase in the number of nuclei and expansion in the cell body size. Fludioxonil exposure disrupted the normal cell cycle phase ratio, resulting in a new peak. In addition, PGCCs showed greater motility than the control and were resistant to anticancer drugs, i.e., doxorubicin, cisplatin, and 5-fluorouracil. Cyclin E1, nuclear factor kappa B (NF-κB), and p53 expressions were remarkably increased, and the expression of cell cycle-, epithelial–mesenchymal-transition (EMT)-, and cancer stemness-related proteins were increased in the PGCCs. The daughter cells obtained from PGCCs had the single nucleus but maintained their enlarged cell size and showed greater cell migration ability and resistance to the anticancer agents. Consequently, fludioxonil accumulated Cyclin E1 and promoted the inflammatory cytokine-enriched microenvironment through the up-regulation of TNF and NF-κB which led to the transformation to PGCCs via abnormal cell cycles such as mitotic delay and mitotic slippage in mutp53 TNBC MDA-MB-231 cells. PGCCs and their daughter cells exhibited significant migration ability, chemo-resistance, and cancer stemness. These results strongly suggest that fludioxonil, as an inducer of potential genotoxicity, may induce the formation of PGCCs, leading to the formation of metastatic and stem cell-like breast cancer cells. [ABSTRACT FROM AUTHOR]

Cholangiocarcinoma (CCA) is a malignant biliary tract tumor with a high mortality rate and refractoriness to chemotherapy. Gemcitabine is an anti-cancer chemotherapeutic agent used for CCA, but the efficacy of gemcitabine in CCA treatment is limited, due to the acquisition of chemoresistance. The present study evaluated the chemosensitizing effects of Amurensin G (AMG), a natural sirtuin-1 inhibitor derived from Vitis amurensis, in the SNU-478 CCA cells. Treatment with AMG decreased the SNU-478 cell viability and the colony formation ability. Annexin V/ Propidium iodide staining showed that the AMG increased apoptotic death. In addition, AMG downregulated anti-apoptotic Bcl-2 expression, while upregulating pro-apoptotic cleaved caspase-3 expression. Treatment with AMG decreased the migratory ability of the cells in a wound healing assay and transwell migration assay. It was observed that AMG decreased the gemcitabine-induced increase in CD44highCD24highCD133high cell populations, and the expression of the Sox-2 protein was decreased by AMG treatment. Co-treatment of AMG with gemcitabine significantly enhanced the production of reactive oxygen species, as observed through mitochondrial superoxide staining, which might be associated with the downregulation of the Sirt1/Nrf2 pathway by AMG. These results indicate that AMG enhances the chemotherapeutic ability of gemcitabine by downregulating cancer stem-like properties in CCA cells. Hence, a combination therapy of AMG with gemcitabine may be an attractive therapeutic strategy for cholangiocarcinoma. [ABSTRACT FROM AUTHOR]

Simple Summary: Upregulation of transforming growth factor-beta (TGF-β) signaling in melanoma contributes to the formation of immune-suppressive tumoral environments and is associated with poor response to immunotherapeutics, including anti-programmed death-1 (PD-1) therapy. Our study aimed to investigate the immunotherapeutic potential of a novel next-generation TGF-β2 antisense oligonucleotide (ngTASO) in combination with anti-PD-1 therapy using a melanoma-bearing human immune system mouse model. Our findings confirm that blockade of TGF-β signaling by ngTASO improves the T cell-mediated antitumor potential of anti-PD-1 therapy via facilitating intratumoral infiltration of CD8+ cytotoxic lymphocytes and their activation. These results suggest that ngTASO is a promising combination strategy with anti-PD-1 therapy for the treatment of immune-excluded melanoma. Anti-programmed death-1 (PD-1) immunotherapy is one of the most promising therapeutic interventions for treating various tumors, including lung cancer, bladder cancer, and melanoma. However, only a subset of patients responds to anti-PD-1 therapy due to complicated immune regulation in tumors and the evolution of resistance. In the current study, we investigate the potential of a novel transforming growth factor-beta2 (TGF-β2) antisense oligonucleotide (ngTASO), as a combination therapy with an anti-PD-1 antibody in melanoma. This study was conducted in a melanoma-bearing human immune system mouse model that recapitulates immune-excluded phenotypes. We observed that the TGF-β2 blockade by ngTASO in combination with PD-1 inhibition downregulated the tumor intrinsic β-catenin, facilitated the infiltration of CD8+ cytotoxic lymphocytes (CTLs) in the tumor, and finally, enhanced the antitumor immune potentials and tumor growth delays. Blockade of TGF-β2 combined with PD-1 inhibition also resulted in downregulating the ratio of regulatory T cells to CTLs in the peripheral blood and tumor, resulting in increased granzyme B expression. In addition, co-treatment of ngTASO and anti-PD-1 augmented the PD-L1 expression in tumors, which is associated with an improved response to anti-PD-1 immunotherapy. These results indicate that the combination of ngTASO and anti-PD-1 exerts an enhanced T cell-mediated antitumor immune potential. Hence, co-inhibition of TGF-β2 and PD-1 is a potentially promising immunotherapeutic strategy for immune-excluded melanoma. [ABSTRACT FROM AUTHOR]

The article offers information on Cancer which is a leading cause of death worldwide, and how current treatment options like chemotherapy have significant side effects and can develop resistance in cancer cells. There is a growing need to explore alternatives, and plant-derived compounds have shown promise in treating cancer. A study highlighted the effectiveness of Punicic acid against colorectal and hypopharyngeal cancer cells.

Cyprodinil (CYP) is a pyrimidine amine fungicide that has been extensively used in agricultural areas. 3,3'-Diindolylmethane (DIM) is a derivative of the dietary phytoestrogen, indole-3-carbinol (I3C), which is derived from cruciferous vegetables and considered to be a cancer-preventive phytonutrient agent. In this study, the effects of CYP and DIM were examined on the cell viability, invasion, and metastasis of human endometrial cancer cells, Ishikawa, via epithelial mesenchymal transition (EMT). CYP increased the level of cell viability of Ishikawa cells compared to DMSO as a control, as did E2. Ishikawa cells lost cell-to-cell contact and obtained a spindle-shaped or fibroblast-like morphology in response to the application of E2 or CYP by the cell morphology assay. In the cell migration and invasion assay, CYP enhanced the ability of migration and invasion of Ishikawa cells, as did E2. E2 and CYP increased the expressions of N-cadherin and Snail proteins, while decreasing the expression of E-cadherin protein as EMT-related markers. In addition, E2 and CYP increased the protein expressions of cathepsin D and MMP-9, metastasis-related markers. Conversely, CYP-induced EMT, cell migration, and invasion were reversed by fulvestrant (ICI 182,780) as an estrogen receptor (ER) antagonist, indicating that CYP exerts estrogenic activity by mediating these processes via an ER-dependent pathway. Similar to ICI 182,780, DIM significantly suppressed E2 and CYP-induced proliferation, EMT, migration, and invasion of Ishikawa cancer cells. Overall, the present study revealed that DIM has an antiestrogenic chemopreventive effect to withdraw the cancer-enhancing effect of E2 and CYP, while CYP has the capacity to enhance the metastatic potential of estrogen-responsive endometrial cancer. [ABSTRACT FROM AUTHOR]

The toxicity of cigarette smoke (CS) is largely attributed to its ability to generate reactive oxygen species (ROS). Reportedly, CS generates superoxide in cell culture systems by stimulating the cells to produce superoxide and through direct chemical reactions with components of the culture media. In this study, we investigated CS-induced superoxide formation in biocompatible aqueous media and its characteristics. Cigarette smoke extract (CSE) and total particulate matter (TPM) were prepared from the mainstream smoke of 3R4F reference cigarettes. CSE and TPM generated superoxide in Hank's balanced salt solution (HBSS), Dulbecco's modified Eagle media (DMEM), and blood plasma, but not in distilled water and phosphate-buffered saline. Each constituent of HBSS in solution was tested, and bicarbonate was found to be responsible for the superoxide generation. More than half of the superoxide formation was abolished by pretreating CSE or TPM with peroxidase, indicating that the substrates of peroxidase, presumably peroxides and peroxy acids, mainly contributed to the superoxide production. In conclusion, the presence of bicarbonate in experimental conditions should be considered carefully in studies of the biological activity of CS. Furthermore, the local amount of bicarbonate in exposed tissues may be a determinant of tissue sensitivity to oxidative damage by CS. [ABSTRACT FROM AUTHOR]

Iridoids are glycosides found in plants, having inherent roles in defending them against infection by viruses and microorganisms, and in the rapid repair of damaged areas. The emerging roles of iridoid glycosides on pharmacological properties have aroused the curiosity of many researchers, and studies undertaken indicate that iridoid glycosides exert inhibitory effects in numerous cancers. This review focuses on the roles and the potential mechanism of iridoid glycosides at each stage of cancer development such as proliferation, epithelial mesenchymal transition (EMT), migration, invasion and angiogenesis. Overall, the reviewed literature indicates that iridoid glycosides inhibit cancer growth by inducing cell cycle arrest or by regulating apoptosis-related signaling pathways. In addition, iridoid glycosides suppress the expression and activity of matrix metalloproteinases (MMPs), resulting in reduced cancer cell migration and invasiveness. The antiangiogenic mechanism of iridoid glycosides was found to be closely related to the transcriptional regulation of pro-angiogenic factors, i.e., vascular endothelial growth factors (VEGFs) and cluster of differentiation 31 (CD31). Taken together, these results indicate the therapeutic potential of iridoid glycosides to alleviate or prevent rapid cancer progression and metastasis. [ABSTRACT FROM AUTHOR]

Simple Summary: Tamoxifen has been clinically applied as a central chemotherapeutic agent for treatment of estrogen receptor (ER)-positive breast cancer. However, many ER-positive breast cancer patients with the high ER level demonstrate intrinsic resistance against the tamoxifen therapy. The aim of our study was to find an effective approach to enhance tamoxifen sensitivity. We found that tumor necrosis factor α (TNFα) has a potential to overcome tamoxifen resistance through disruption of nuclear receptor corepressor 1 (NCOR1)-p53-ERα complexes in ER-positive MCF7 xenograft mice. NCOR1 knock-down with TNFα treatment induced ERα destabilization and increased the occupancy of p53 at the p21 promoter. Finally, we confirmed the combinational application with tamoxifen, TNFα and short-hairpin NCOR1 showed the enhanced suppressive effect of tumor growth in MCF xenograft mice compared to single tamoxifen treatment. These results provide a possibility for application of NCOR1 as a putative therapeutic target to overcome tamoxifen resistance in ERα-positive breast cancer. Tamoxifen is widely used as a medication for estrogen receptor α (ERα)-positive breast cancer, despite the ~50% incidence of tamoxifen resistance. To overcome such resistance, combining tamoxifen with other agents is considered an effective approach. Here, through in vitro studies with ER-positive MCF7 cells and ER-negative MDA-MB-231 cells, validated by the use of xenograft mice, we investigated the potential of tumor necrosis factor α (TNFα) to enhance tamoxifen sensitivity and identified NCOR1 as a key downstream regulator. TNFα specifically degraded nuclear receptor corepressor 1 (NCOR1) in MCF7 cells. Moreover, knockdown of NCOR1, similar to TNFα treatment, suppressed cancer cell growth and promoted apoptosis only in MCF7 cells and MCF7 xenograft mice through the stabilization of p53, a tumor suppressor protein. Interestingly, NCOR1 knockdown with TNFα treatment increased the occupancy of p53 at the p21 promoter, while decreasing that of ERα. Notably, NCOR1 formed a complex with p53 and ERα, which was disrupted by TNFα. Finally, combinatorial treatment with tamoxifen, TNFα and short–hairpin (sh)-NCOR1 resulted in enhanced suppression of tumor growth in MCF7 xenograft mice compared to single tamoxifen treatment. In conclusion, TNFα promoted tamoxifen sensitivity through the dissociation of the ERα-p53-NCOR1 complex, pointing at NCOR1 as a putative therapeutic target for overcoming tamoxifen resistance in ERα-positive breast cancer. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is a chronic inflammatory skin disease caused by immune hypersensitivity reaction. The cause of AD is unclear, but its symptoms have a negative effect on quality of life; various treatment methods to alleviate these symptoms are underway. In the present study, we aimed to evaluate in vitro antioxidant and anti-inflammatory effects of Rubus coreanus water extract (RCW) on AD. Total phenolic compounds and flavonoid content of RCW were 4242.40 ± 54.84 mg GAE/g RCE and 1010.99 ± 14.75 mg CE/g RCW, respectively. RCW reduced intracellular reactive oxygen species level and increased the action of antioxidant enzymes, such as catalase, superoxide dismutase, and glutathione peroxidase in tumor necrosis factor-α (TNF-α)/interferon-γ (IFN-γ)-stimulated HaCaT cells. Moreover, mRNA expression of the pro-inflammatory cytokines, including TNF-α, interleukin-1β, and interleukin-6, was downregulated by RCW in the TNF-α/IFN-γ-stimulated cells. The levels of inflammatory chemokines (thymus- and activation-regulated chemokine; eotaxin; macrophage-derived chemokine; regulated on activation, normal T-cell expressed and secreted; and granulocyte-macrophage colony-stimulating factor) and intercellular adhesion molecule-1 were decreased in the TNF-α/IFN-γ-stimulated HaCaT cells after RCW treatment. Additionally, the mRNA expression levels of filaggrin and involucrin, proteins that form the skin, were increased by RCW. Furthermore, RCW inhibited the nuclear factor kappa-light-chain-enhancer of the activated B cells pathway in the TNF-α/IFN-γ-stimulated HaCaT cells. Collectively, the present investigation indicates that RCW is a potent substance that inhibits AD. [ABSTRACT FROM AUTHOR]

Metabolic syndrome is a worldwide health problem, and obesity is closely related to type 2 diabetes, cardiovascular disease, hypertension, and cancer. According to WHO in 2018, the prevalence of obesity in 2016 tripled compared to 1975. D. morbifera reduces bad cholesterol and triglycerides levels in the blood and provides various antioxidant nutrients and germicidal sub-stances, as well as selenium, which helps to remove active oxygen. Moreover, D. morbifera is useful for treating cardiovascular diseases, hypertension, hyperlipidemia, and diabetes. Therefore, we study in vivo efficacy of D. morbifera to investigate the prevention effect of obesity and cholesterol. The weight and body fat were effectively reduced by D. morbifera water (DLW) extract administration to high-fat diet-fed C57BL/6 mice compared to those of control mice. The group treated with DLW 500 mg∙kg−1∙d−1 had significantly lower body weights compared to the control group. In addition, High-density lipoprotein (HDL) cholesterol increased in the group treated with DLW 500 mg∙kg−1∙d−1. The effect of DLW on the serum lipid profile could be helpful to prevent obesity. DLW suppresses lipid formation in adipocytes and decreases body fat. In conclusion, DLW can be applied to develop anti-obesity functional foods and other products to reduce body fat. [ABSTRACT FROM AUTHOR]

Simple Summary: Pancreatic cancer is a highly lethal tumor with poor prognosis. In general, pancreatic cancer is not detected in its early stages since there are no signs or symptoms. A surgical resection gives the best chance for a cure, but these lesions are detected at the terminal or metastatic stages in most patients and surgery is therefore no longer feasible. New therapeutic options are thus necessary for the pancreatic cancer treatment. Alterations to metabolic pathways have recently attracted great interest as possible cancer treatments and many studies have reported that targeting glutaminase is an ideal approach in many cancers. Here, we provide reliable evidence that pancreatic cancer requires TFEB for maintaining glutaminase-mediated glutamine metabolism, and that this is an attractive new target for pancreatic cancer therapy. Transcription factor EB (TFEB) is a master regulator of lysosomal function and autophagy. In addition, TFEB has various physiological roles such as nutrient sensing, cellular stress responses, and immune responses. However, the precise roles of TFEB in pancreatic cancer growth remain unclear. Here, we show that pancreatic cancer cells exhibit a significantly elevated TFEB expression compared with normal tissue samples and that the genetic inhibition of TFEB results in a significant inhibition in both glutamine and mitochondrial metabolism, which in turn suppresses the PDAC growth both in vitro and in vivo. High basal levels of autophagy are critical for pancreatic cancer growth. The TFEB knockdown had no significant effect on the autophagic flux under normal conditions but interestingly caused a profound reduction in glutaminase (GLS) transcription, leading to an inhibition of glutamine metabolism. We observed that the direct binding of TFEB to the GLS and TFEB gene promotors regulates the transcription of GLS. We also found that the glutamate supplementation leads to a significant recovery of the PDAC growth that had been reduced by a TFEB knockdown. Taken together, our current data demonstrate that TFEB supports the PDAC cell growth by regulating glutaminase-mediated glutamine metabolism. [ABSTRACT FROM AUTHOR]

Transforming growth factor-β1 (TGF-β1) is highly expressed in the tumor microenvironment and known to play a multifunctional role in cancer progression. In addition, TGF-β1 promotes metastasis by inducing epithelial–mesenchymal transition (EMT) in a variety of tumors. Thus, inhibition of TGF-β1 is considered an important strategy in the treatment of cancer. In most tumors, TGF-β1 signal transduction exhibits modified or non-functional characteristics, and TGF-β1 inhibitors have various inhibitory effects on cancer cells. Currently, many studies are being conducted to develop TGF-β1 inhibitors from non-toxic natural compounds. We aimed to develop a new TGF-β1 inhibitor to suppress EMT in cancer cells. As a result, improved chalcone-like chain CTI-82 was identified, and its effect was confirmed in vitro. We showed that CTI-82 blocked TGF-β1-induced EMT by inhibiting the cell migration and metastasis of A549 lung cancer cells. In addition, CTI-82 reduced the TGF-β1-induced phosphorylation of SMAD2/3 and inhibited the expression of various EMT markers. Our results suggest that CTI-82 inhibits tumor growth, migration, and metastasis. [ABSTRACT FROM AUTHOR]

Tumor necrosis factor-α (TNF-α) plays a significant role in inflammation and cancer-related apoptosis. We identified a TNF-α-mediated epigenetic mechanism of apoptotic cell death regulation in estrogen receptor-α (ERα)-positive human breast cancer cells. To assess the apoptotic effect of TNF-α, annexin V/ propidium iodide (PI) double staining, cell viability assays, and Western blotting were performed. To elucidate this mechanism, histone deacetylase (HDAC) activity assay and immunoprecipitation (IP) were conducted; the mechanism was subsequently confirmed through chromatin IP (ChIP) assays. Finally, we assessed HDAC3–ERα-mediated apoptotic cell death after TNF-α treatment in ERα-positive human breast cancer (MCF-7) cells via the transcriptional activation of p53 target genes using luciferase assay and quantitative reverse transcription PCR. The TNF-α-induced selective apoptosis in MCF-7 cells was negatively regulated by the HDAC3–ERα complex in a caspase-7-dependent manner. HDAC3 possessed a p53-binding element, thus suppressing the transcriptional activity of its target genes. In contrast, MCF-7 cell treatment with TNF-α led to dissociation of the HDAC3–ERα complex and substitution of the occupancy on the promoter by the p53–p300 complex, thus accelerating p53 target gene expression. In this process, p53 stabilization was accompanied by its acetylation. This study showed that p53-mediated apoptosis in ERα-positive human breast cancer cells was negatively regulated by HDAC3–ERα in a caspase-7-dependent manner. Therefore, these proteins have potential application in therapeutic strategies. [ABSTRACT FROM AUTHOR]

Our aim was to investigate whether hot water extract (CLW) of Curcuma longa L. could prevent non-alcoholic fatty liver disease (NAFLD). HepG2 cells were treated with free fatty acid (FFA) mixture (oleic acid: palmitic acid, 2:1) for 24 h to stimulate in vitro fatty liver. In addition, C57BL/6 mice were fed 60 kcal% high-fat (HF) diet for eight weeks to induce fatty liver in vivo. Intracellular reactive oxygen species (ROS) and malondialdehyde (MDA) productions were increased by FFA and HF-diet, but supplementation with CLW significantly decreased these levels. CLW treatment ameliorated antioxidant activities that were suppressed by exposure to the FFA and HF-diet. Cluster of differentiation 36 (CD36) and fatty acid transport proteins (FATP2 and FATP5) were increased in HF-diet groups, while CLW suppressed their expression levels. Moreover, sterol regulatory element-binding protein-1c (SREBP-1c), acetyl-coenzyme A carboxylase (ACC), and fatty acid synthase (FAS) expression levels were down-regulated in the CLW groups compared to HF-diet groups. On the other hand, 5′ adenosine monophosphate-activated protein kinase (AMPK), Peroxisome proliferator-activated receptor alpha (PPAR-α), and carnitine palmitoyltransferase 1 (CPT-1) expressions were up-regulated in the CLW groups. HF-diet fed mice showed high hepatic triglycerides (TG) content compared to the normal diet mice. However, the administration of CLW restored the hepatic TG level, indicating an inhibitory effect against lipid accumulation by CLW. These results suggest that CLW could be a potentially useful agent for the prevention of NAFLD through modulating fatty acid uptake. [ABSTRACT FROM AUTHOR]

Fludioxonil is fungicide used in agriculture, which is present in fruits and vegetables. In this study, the effects of fludioxonil on human immune cell viability, apoptosis, cell cycle arrest, and mitochondrial membrane potential were examined in human immune cells, such as Jurkat T cells and Ramos B cells. To examine the cell viability, Jurkat T cells and Ramos B cells were treated with fludioxonil (10−9–10−5 M) for 24 h and 48 h. Water soluble tetrazolium salt assay showed that fludioxonil decreased Jurkat T cell and Ramos B cell viability. Jurkat T cell viability decreased at 24 and 48 h, but Ramos B cell viability decreased only at 48 h. JC-1 dye revealed decreased mitochondrial membrane potential in fludioxonil-treated Jurkat T cells and Ramos B cells. To evaluate apoptosis, annexin-V conjugated FITC, AF488, and propidium iodide (PI) were used and to evaluate cell cycle arrest PI was used. Apoptosis and cell cycle arrest were induced by fludioxonil (10−7–10−5 M) in the Jurkat T cells at 24 and 48 h and Ramos B cells at 48 h. Moreover, the protein levels of pro-apoptotic proteins, such as p53, BAX, and cleaved caspase 3, were increased and anti-apoptotic protein Bcl-2 was decreased by fludioxonil. Expression of the Fas receptor related to the extrinsic apoptosis pathway was increased by fludioxonil. Additionally, cyclin D1 and cyclin E1 were decreased by fludioxonil. In the present study, fludioxonil induced immunotoxicity in human T cells and B cells through apoptosis and cell cycle arrest. Therefore, the present study suggests that fludioxonil induces the cellular toxicity in immune cells. [ABSTRACT FROM AUTHOR]

Breast cancer is one of the leading causes of morbidity and mortality among women. Epidermal growth factor receptor (EGFR) and proto-oncogene tyrosine-protein kinase Src (c-Src) are critical components of the signaling pathways that are associated with breast cancer. However, the regulatory mechanism of histone deacetylase 3 (HDAC3) in these pathways remains unclear. Using the Net Phos 3.1 program for the analysis of kinase consensus motifs, we found two c-Src-mediated putative phosphorylation sites, tyrosine (Tyr, Y)-328 and Y331 on HDAC3, and generated a phospho-specific HDAC3 antibody against these sites. c-Src-mediated phosphorylation was observed in the cells expressing wild-type HDAC3 (HDAC3WT), but not in cells overexpressing phosphorylation-defective HDAC3 (HDAC3Y328/331A). Phosphorylated HDAC3 showed relatively higher deacetylase activity, and PP2, which is a c-Src inhibitor, blocked HDAC3 phosphorylation and reduced its enzymatic activity. EGF treatment resulted in HDAC3 phosphorylation in both MDA-MB-231 and EGFR-overexpressing MCF7 (MCF7-EGFR) cells, but not in MCF7 cells. Total internal reflection fluorescence analysis showed that HDAC3 was recruited to the plasma membrane following EGF stimulation. HDAC3 inhibition with either c-Src knockdown or PP2 treatment significantly ameliorated the invasiveness of breast cancer cells. Altogether, our findings reveal an EGF signaling cascade involving EGFR, c-Src, and HDAC3 in breast cancer cells. [ABSTRACT FROM AUTHOR]

Thyroid cancers developed from the tissues of the thyroid gland are classified into papillary (PTC), follicular (FTC), medullary (MTC), and anaplastic thyroid cancer (ATC). Although thyroid cancers have been generally known as mild forms of cancer, undifferentiated MTC and ATC have a more unfavorable prognosis than differentiated PTC and FTC because they are more aggressive and early metastatic. A variety of therapies such as surgery, radiotherapy, and chemotherapy have been currently used to treat thyroid cancer, but they still have limitations including drug resistance or unfavorable side effects. Phytochemicals are plant-derived chemicals having various physiological activities that are expected to be effective in cancer treatment. In this review, anticancer efficacy of phytochemicals, such as resveratrol, genistein, curcumin, and other substances in each type of thyroid cancer was introduced with their chemopreventive mechanisms. English articles related with thyroid cancer and anti-thyroid cancer of phytochemicals were searched from PubMed and Google Scholar. This article mainly focused on in vitro or animal studies on phytochemicals with anti-thyroid cancer activity. These various phytochemicals have been shown to induce apoptosis in all types of thyroid cancer cells, inhibit cell proliferation and invasion, and to be helpful in enhancing the effect of radioiodine therapy that is a typical therapy to thyroid cancer. These results suggest that thyroid cancer can be more effectively treated by the combinations of phytochemicals and the existing therapies or substances. [ABSTRACT FROM AUTHOR]

Rosmarinic acid (RA), a main phenolic compound contained in rosemary which is used as tea, oil, medicine and so on, has been known to present anti-inflammatory, anti-oxidant and anti-cancer effects. Histone deacetylases (HDACs) are enzymes that play important roles in gene expression by removing the acetyl group from histone. The aberrant expression of HDAC in human tumors is related with the onset of human cancer. Especially, HDAC2, which belongs to HDAC class I composed of HDAC 1, 2, 3 and 8, has been reported to be highly expressed in prostate cancer (PCa) where it downregulates the expression of p53, resulting in an inhibition of apoptosis. The purpose of this study is to investigate the effect of RA in comparison with suberoylanilide hydroxamic acid (SAHA), an HDAC inhibitor used as an anti-cancer agent, on survival and apoptosis of PCa cell lines, PC-3 and DU145, and the expression of HDAC. RA decreased the cell proliferation in cell viability assay, and inhibited the colony formation and tumor spheroid formation. Additionally, RA induced early- and late-stage apoptosis of PC-3 and DU145 cells in Annexin V assay and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, respectively. In western blot analysis, RA inhibited the expression of HDAC2, as SAHA did. Proliferating cell nuclear antigen (PCNA), cyclin D1 and cyclin E1 were downregulated by RA, whereas p21 was upregulated. In addition, RA modulated the protein expression of intrinsic mitochondrial apoptotic pathway-related genes, such as Bax, Bcl-2, caspase-3 and poly (ADP-ribose) polymerase 1 (PARP-1) (cleaved) via the upregulation of p53 derived from HDAC2 downregulation, leading to the increased apoptosis of PC-3 and DU145 cells. Taken together, treatment of RA to PCa cell lines inhibits the cell survival and induces cell apoptosis, and it can be used as a novel therapeutic agent toward PCa. [ABSTRACT FROM AUTHOR]

Cortisol is a steroid hormone essential to the maintenance of homeostasis that is released in response to stress and low blood glucose concentration. Cortisol is converted from cortisone by 11βhydroxysteroid dehydrogenase type 1 (HSD11B1). It has been reported that too much cortisol or overexpression of HSD11B1 induces obesity and the insulin resistance that accompanies metabolic syndrome in rodent adipose tissue. In our previous study, HSD11B1 -transgenic (TG) fibroblasts were established, and a porcine model was generated by SCNT using those fibroblasts. Hepatocytes overexpressing HSD11B1 were obtained from livers of this porcine model and cultured in vitro. However, the primary hepatocytes were found to have a short life span or low proliferation rate. To overcome these problems, the SV40 large T antigen was transduced into primary HSD11B1 -TG hepatocytes, and those cells were immortalized. Immortalized HSD11B1 -TG hepatocytes showed restored morphology, more rapid proliferation rate, and more expression of HSD11B1 than primary hepatocytes. As well, these cells kept the hepatic characteristics such as gluconeogenic response to cortisone and increased expression of hepatic makers. The immortalized HSD11B1 -TG hepatocytes may be useful for studying traits and potential therapeutic drugs for treatment of metabolic disorders induced by overexpression of HSD11B1., Competing Interests: The authors declare no conflict of interest.

Cigarette smoke (CS) causes about 480,000 deaths each year worldwide, and it is well-known to have harmful effects on the human body, leading to heart disease, stroke, lung cancer, and cardiovascular problems. In this study, the effects of formaldehyde (FA) and benzene (Bz), the main components of CS, on cell proliferation and epithelial mesenchymal transition (EMT) of JEG-3 human choriocarcinoma cells were examined to confirm the relationship between CS components and placenta carcinoma. Upon MTT assay, FA (10 -8 M to 10 -5 M) and Bz (10 -11 M to 10 -8 M) increased JEG-3 cell proliferation. Western blot assay revealed that the protein expression of cyclin D1 and E1 increased, while the levels of p21 and p27 were reduced following treatment. In Scratch assay, FA (10 -8 M and 10 -5 M) and Bz (10 -11 M and 10 -8 M) increased migration of JEG-3 cells at 24 h and 48 h compared with that at 0 h. In addition, the expression of the epithelial marker, E-cadherin, was significantly decreased, while the expression of the mesenchymal marker, N-cadherin, was significantly increased by FA (10 -8 M and 10 -5 M) and Bz (10 -11 M and 10 -8 M). snail and slug transcriptional factors were associated with EMT, which were also up-regulated by FA and Bz, indicating that FA and Bz lead to an increase in the EMT process in JEG-3 choriocarcinoma cells. We further evaluated reactive oxygen species (ROS) and activation of antioxidant effect using dichlorofluorescin diacetate (DCFH-DA) and Western blot assay. FA and Bz increased the ROS production and an antioxidant related marker, Nrf2, in JEG-3 cells. However, eIF2α levels were reduced by FA and Bz via activation of the antioxidant reaction. Taken together, these results indicated that FA and Bz induce the growth and migration of human choriocarcinoma cells via regulation of the cell cycle and EMT and activation of ROS and antioxidant related markers., Competing Interests: The authors declare no conflict of interest.

Octylphenol (OP) and bisphenol A (BPA) are known as endocrine-disrupting chemicals (EDCs). During pregnancy, the expression of steroid hormone receptors is controlled by maternal and fetal nutrition. To evaluate the impact of EDCs during pregnancy, ethinyl estradiol (EE, 0.2 mg/kg/day), OP (50 mg/kg/day), and BPA (50 mg/kg/day) were administered to pregnant mice. The mRNA levels of TRPV6 (transient receptor potential cation channels in subfamily V, member 6) decreased significantly by EE and OP. The PMCA1 (ATPase, Ca ++ transporting, plasma membrane 1) mRNA and protein levels decreased significantly by EE, OP, and BPA. CTR1 (solute carrier family 31, member 1) and ATP7A (ATPase, Cu ++ transporting, alpha polypeptide) expression decreased significantly by EE, OP, and BPA. The mRNA levels of IREG1 (iron-regulated transporter, member 1) decreased significantly by EE. Hephaestin (HEPH) mRNA levels decreased significantly by EE, OP, and BPA, and protein levels decreased significantly by BPA. As a result of immunohistochemistry analysis, all cation transporter proteins were found in labyrinth of placenta. To confirm the cytosolic level of cations, levels of cation level in fetal serum were measured. EE, OP, and BPA significantly reduced serum calcium and copper levels, and iron levels were reduced by BPA. Taken together, some EDCs, such as OP and BPA, could modulate the calcium, copper, and iron ion-transporting channels during pregnancy. The fetus relies on the mother for ionic transportation, and, therefore, pregnant women should avoid exposure to cation-channel-disrupting chemicals., Competing Interests: The authors declare no conflict of interest.

2,4,6-Tribromophenol (TBP) is a brominated flame retardant (BFR). Based on its affinity for transthyretin, TBP could compete with endogenous thyroid hormone. In this study, the effects of TBP on the thyroid hormone system were assessed in mice. Briefly, animals were exposed to 40 and 250 mg/kg TBP. Thyroid hormones were also administered with or without TBP. When mice were treated with TBP, deiodinase 1 (Dio1) and thyroid hormone receptor β isoform 2 (Thrβ2) decreased in the pituitary gland. The levels of deiodinase 2 (Dio2) and growth hormone (Gh) mRNA increased in response to 250 mg/kg of TBP, and the relative mRNA level of thyroid stimulating hormone β (Tshβ) increased in the pituitary gland. Dio1 and Thrβ1 expression in the liver were not altered, while Dio1 decreased in response to co-treatment with thyroid hormones. The thyroid gland activity decreased in response to TBP, as did the levels of free triiodothyronine and free thyroxine in serum. Taken together, these findings indicate that TBP can disrupt thyroid hormone homeostasis and the presence of TBP influenced thyroid actions as regulators of gene expression. These data suggest that TBP interferes with thyroid hormone systems.

Epithelial-mesenchymal transition (EMT) plays a key role in tumor progression. The cells undergoing EMT upregulate the expression of cell motility-related proteins and show enhanced migration and invasion. The hallmarks of EMT in cancer cells include changed cell morphology and increased metastatic capabilities in cell migration and invasion. Therefore, prevention of EMT is an important tool for the inhibition of tumor metastasis. A novel preventive therapy is needed, such as treatment of natural dietary substances that are nontoxic to normal human cells, but effective in inhibiting cancer cells. Phytoestrogens, such as genistein, resveratrol, kaempferol and 3,3'-diindolylmethane (DIM), can be raised as possible candidates. They are plant-derived dietary estrogens, which are found in tea, vegetables and fruits, and are known to have various biological efficacies, including chemopreventive activity against cancers. Specifically, these phytoestrogens may induce not only anti-proliferation, apoptosis and cell cycle arrest, but also anti-metastasis by inhibiting the EMT process in various cancer cells. There have been several signaling pathways found to be associated with the induction of the EMT process in cancer cells. Phytoestrogens were demonstrated to have chemopreventive effects on cancer metastasis by inhibiting EMT-associated pathways, such as Notch-1 and TGF-beta signaling. As a result, phytoestrogens can inhibit or reverse the EMT process by upregulating the expression of epithelial phenotypes, including E-cadherin, and downregulating the expression of mesenchymal phenotypes, including N-cadherin, Snail, Slug, and vimentin. In this review, we focused on the important roles of phytoestrogens in inhibiting EMT in many types of cancer and suggested phytoestrogens as prominent alternative compounds to chemotherapy.

The risk of prostate cancer has been increasing in men by degrees. To develop a new prostate cancer therapy, we used a stem cell-derived gene directed prodrug enzyme system using human neural stem cells (hNSCs) that have a tumor-tropic effect. These hNSCs were transduced with the therapeutic genes for bacterial cytosine deaminase (CD), alone or in combination with the one encoding human interferon-beta (IFN-β) or rabbit carboxyl esterase (CE) to generate HB1.F3.CD, HB1.F3.CD.IFN-β, and HB1.F3.CE cells, respectively. CD enzyme can convert the prodrug 5-fluorocytosine (5-FC) into the activated form 5-fluorouracil (5-FU). In addition, CE enzyme can convert the prodrug CPT-11 into a toxic agent, SN-38. In our study, the human stem cells were found to migrate toward LNCaP human prostate cancer cells rather than primary cells. This phenomenon may be due to interactions between chemoattractant ligands and receptors, such as VEGF/VEGFR2 and SCF/c-Kit, expressed as cancer and stem cells, respectively. The HB1.F3.CE, HB.F3.CD, or HB1.F3.CD.IFN-β cells significantly reduced the LNCaP cell viability in the presence of the prodrugs 5-FC or CPT-11. These results indicate that stem cells expressing therapeutic genes can be used to develop a new strategy for selectively treating human prostate cancer.

Endocrine disruptors (EDs) are compounds used in various industrial products, drugs, and cosmetics. They can be found in the environment and disturb the endocrine and reproductive systems, resulting in adverse effects to humans and wildlife such as birth defects and developmental disorders. Since several EDs have a structure similar to that of endogenous steroid hormones such as estrogens, they intend to have an affinity for steroid hormone receptors and alter hormone-mediated metabolism by binding to these receptors. EDs are therefore a global concern and assays should be developed to efficiently determine whether these compounds are detrimental to biological systems. Diverse experimental methods may help determine the endocrine disrupting potential of EDs and evaluate the adverse effects of a single and/or combination of these reagents. Currently, biomarkers have been employed to objectively measure EDs potency and understand the underlying mechanisms. Further studies are required to develop ideal screening methods and biomarkers to determine EDs potency at environmentally relevant concentrations. In this review, we describe the biomarkers for estrogenicity of EDs identified both in vitro and in vivo, and introduce a biomarker, cabindin-D(9k) (CaBP-9k), that may be used to assess estrogenic activity of EDs.