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The cause and pathogenesis of sudden sensorineural hearing loss (SSNHL) remain unknown. IL-1β is one of the most powerful inflammatory cytokines. The aim of this study was to evaluate the relationships between interleukin-1 β (IL-1β) gene polymorphisms (−511 C/T and +3953 C/T) in patients with SSNHL. One hundred two patients affected by SSNHL and 595 controls were genotyped for IL-1β gene polymorphisms. The polymorphisms were analyzed by polymerase chain reaction amplification and DNA fragment separation via electrophoresis. Compared to controls, the IL-1β (+3953) T allele increased the relative risk of SSNHL in subjects with IL-1β (−511) TT genotype ( p = 0.022, OR = 9.111, 95% CI = 1.441-57.618). In this study, polymorphisms in the IL-1β −511 and IL-1β +3953 loci were assessed for evidence of association with SSNHL. From this assessment, a significant difference in carriage of both the IL-1β −511 T allele and the IL-1β +3953 T allele was observed between SSNHL and controls. This suggests that the IL-1β −511 and +3953 loci may play an important role in the etiopathogenesis of SSNHL. [ABSTRACT FROM AUTHOR]

The aerial parts of Artemisia capillaris (Compositae) have been used in traditional Korean medicine as a cholagogic, antipyretic, anti-inflammatory, and diuretic purposes. In our previous study, ethanolic extracts of the plant demonstrated a marked anti-inflammatory effect in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells (J. Korean Soc. Appl. Biol. Chem., 2010, 53, 275-282). In the present study, capillarisin (CPS), a flavone, main constituent of A. capillaris, was examined for its anti-inflammatory activity in the cells. We found that CPS highly suppressed LPS-induced nitric oxide (NO) without exerting cytotoxic effects on RAW 264.7 cells. CPS inhibited the expression of LPS-induced inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) protein and their mRNA in a dose-dependent manner. Also, tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1β, and prostaglandin E2 (PGE2) secretion were decreased by CPS in LPS-stimulated macrophages. As a result, CPS inhibited proinflammatory cytokines, iNOS, and COX-2, which is attributed to the suppression of LPS-induced ERK, JNK, and nuclear factor-κB (NF-κB) activation. Therefore, we demonstrate here that CPS potentially inhibits the biomarkers related to inflammation through the abrogation of ERK, JNK, and NF-κB p65 activation, and it may be a potential therapeutic candidate for the treatment of inflammatory diseases. [ABSTRACT FROM AUTHOR]

Reynoutria elliptica has been used in traditional Korean medicine to promote blood circulation, relieve pain, increase dieresis, and alleviate respiratory problems, through as yet undefined mechanisms. We set out to determine whether the anti-inflammatory effects of this plant are linked with its ability to suppress mitogen-activated protein kinases (MAPKs) and nuclear factor-κB (NF-κB) activation in lipopolysaccharide (LPS)-activated RAW 264.7 cells. We found for the first time that the hexane fraction of Reynoutria elliptica (HRE) significantly inhibited LPS-stimulated NO and PGE2 synthesis. This is due to the diminishing of the mRNA and protein expression of iNOS and COX-2, respectively. HRE also suppressed LPS-stimulated TNF-α secretion in a dose-dependent manner, which might be due to the suppression of LPS-induced MAPKs and NF-κB activation. Moreover, our HPLC data demonstrated that the major components of the HRE were bioactive compounds such as emodin-6-Glc, emodin, and physcion. Overall, our results indicate that Reynoutria elliptica could be provided as a potential candidate for anti-inflammation treatment. [ABSTRACT FROM AUTHOR]

The Ras effector NORE1 is frequently silenced in primary adenocarcinomas, although the significance of this silencing for tumorigenesis is unclear. Here we show that NORE1 induces polyubiquitination and proteasomal degradation of oncoprotein HIPK1 by facilitating its interaction with the Mdm2 E3 ubiquitin ligase. Endogenous HIPK1 is stabilized in Nore1-deficient mouse embryonic fibroblasts, and depletion of HIPK1 in NORE1-silenced lung adenocarcinoma cells inhibits anchorage-independent cell growth and tumour formation in nude mice. These findings indicate that the control of HIPK1 stability by Mdm2-NORE1 has a major effect on cell behaviour, and epigenetic inactivation of NORE1 enables adenocarcinoma formation in vivo through HIPK1 stabilization. [ABSTRACT FROM AUTHOR]

The appearance of the super bacteria arose from mis- or abuse of antibiotics lead to the increasing interest about strong and safety new antibiotics. Angelica dahurica Bentham et Hooker (ADBH) is a herbal antibiotic drug which has been frequently prescribed in oriental pharmacology and has historically proven to be effective for bacterial infection. However, the molecular mechanism of the herbal antibiotic has not been cleared. Here, we examined the ADBH's antibiotic mechanism at the molecular level. We have focused on the simultaneous multi-target inhibitory effect of the of the ADBH ethyl acetate (EA) fraction on the enterohemorrhagic Escherichia coli O157:H7. Disk diffusion and DNA microarray was performed to investigate the molecular mechanism of the ADBH's antibiotic effect, and real-time quantitative PCR was employed to confirm the microarray data. The inhibitory effect of the ADBH EA fraction was on the bacterial cell envelope formation, folate biosynthesis, DNA replication and etiological factors of the E. coli O157:H7. This multi-target efficacy of the herbal antibiotic may be used as more effective and safer drugs that substitute existing antibiotics. [ABSTRACT FROM AUTHOR]

In prescribing natural compounds, it is important matching scientific names of medicinal materials which I want to use and those which have been found those effects. This point is also important in Oriental medicine but isn't kept because of differences in traditional sorting system and latest sorting system, external forms which are difficult to sort, and so on. Baekbuja (白附子) is a good example. In traditional Korean medicine, Aconitum koreanum Raymond (AKR) has been used as a Baekbuja, but in traditional Chinese medicine, Typhonium gigantum Engl. (TGE) has been used as a Baekbuja. Added to this, Helianthus tuberosis Linne (HTL) is used as an imitational Baekbuja in distribution channels and prescriptions now. In Treasured Mirror of Eastern Medicine (東醫寶鑑) registered in UNESCO Memory of the World, Baekbuja has effects on deviated eye and mouth (=bell's palsy, 口眼斜), inflammation of the throat and throat pain (喉痺咽痛), phlegm syncope headache (痰厥頭痛), tetanus (破傷風), snake bite (毒蛇咬傷), stammer (言語蹇澁), migraine and headache (偏正頭痛), and wind stroke phlegm congesting (中風痰壅). Treating three other medicines in cell line and studying the results would help to understand the precise effects between AKR and TGE and to reveal the effects of HTL, the imitational Baekbuja. In this need, three other medicines were treated in cell line and the results were analyzed through variance, functional classification, metabolic pathway, Venn diagram, and principal component. In metabolic pathway analysis, it is found that AKR upregulates connexin protein, TUBA and TUBB activities, which are in gap junction pathway. Considering that traditional medicinal references infer Baekbuja has effects on deviated eye and mouth, which is a disease about craniofacial neuron and that gap junction has important roles in neuron, it is a significant discovery. [ABSTRACT FROM AUTHOR]

Houttuynia Cordata Thunb (HCT; Saururaceae), known as 'Eosungcho' in Korea, has been traditionally used for antibiotic treatment and has proved its effect through clinical demonstrations. In spite of it s being used quite frequently in traditional prescriptions because of its superior antibiotic effect, HCT's molecular mechanisms on its antibiotic effect have not been understood. Hence, this is the first study about HCT's antibiotic mechanisms at the molecular level. HCT was extracted to acquire the fractions, then inoculated to confirm its antibiotic effect toward the bacteria Escherichia coli O157:H7 ( E. coli O157:H7; ATCC 43894) through the disc diffusion method. The antibacterial efficacy of HCT was measured by diameter of cleared zone. Thereafter, we isolated the RNA of affected cells and analyzed it's expressions through the microarray. To confirm the accuracy of the acquired data, RT-PCR was carried out. Results from this study indicate that E. coli O157:H7 exposures to HCT fractions, a number of genes that have been related to the synthesis of bacterial cell wall are downregulated, while some of the cell wall synthesis inhibitory genes are upregulated. Both results indicate that HCT fractions inhibit cell wall synthesis as like as β-lactam antibiotics. Furthermore, a few genes that have a critical role to DNA replication are downregulated. These genes, including folA, are closely related to the folate biosynthesis. Remarkable abnormal regulations that show antibiotic resistance activity of the E. coli O157: H7 are found, and are seem to be closely linked to the multidrug efflux pumps, especially upregulation of marRAB operon. The results of this study improve our understanding of the mode of action of HCT on E. coli O157:H7 and may show the usefulness of HCT fractions in the antibacterial treatment. [ABSTRACT FROM AUTHOR]

Melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24) uniquely displays broad cancer-specific apoptosis-inducing activity through induction of endoplasmic reticulum (ER) stress. We hypothesize that ceramide, a promoter of apoptosis, might contribute to mda-7/IL-24 induction of apoptosis. Ad.mda-7-infected tumor cells, but not normal cells, showed increased ceramide accumulation. Infection with Ad.mda-7 induced a marked increase in various ceramides (C16, C24, C24:1) selectively in prostate cancer cells. Inhibiting the enzyme serine palmitoyltransferase (SPT) using the potent SPT inhibitor myriocin (ISP1), impaired mda-7/IL-24-induced apoptosis and ceramide production, suggesting that ceramide formation caused by Ad.mda-7 occurs through de novo synthesis of ceramide and that ceramide is required for mda-7/IL-24-induced cell death. Fumonisin B1 (FB1) elevated ceramide formation as well as apoptosis induced by Ad.mda-7, suggesting that ceramide formation may also occur through the salvage pathway. Additionally, Ad.mda-7 infection enhanced expression of acid sphingomyelinase (ASMase) with a concomitant increase in ASMase activity and decreased sphingomyelin in cancer cells. ASMase silencing by RNA interference inhibited the decreased cell viability and ceramide formation after Ad.mda-7 infection. Ad.mda-7 activated protein phosphatase 2A (PP2A) and promoted dephosphorylation of the anti-apoptotic molecule BCL-2, a downstream ceramide-mediated pathway of mda-7/IL-24 action. Pretreatment of cells with FB1 or ISP-1 abolished the induction of ER stress markers (BiP/GRP78, GADD153 and pospho-eIF2α) triggered by Ad.mda-7 infection indicating that ceramide mediates ER stress induction by Ad.mda-7. Additionally, recombinant MDA-7/IL-24 protein induced cancer-specific production of ceramide. These studies define ceramide as a key mediator of an ER stress pathway that may underlie mda-7/IL-24 induction of cancer-specific killing. J. Cell. Physiol. 222: 546–555, 2010. © 2009 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Ribosomal protein S6 (RPS6) is a component of the 40S small ribosomal subunit and participates in the control of mRNA translation. Additionally, phospho (p)-RPS6 has been recognized as a surrogate marker for the activated PI3K/AKT/mTORC1 pathway, which occurs in many cancer types. However, downstream mechanisms regulated by RPS6 or p-RPS remains elusive, and the therapeutic implication of RPS6 is underappreciated despite an approximately half a century history of research on this protein. In addition, substantial evidence from RPS6 knockdown experiments suggests the potential role of RPS6 in maintaining cancer cell proliferation. This motivates us to investigate the current knowledge of RPS6 functions in cancer. In this review article, we reviewed the current information about the transcriptional regulation, upstream regulators, and extra-ribosomal roles of RPS6, with a focus on its involvement in cancer. We also discussed the therapeutic potential of RPS6 in cancer. [ABSTRACT FROM AUTHOR]

Abnormal inflammation and oxidative stress are involved in various diseases. Papaver rhoeas L. possesses various pharmacological activities, and a previously reported analysis of the anti-inflammatory effect of P. nudicaule ethanol extracts and alkaloid profiles of the plants suggest isoquinoline alkaloids as potential pharmacologically active compounds. Here, we investigated anti-inflammatory and antioxidant activities of ethyl acetate (EtOAc) fractions of P. nudicaule and P. rhoeas extracts in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. EtOAc fractions of P. nudicaule and P. rhoeas compared to their ethanol extracts showed less toxicity but more inhibitory activity against LPS-induced nitric oxide production. Moreover, EtOAc fractions lowered the LPS-induced production of proinflammatory molecules and cytokines and inhibited LPS-activated STAT3 and NF-κB, and additionally showed significant free radical scavenging activity and decreased LPS-induced reactive oxygen species and oxidized glutathione. EtOAc fractions of P. nudicaule increased the expression of HO-1, GCLC, NQO-1, and Nrf2 in LPS-stimulated cells and that of P. rhoeas enhanced NQO-1. Furthermore, metabolomic and biochemometric analyses of ethanol extracts and EtOAc fractions indicated that EtOAc fractions of P. nudicaule and P. rhoeas have potent anti-inflammatory and antioxidant activities, further suggesting that alkaloids in EtOAc fractions are potent active molecules of tested plants. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To know the effect of adenosine 5′-triphosphate (ATP) on intracellular calcium level and cell proliferation in cervical cancer cells. Study design: Four different human cervical cancer cell lines (Caski, C33A, HeLaS3 and SiHa) were used in this study. The change of intracellular calcium level, cell proliferation and the activity of proliferation- and calcium-related transcription factors by extracellular ATP were examined in these cell lines. Results: Extracellular ATP induced calcium mobilization, cell proliferation and the activation of NF-κB in all cell lines used. Conclusion: These results suggest that calcium mobilization and NF-κB dependent signaling pathway play an important role in the cell proliferation by ATP in cervical cancer. [Copyright &y& Elsevier]

Hepatitis B viral X protein (HBx) and the human p53 protein (p53) have been known as a transactivator and as a tumor suppressor, respectively. These two proteins have also been known to interact with each other to neutralize their authentic functions and the p53 represses the HBV enhancer/X promoter activity. Here we report that the promoter activity of the human p53 gene was strongly repressed by the HBx using the chloramphenicol acetyl transferase (CAT) assay. Analyses of serial deletion, site-directed mutagenesis and the heterologous promoter system showed that the site responsible for the repression was the E-box element in the promoter of the p53 gene. In addition, HBx as expected also repressed the activation of the p53 promoter by c-Myc through the E-box element. Northern blot analyses also showed that the expression of the p53 gene in the HepG2-K8 cell line, which expresses HBV genes including HBx, was much more repressed than that of the control cell HepG2. These results with previous data suggest that the shift of the reciprocal inhibitory activities at the levels of protein-protein interaction and transcription between HBx and p53 may play a decisive role in the HBV-related hepatocarcinogenesis. Oncogene (2000) 19, 468–471. [ABSTRACT FROM AUTHOR]

Simple Summary: Cell death was once thought of as two distinct processes involving mainly apoptosis or necrosis. In recent years, several different forms of cell death have gained importance, such as autophagy, paraptosis, and ferroptosis. Brassinin (BSN) is a phytoalexin identified from Cruciferase vegetables (Brassica) and various pharmacological properties have been reported. However, the efficacy of BSN for chronic myelogenous leukemia has not been elucidated. In our study, we confirmed whether BSN modulates the different cell death processes including apoptosis, autophagy, and paraptosis in chronic myelogenous leukemia cells. In addition, we confirmed that BSN promotes the activation of the MAPK signaling pathway. In this study, BSN could stimulate the activation of apoptosis, autophagy, and paraptosis by modulating the MAPK signaling cascade. Brassinin (BSN), a potent phytoalexin found in cruciferous vegetables, has been found to exhibit diverse anti-neoplastic effects on different cancers. However, the impact of BSN on chronic myelogenous leukemia (CML) cells and the possible mode of its actions have not been described earlier. We investigated the anti-cytotoxic effects of BSN on the KBM5, KCL22, K562, and LAMA84 CML cells and its underlying mechanisms of action in inducing programmed cell death. We noted that BSN could induce apoptosis, autophagy, and paraptosis in CML cells. BSN induced PARP cleavage, subG1 peak increase, and early apoptosis. The potential action of BSN on autophagy activation was confirmed by an LC3 expression and acridine orange assay. In addition, BSN induced paraptosis through increasing the reactive oxygen species (ROS) production, mitochondria damage, and endoplasmic reticulum (ER) stress. Moreover, BSN promoted the activation of the MAPK signaling pathway, and pharmacological inhibitors of this signaling pathway could alleviate all three forms of cell death induced by BSN. Our data indicated that BSN could initiate the activation of apoptosis, autophagy, and paraptosis through modulating the MAPK signaling pathway. [ABSTRACT FROM AUTHOR]

Pyrimethamine (Pyri) is being used in combination with other medications to treat serious parasitic infections of the body, brain, or eye and to also reduce toxoplasmosis infection in the patients with HIV infection. Additionally, Pyri can display significant anti-cancer potential in different tumor models, but the possible mode of its actions remains unclear. Hence, in this study, the possible anti-tumoral impact of Pyri on human chronic myeloid leukemia (CML) was deciphered. Pyri inhibited cell growth in various types of tumor cells and exhibited a marked inhibitory action on CML cells. In addition to apoptosis, Pyri also triggered sustained autophagy. Targeted inhibition of autophagy sensitized the tumor cells to Pyri-induced apoptotic cell death. Moreover, the activation of signal transducer and activator of transcription 5 (STAT5) and its downstream target gene Bcl-2 was attenuated by Pyri. Accordingly, small interfering RNA (siRNA)-mediated STAT5 knockdown augmented Pyri-induced autophagy and apoptosis and promoted the suppressive action of Pyri on cell viability. Moreover, ectopic overexpression of Bcl-2 protected the cells from Pyri-mediated autophagy and apoptosis. Overall, the data indicated that the attenuation of STAT5-Bcl-2 cascade by Pyri can regulate its growth inhibitory properties by simultaneously targeting both apoptosis and autophagy cell death mechanism(s). [ABSTRACT FROM AUTHOR]

Simple Summary: Although the genetic event that initiates liposarcoma is relatively well studied, understanding how the tumor progresses and displays differential severities will shed new insights into the diagnosis and prognosis determination of patients with liposarcoma. We analyzed the genome and transcriptome of liposarcoma samples and found that the overexpression of the histone gene cluster is an important determinant for dedifferentiated liposarcoma in predicting genome instability and cell proliferation. The overexpression of histone genes was caused by increased HMGA2 with amplification of chromosome 12q13-14. This dedifferentiated liposarcoma-specific genetic signature may serve as a biomarker for prognosis prediction. Liposarcoma (LPS) is an adult soft tissue malignancy that arises from fat tissue, where well-differentiated (WD) and dedifferentiated (DD) forms are the most common. DDLPS represents the progression of WDLPS into a more aggressive high-grade and metastatic form. Although a few DNA copy-number amplifications are known to be specifically found in WD- or DDLPS, systematic genetic differences that signify subtype determination between WDLPS and DDLPS remain unclear. Here, we profiled the genome and transcriptome of 38 LPS tumors to uncover the genetic signatures of subtype differences. Replication-dependent histone (RD-HIST) mRNAs were highly elevated and their regulation was disrupted in a subset of DDLPS, increasing cellular histone molecule levels, as measured using RNA-seq (the averaged fold change of 53 RD-HIST genes between the DD and WD samples was 10.9) and immunohistochemistry. The change was not observed in normal tissues. Integrated whole-exome sequencing, RNA-seq, and methylation analyses revealed that the overexpressed HMGA2 (the fold change between DD and WD samples was 7.3) was responsible for the increased RD-HIST level, leading to aberrant cell proliferation. Therefore, HMGA2-mediated elevation of RD-HISTs were crucial events in determining the aggressiveness of DDLPS, which may serve as a biomarker for prognosis prediction for liposarcoma patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast cancer is one of the most common cancers affecting women today. Astrocyte Elevated Gene-1 (AEG-1) is elevated in breast cancer patients and is associated with metastasis and poor prognosis. However, the mechanisms by which AEG-1 promotes breast cancer are not fully understood. This report focuses on a novel AEG-1 interacting protein, nucleolin (NCL), which we identified via mass spectrometry-based interactome profiling. We found NCL to be important for the oncogenic function of AEG-1 in breast cancer. Further, c-Met was identified as a novel mediator of the oncogenic function of the AEG-1-NCL complex. Collectively, our study suggests that targeting the AEG-1-NCL protein complex could be an effective therapeutic approach for the treatment of some breast cancers. Breast cancer is one of the most common malignant diseases worldwide. Astrocyte elevated gene-1 (AEG-1) is upregulated in breast cancer and regulates breast cancer cell proliferation and invasion. However, the molecular mechanisms by which AEG-1 promotes breast cancer have yet to be fully elucidated. In order to delineate the function of AEG-1 in breast cancer development, we mapped the AEG-1 interactome via affinity purification followed by LC-MS/MS. We identified nucleolin (NCL) as a novel AEG-1 interacting protein, and co-immunoprecipitation experiments validated the interaction between AEG-1 and NCL in breast cancer cells. The silencing of NCL markedly reduced not only migration/invasion, but also the proliferation induced by the ectopic expression of AEG-1. Further, we found that the ectopic expression of AEG-1 induced the tyrosine phosphorylation of c-Met, and NCL knockdown markedly reduced this AEG-1 mediated phosphorylation. Taken together, our report identifies NCL as a novel mediator of the oncogenic function of AEG-1, and suggests that c-Met could be associated with the oncogenic function of the AEG-1-NCL complex in the context of breast cancer. [ABSTRACT FROM AUTHOR]