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The protective effect of Amomum xanthoides extract against alloxan-induced diabetes through the suppression of NFkappaB activation.

Byung Hyun PARK ; Jin Woo PARK

Experimental & Molecular Medicine.2001;33(2):64-68.

This study was undertaken to investigate the preventive mechanism of Amomum xanthoides extract against the development of alloxan-induced diabetics of mice. Pretreatment of mice with A. xanthoides extract via intraperitoneum prevented alloxan-induced hyperglycemia and hypoinsulinemia in a dose dependent manner. Histological examination of pancreatic tissue from A. xanthoides extract treated mice showed that the islet cells remain unaffected by alloxan treatment. NFkappaB activation in the pancreas 30 min after alloxan injection (60 mg/kg, iv), as assessed by an electrophoretic mobility shift assay, was not detected in the mice pretreated with A. xanthoides extract. These results suggest that NFkappaB activation may be one of the critical determinant in the progression of the disease. Considering the preventive effect of A. xanthoides extract from alloxan-induced diabetics development, these results may provide the possible therapeutic value of A. xanthoides extract for the prevention of diabetes mellitus progression.
Alloxan/*pharmacology ; Animal ; Blood Glucose/metabolism ; Cell Nucleus/metabolism ; Diabetes Mellitus, Experimental/*prevention & control ; Dose-Response Relationship, Drug ; Female ; Hyperglycemia/prevention & control ; Islets of Langerhans/metabolism ; Mice ; Mice, Inbred ICR ; NF-kappa B/*antagonists & inhibitors ; Pancreas/metabolism ; Plant Extracts/*therapeutic use ; Time Factors

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HNF1 and/or HNF3 may contribute to the tissue specific expression of glucokinase gene.

Ji Young CHA ; Ha Il KIM ; Seung Soon IM ; Tian Zhu LI ; Yong Ho AHN

Experimental & Molecular Medicine.2001;33(2):59-63.

A possible role of hepatocyte nuclear factor 1 (HNF1) or HNF3, a predominant trans-acting factors of hepatic or pancreatic beta-cells, was examined on the tissue specific interdependent expression of glucokinase (GK) in liver, H4IIE, HepG2, HIT-T15 and MIN6 cell line. The tissues or cell lines known to express GK showed abundant levels of HNF1 and HNF3 mRNA as observed in liver, H4IIE, HepG2, HIT-T15 and MIN6 cells, whereas they were not detected in brain, heart, NIH 3T3, HeLa cells. The promoter of glucokinase contains several HNF3 consensus sequences and are well conserved in human, mouse and rat. Transfection of the glucokinase promotor linked with luciferase reporter to liver or pancreatic beta cell lines showed high interacting activities with HNF1 and HNF3, whereas minimal activities were detected in the cells expressing very low levels of HNFs. The binding of HNF1 or HNF3 to the GK promoter genes was confirmed by electrophoretic mobility shift assay (EMSA). From these data, we propose that the expression of HNF1 and/or HNF3 may, in part, contribute to the tissue specific expression of GK.
3T3 Cells ; Animal ; Blotting, Northern ; Cell Line ; Cell Nucleus/metabolism ; Cells, Cultured ; DNA-Binding Proteins/genetics/*physiology ; Genes, Reporter ; Glucokinase/*biosynthesis/*genetics ; Hela Cells ; Human ; Liver/metabolism ; Luciferase/metabolism ; Mice ; Models, Genetic ; Nuclear Proteins/genetics/*physiology ; Plasmids/metabolism ; Promoter Regions (Genetics) ; Protein Binding ; Rats ; Support, Non-U.S. Gov't ; Tissue Distribution ; Transcription Factors/genetics/*physiology ; Transcription, Genetic ; Transfection

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miR-98 suppresses melanoma metastasis through a negative feedback loop with its target gene IL-6.

Fei LI ; Xin ji LI ; Li QIAO ; Fei SHI ; Wen LIU ; You LI ; Yu ping DANG ; Wei jie GU ; Xiao gang WANG ; Wei LIU

Experimental & Molecular Medicine.2014;46(10):e116-. doi:10.1038/emm.2014.63

Dysregulated microRNA (miRNA) expression has a critical role in tumor development and metastasis. However, the mechanism by which miRNAs control melanoma metastasis is unknown. Here, we report reduced miR-98 expression in melanoma tissues with increasing tumor stage as well as metastasis; its expression is also negatively associated with melanoma patient survival. Furthermore, we demonstrate that miR-98 inhibits melanoma cell migration in vitro as well as metastatic tumor size in vivo. We also found that IL-6 is a target gene of miR-98, and IL-6 represses miR-98 levels via the Stat3-NF-kappaB-lin28B pathway. In an in vivo melanoma model, we demonstrate that miR-98 reduces melanoma metastasis and increases survival in part by reducing IL-6 levels; it also decreases Stat3 and p65 phosphorylation as well as lin28B mRNA levels. These results suggest that miR-98 inhibits melanoma metastasis in part through a novel miR-98-IL-6-negative feedback loop.
Animals ; Cell Line, Tumor ; Down-Regulation ; Gene Expression Regulation, Neoplastic ; Humans ; Interleukin-6/*genetics ; Male ; Melanoma/epidemiology/*genetics/*pathology ; Mice ; Mice, Inbred C57BL ; MicroRNAs/*genetics ; Neoplasm Metastasis/genetics/pathology ; Signal Transduction ; Survival Analysis

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Growth hormone receptor inhibition decreases the growth and metastasis of pancreatic ductal adenocarcinoma.

Ramadevi SUBRAMANI ; Rebecca LOPEZ-VALDEZ ; Alyssa SALCIDO ; Thiyagarajan BOOPALAN ; Arunkumar ARUMUGAM ; Sushmita NANDY ; Rajkumar LAKSHMANASWAMY

Experimental & Molecular Medicine.2014;46(10):e117-. doi:10.1038/emm.2014.61

Pancreatic cancer is the only major cancer with very low survival rates (1%). It is the fourth leading cause of cancer-related death. Hyperactivated growth hormone receptor (GHR) levels have been shown to increase the risk of cancer in general and this pathway is a master regulator of key cellular functions like proliferation, apoptosis, differentiation, metastasis, etc. However, to date there is no available data on how GHR promotes pancreatic cancer pathogenesis. Here, we used an RNA interference approach targeted to GHR to determine whether targeting GHR is an effective method for controlling pancreatic cancer growth and metastasis. For this, we used an in vitro model system consisting of HPAC and PANC-1 pancreatic cancer cells lines. GHR is upregulated in both of these cell lines and silencing GHR significantly reduced cell proliferation and viability. Inhibition of GHR also reduced the metastatic potential of pancreatic cancer cells, which was aided through decreased colony-forming ability and reduced invasiveness. Flow cytometric and western blot analyses revealed the induction of apoptosis in GHR silenced cells. GHR silencing affected phosphatidylinositol 3 kinase/AKT, mitogen extracellular signal-regulated kinase/extracellular signal-regulated kinase, Janus kinase/signal transducers and activators of transcription and mammalian target of rapamycin signaling, as well as, epithelial to mesenchymal transition. Interestingly, silencing GHR also suppressed the expression of insulin receptor-beta and cyclo-oxygenease-2. Altogether, GHR silencing controls the growth and metastasis of pancreatic cancer and reveals its importance in pancreatic cancer pathogenesis.
Carcinoma, Pancreatic Ductal/*genetics/*pathology ; Cell Line, Tumor ; Cell Movement ; Gene Expression Regulation, Neoplastic ; Humans ; Neoplasm Metastasis/genetics/pathology ; Pancreatic Ducts/metabolism/*pathology ; Pancreatic Neoplasms/*genetics/*pathology ; *RNA Interference ; RNA, Small Interfering/administration & dosage/genetics ; Receptors, Somatotropin/*genetics ; Transfection

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Chronic stress enhances progression of periodontitis via alpha1-adrenergic signaling: a potential target for periodontal disease therapy.

Huaixiu LU ; Minguang XU ; Feng WANG ; Shisen LIU ; Jing GU ; Songshan LIN

Experimental & Molecular Medicine.2014;46(10):e118-. doi:10.1038/emm.2014.65

This study assessed the roles of chronic stress (CS) in the stimulation of the sympathetic nervous system and explored the underlying mechanisms of periodontitis. Using an animal model of periodontitis and CS, the expression of tyrosine hydroxylase (TH) and the protein levels of the alpha1-adrenergic receptor (alpha1-AR) and beta2-adrenergic receptor (beta2-AR) were assessed. Furthermore, human periodontal ligament fibroblasts (HPDLFs) were stimulated with lipopolysaccharide (LPS) to mimic the process of inflammation. The proliferation of the HPDLFs and the expression of alpha1-AR and beta2-AR were assessed. The inflammatory-related cytokines interleukin (IL)-1beta, IL-6 and IL-8 were detected after pretreatment with the alpha1/beta2-AR blockers phentolamine/propranolol, both in vitro and in vivo. Results show that periodontitis under CS conditions enhanced the expression of TH, alpha1-AR and beta2-AR. Phentolamine significantly reduced the inflammatory cytokine levels. Furthermore, we observed a marked decrease in HPDLF proliferation and the increased expression of alpha1-ARfollowing LPS pretreatment. Pretreatment with phentolamine dramatically ameliorated LPS-inhibited cell proliferation. In addition, the blocking of alpha1-ARsignaling also hindered the upregulation of the inflammatory-related cytokines IL-1beta, IL-6 and IL-8. These results suggest that CS can significantly enhance the pathological progression of periodontitis by an alpha1-adrenergic signaling-mediated inflammatory response. We have identified a potential therapeutic target for the treatment of periodontal disease, particularly in those patients suffering from concurrent CS.
Adrenergic alpha-1 Receptor Antagonists/*therapeutic use ; Animals ; Cells, Cultured ; Cytokines/immunology ; Fibroblasts/immunology/pathology ; Humans ; Lipopolysaccharides/administration & dosage/immunology ; Male ; Periodontal Ligament/cytology/immunology/pathology ; Periodontitis/*drug therapy/*etiology/immunology/pathology ; Phentolamine/*therapeutic use ; Rats ; Rats, Wistar ; Receptors, Adrenergic, alpha-1/analysis/*immunology ; Signal Transduction/drug effects ; *Stress, Physiological/drug effects ; Tyrosine 3-Monooxygenase/analysis/immunology

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A putative pH-dependent nuclear localization signal in the juxtamembrane region of c-Met.

Shubhash Chandra CHAUDHARY ; Min Guk CHO ; Tuyet Thi NGUYEN ; Kyu Sang PARK ; Myung Hee KWON ; Jae Ho LEE

Experimental & Molecular Medicine.2014;46(10):e119-. doi:10.1038/emm.2014.67

The C-terminal fragment of the c-Met receptor tyrosine kinase is present in the nuclei of some cells irrespective of ligand stimulation, but the responsible nuclear localization signal (NLS) has not been previously reported. Here, we report that two histidine residues separated by a 10-amino-acid spacer (H1068-H1079) located in the juxtamembrane region of c-Met function as a putative novel NLS. Deletion of these sequences significantly abolished the nuclear translocation of c-Met, as did substitution of the histidines with alanines. This substitution also decreased the association of c-Met fragment with importin beta. The putative NLS of c-Met is unique in that it relies on histidines, whose positive charge changes depending on pH, rather than the lysines or arginines, commonly found in classical bipartite NLSs, suggesting the possible 'pH-dependency' of this NLS. Indeed, decreasing the cytosolic pH either with nigericin, an Na+/H+ exchanger or pH 6.5 KRB buffer significantly increased the level of nuclear c-Met and the interaction of the c-Met fragment with importin beta, indicating that low pH itself enhanced nuclear translocation. Consistent with this, nigericin treatment also increased the nuclear level of endogenous c-Met in HeLa cells. The putative aberrant bipartite NLS of c-Met seems to be the first example of what we call a 'pH-dependent' NLS.
Active Transport, Cell Nucleus ; Amino Acid Sequence ; HeLa Cells ; Humans ; Hydrogen-Ion Concentration ; Molecular Sequence Data ; *Nuclear Localization Signals ; Protein Structure, Tertiary ; Proto-Oncogene Proteins c-met/*analysis/genetics/*metabolism ; Sequence Deletion

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Therapeutic effect of the immunomodulatory drug lenalidomide, but not pomalidomide, in experimental models of rheumatoid arthritis and inflammatory bowel disease.

Belen LOPEZ-MILLAN ; Rafael DIAZ DE LA GUARDIA ; Heleia ROCA-HO ; Carmen M GARCÍA-HERRERO ; Jessie R LAVOIE ; Michael ROSU-MYLES ; Elena GONZALEZ-REY ; Francisco O'VALLE ; Gabriel CRIADO ; Mario DELGADO ; Pablo MENENDEZ

Experimental & Molecular Medicine.2017;49(2):e290-. doi:10.1038/emm.2016.143

Thalidomide is an immunomodulatory drug (IMiD) with proven therapeutic action in several autoimmune/inflammatory diseases; however, its inherent high toxicity has led to the development of more powerful and safer thalidomide analogs, including lenalidomide and pomalidomide. These are new generation IMiDs that exhibit direct antitumor activity as well as anti-inflammatory/immunomodulatory properties, and are FDA-approved for the treatment of several hematological malignances. Here we investigated the potential therapeutic effects of lenalidomide and pomalidomide in several experimental murine models of autoimmune/inflammatory diseases: 2,4,6-trinitrobenzene sulfonic acid- and dextran sulfate sodium-induced inflammatory bowel disease and type II collagen-induced arthritis. Lenalidomide displayed a strong therapeutic effect in all these models of autoimmune/inflammatory diseases, while the effect of pomalidomide was less pronounced. In vitro experiments confirmed the immunosuppressive effect of both IMiDs on the proliferative response of stimulated human lymphocytes and on the balance of secreted cytokines toward an anti-inflammatory profile. We conclude that lenalidomide may offer a therapeutic opportunity against autoimmune/inflammatory diseases.
Arthritis, Experimental ; Arthritis, Rheumatoid* ; Cytokines ; Dextran Sulfate ; Humans ; In Vitro Techniques ; Inflammatory Bowel Diseases* ; Lymphocytes ; Models, Theoretical* ; Thalidomide ; Therapeutic Uses

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HOXC10 suppresses browning of white adipose tissues.

Yvonne NG ; Shi Xiong TAN ; Sook Yoong CHIA ; Hwee Yim Angeline TAN ; Sin Yee GUN ; Lei SUN ; Wanjin HONG ; Weiping HAN

Experimental & Molecular Medicine.2017;49(2):e292-. doi:10.1038/emm.2016.144

Given that increased thermogenesis in white adipose tissue, also known as browning, promotes energy expenditure, significant efforts have been invested to determine the molecular factors involved in this process. Here we show that HOXC10, a homeobox domain-containing transcription factor expressed in subcutaneous white adipose tissue, is a suppressor of genes involved in browning white adipose tissue. Ectopic expression of HOXC10 in adipocytes suppresses brown fat genes, whereas the depletion of HOXC10 in adipocytes and myoblasts increases the expression of brown fat genes. The protein level of HOXC10 inversely correlates with brown fat genes in subcutaneous white adipose tissue of cold-exposed mice. Expression of HOXC10 in mice suppresses cold-induced browning in subcutaneous white adipose tissue and abolishes the beneficial effect of cold exposure on glucose clearance. HOXC10 exerts its effect, at least in part, by suppressing PRDM16 expression. The results support that HOXC10 is a key negative regulator of the process of browning in white adipose tissue.
Adipocytes ; Adipose Tissue, Brown ; Adipose Tissue, White ; Animals ; Ectopic Gene Expression ; Energy Metabolism ; Genes, Homeobox ; Glucose ; Mice ; Myoblasts ; Thermogenesis ; Transcription Factors

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NF-κB signaling regulates cell-autonomous regulation of CXCL10 in breast cancer 4T1 cells.

Won Jong JIN ; Bongjun KIM ; Darong KIM ; Hea Young PARK CHOO ; Hong Hee KIM ; Hyunil HA ; Zang Hee LEE

Experimental & Molecular Medicine.2017;49(2):e295-. doi:10.1038/emm.2016.148

The chemokine CXCL10 and its receptor CXCR3 play a role in breast cancer metastasis to bone and osteoclast activation. However, the mechanism of CXCL10/CXCR3-induced intracellular signaling has not been fully investigated. To evaluate CXCL10-induced cellular events in the mouse breast cancer cell line 4T1, we developed a new synthetic CXCR3 antagonist JN-2. In this study, we observed that secretion of CXCL10 in the supernatant of 4T1 cells was gradually increased during cell growth. JN-2 inhibited basal and CXCL10-induced CXCL10 expression and cell motility in 4T1 cells. Treatment of 4T1 cells with CXCL10 increased the expression of P65, a subunit of the NF-κB pathway, via activation of the NF-κB transcriptional activity. Ectopic overexpression of P65 increased CXCL10 secretion and blunted JN-2-induced suppression of CXCL10 secretion, whereas overexpression of IκBα suppressed CXCL10 secretion. These results indicate that the CXCL10/CXCR3 axis creates a positive feedback loop through the canonical NF-κB signaling pathway in 4T1 cells. In addition, treatment of osteoblasts with conditioned medium from JN-2-treated 4T1 cells inhibited the expression of RANKL, a crucial cytokine for osteoclast differentiation, which resulted in an inhibitory effect on osteoclast differentiation in the co-culture system of bone marrow-derived macrophages and osteoblasts. Direct intrafemoral injection of 4T1 cells induced severe bone destruction; however, this effect was suppressed by the CXCR3 antagonist via downregulation of P65 expression in an animal model. Collectively, these results suggest that the CXCL10/CXCR3-mediated NF-κB signaling pathway plays a role in the control of autonomous regulation of CXCL10 and malignant tumor properties in breast cancer 4T1 cells.
Animals ; Breast Neoplasms* ; Breast* ; Cell Line ; Cell Movement ; Chemokine CXCL10 ; Coculture Techniques ; Culture Media, Conditioned ; Down-Regulation ; Macrophages ; Mice ; Models, Animal ; Neoplasm Metastasis ; Osteoblasts ; Osteoclasts

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Cancer cell metabolism: implications for therapeutic targets.

Miran JANG ; Sung Soo KIM ; Jinhwa LEE

Experimental & Molecular Medicine.2013;45(10):e45-.

Cancer cell metabolism is characterized by an enhanced uptake and utilization of glucose, a phenomenon known as the Warburg effect. The persistent activation of aerobic glycolysis in cancer cells can be linked to activation of oncogenes or loss of tumor suppressors, thereby fundamentally advancing cancer progression. In this respect, inhibition of glycolytic capacity may contribute to an anticancer effect on malignant cells. Understanding the mechanisms of aerobic glycolysis may present a new basis for cancer treatment. Accordingly, interrupting lactate fermentation and/or other cancer-promoting metabolic sites may provide a promising strategy to halt tumor development. In this review, we will discuss dysregulated and reprogrammed cancer metabolism followed by clinical relevance of the metabolic enzymes, such as hexokinase, phosphofructokinase, pyruvate kinase M2, lactate dehydrogenase, pyruvate dehydrogenase kinase and glutaminase. The proper intervention of these metabolic sites may provide a therapeutic advantage that can help overcome resistance to chemotherapy or radiotherapy.
Animals ; Antineoplastic Agents/*pharmacology/therapeutic use ; Carcinogenesis/drug effects/metabolism ; Glycolysis/*drug effects ; Humans ; Neoplasms/drug therapy/*metabolism

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