Targeted Anticancer Immunotoxins and Cytotoxic Agents with Direct Killing Moieties

Directory of Open Access Journals (Sweden)

Koji Kawakami

2006-01-01

Full Text Available Despite the progress of the bioinformatics approach to characterize cell-surface antigens and receptors on tumor cells, it remains difficult to generate novel cancer vaccines or neutralizing monoclonal antibody therapeutics. Among targeted cancer therapeutics, biologicals with targetable antibodies or ligands conjugated or fused to toxins or chemicals for direct cell-killing ability have been developed over the last 2 decades. These conjugated or fused chimeric proteins are termed immunotoxins or cytotoxic agents. Two agents, DAB389IL-2 (ONTAKTM targeting the interleukin-2 receptor and CD33-calicheamicin (Mylotarg®, have been approved by the FDA for cutaneous T-cell lymphoma (CTCL and relapsed acute myeloid leukemia (AML, respectively. Such targetable agents, including RFB4(dsFv-PE38 (BL22, IL13-PE38QQR, and Tf-CRM107, are being tested in clinical trials. Several agents using unique technology such as a cleavable adapter or immunoliposomes with antibodies are also in the preclinical stage. This review summarizes the generation, mechanism, and development of these agents. In addition, possible future directions of this therapeutic approach are discussed.

Trauma and the endocrine system.

Science.gov (United States)

Mesquita, Joana; Varela, Ana; Medina, José Luís

2010-12-01

The endocrine system may be the target of different types of trauma with varied consequences. The present article discusses trauma of the hypothalamic-pituitary axes, adrenal glands, gonads, and pancreas. In addition to changes in circulating hormone levels due to direct injury to these structures, there may be an endocrine response in the context of the stress caused by the trauma. Copyright © 2010 SEEN. Published by Elsevier Espana. All rights reserved.

Management of endocrine orbitopathy

International Nuclear Information System (INIS)

Kahaly, G.J.

2001-01-01

Endocrine orbitopathy is the most common extrathyroidal manifestation of Basedow's disease and is characterized by a lymphocyte infiltration of the peribulbar space. Infiltrating and activated T cells react with orbital target cells and secrete cytokines, leading to accumulation of glycosaminoglycans, interstitial edema, and enlargement of the extra ocular muscels. Interdisciplinary management is recommended for rapid diagnosis and effective therapy of patients with endocrine orbitopathy. Immunosuppressive treatment is often used initially, and by suppressing inflammatory changes, it can result in subjective and objective improvement of thyroid eye disease. (orig.) [de

Abrogating endocrine resistance by targeting ERα and PI3K in breast cancer

International Nuclear Information System (INIS)

Fox, Emily M.; Arteaga, Carlos L.; Miller, Todd W.

2012-01-01

Antiestrogen therapies targeting estrogen receptor α (ER) signaling are a mainstay for patients with ER+ breast cancer. While many cancers exhibit resistance to antiestrogen therapies, a large body of clinical and experimental evidence indicates that hyperactivation of the phosphatidylinositol 3-kinase (PI3K) pathway promotes antiestrogen resistance. In addition, continued ligand-independent ER signaling in the setting of estrogen deprivation may contribute to resistance to endocrine therapy. PI3K activates several proteins which promote cell cycle progression and survival. In ER+ breast cancer cells, PI3K promotes ligand-dependent and -independent ER transcriptional activity. Models of antiestrogen-resistant breast cancer often remain sensitive to estrogen stimulation and PI3K inhibition, suggesting that clinical trials with combinations of drugs targeting both the PI3K and ER pathways are warranted. Herein, we review recent findings on the roles of PI3K and ER in antiestrogen resistance, and clinical trials testing drug combinations which target both pathways. We also discuss the need for clinical investigation of ER downregulators in combination with PI3K inhibitors.

Phosphodiesterases in endocrine physiology and disease.

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Vezzosi, Delphine; Bertherat, Jérôme

2011-08-01

The cAMP-protein kinase A pathway plays a central role in the development and physiology of endocrine tissues. cAMP mediates the intracellular effects of numerous peptide hormones. Various cellular and molecular alterations of the cAMP-signaling pathway have been observed in endocrine diseases. Phosphodiesterases (PDEs) are key regulatory enzymes of intracellular cAMP levels. Indeed, PDEs are the only known mechanism for inactivation of cAMP by catalysis to 5'-AMP. It has been suggested that disruption of PDEs could also have a role in the pathogenesis of many endocrine diseases. This review summarizes the most recent advances concerning the role of the PDEs in the physiopathology of endocrine diseases. The potential significance of this knowledge can be easily envisaged by the development of drugs targeting specific PDEs.

Modularly Constructed Synthetic Granzyme B Molecule Enables Interrogation of Intracellular Proteases for Targeted Cytotoxicity.

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Ho, Patrick; Ede, Christopher; Chen, Yvonne Y

2017-08-18

Targeted therapies promise to increase the safety and efficacy of treatments against diseases ranging from cancer to viral infections. However, the vast majority of targeted therapeutics relies on the recognition of extracellular biomarkers, which are rarely restricted to diseased cells and are thus prone to severe and sometimes-fatal off-target toxicities. In contrast, intracellular antigens present a diverse yet underutilized repertoire of disease markers. Here, we report a protein-based therapeutic platform-termed Cytoplasmic Oncoprotein VErifier and Response Trigger (COVERT)-which enables the interrogation of intracellular proteases to trigger targeted cytotoxicity. COVERT molecules consist of the cytotoxic protein granzyme B (GrB) fused to an inhibitory N-terminal peptide, which can be removed by researcher-specified proteases to activate GrB function. We demonstrate that fusion of a small ubiquitin-like modifier 1 (SUMO1) protein to GrB yields a SUMO-GrB molecule that is specifically activated by the cancer-associated sentrin-specific protease 1 (SENP1). SUMO-GrB selectively triggers apoptotic phenotypes in HEK293T cells that overexpress SENP1, and it is highly sensitive to different SENP1 levels across cell lines. We further demonstrate the rational design of additional COVERT molecules responsive to enterokinase (EK) and tobacco etch virus protease (TEVp), highlighting the COVERT platform's modularity and adaptability to diverse protease targets. As an initial step toward engineering COVERT-T cells for adoptive T-cell therapy, we verified that primary human T cells can express, package, traffic, and deliver engineered GrB molecules in response to antigen stimulation. Our findings set the foundation for future intracellular-antigen-responsive therapeutics that can complement surface-targeted therapies.

Endocytosis of Cytotoxic Granules Is Essential for Multiple Killing of Target Cells by T Lymphocytes.

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Chang, Hsin-Fang; Bzeih, Hawraa; Schirra, Claudia; Chitirala, Praneeth; Halimani, Mahantappa; Cordat, Emmanuelle; Krause, Elmar; Rettig, Jens; Pattu, Varsha

2016-09-15

CTLs are serial killers that kill multiple target cells via exocytosis of cytotoxic granules (CGs). CG exocytosis is tightly regulated and has been investigated in great detail; however, whether CG proteins are endocytosed following exocytosis and contribute to serial killing remains unknown. By using primary CTLs derived from a knock-in mouse of the CG membrane protein Synaptobrevin2, we show that CGs are endocytosed in a clathrin- and dynamin-dependent manner. Following acidification, endocytosed CGs are recycled through early and late, but not recycling endosomes. CGs are refilled with granzyme B at the late endosome stage and polarize to subsequent synapses formed between the CTL and new target cells. Importantly, inhibiting CG endocytosis in CTLs results in a significant reduction of their cytotoxic activity. Thus, our data demonstrate that continuous endocytosis of CG membrane proteins is a prerequisite for efficient serial killing of CTLs and identify key events in this process. Copyright © 2016 by The American Association of Immunologists, Inc.

Endocrine Disrupting Contaminants—Beyond the Dogma

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Guillette, Louis J.

2006-01-01

Descriptions of endocrine disruption have largely been associated with wildlife and driven by observations documenting estrogenic, androgenic, antiandrogenic, and antithyroid actions. These actions, in response to exposure to ecologically relevant concentrations of various environmental contaminants, have now been established in numerous vertebrate species. However, many potential mechanisms and endocrine actions have not been studied. For example, the DDT [1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane] metabolite, p,p′-DDE [1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene] is known to disrupt prostaglandin synthesis in the uterus of birds, providing part of the explanation for DDT-induced egg shell thinning. Few studies have examined prostaglandin synthesis as a target for endocrine disruption, yet these hormones are active in reproduction, immune responses, and cardiovascular physiology. Future studies must broaden the basic science approach to endocrine disruption, thereby expanding the mechanisms and endocrine end points examined. This goal should be accomplished even if the primary influence and funding continue to emphasize a narrower approach based on regulatory needs. Without this broader approach, research into endocrine disruption will become dominated by a narrow dogma, focusing on a few end points and mechanisms. PMID:16818240

The molecular classification of hereditary endocrine diseases.

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Ye, Lei; Ning, Guang

2015-12-01

Hereditary endocrine diseases are an important group of diseases with great heterogeneity. The current classification for hereditary endocrine disease is mostly based upon anatomy, which is helpful for pathophysiological interpretation, but does not address the pathogenic variability associated with different underlying genetic causes. Identification of an endocrinopathy-associated genetic alteration provides evidence for differential diagnosis, discovery of non-classical disease, and the potential for earlier diagnosis and targeted therapy. Molecular diagnosis should be routinely applied when managing patients with suspicion of hereditary disease. To enhance the accurate diagnosis and treatment of patients with hereditary endocrine diseases, we propose categorization of endocrine diseases into three groups based upon the function of the mutant gene: cell differentiation, hormone synthesis and action, and tumorigenesis. Each category was further grouped according to the specific gene function. We believe that this format would facilitate practice of precision medicine in the field of hereditary endocrine diseases.

Oxidative Mechanisms of Monocyte-Mediated Cytotoxicity

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Weiss, Stephen J.; Lobuglio, Albert F.; Kessler, Howard B.

1980-01-01

Human monocytes stimulated with phorbol myristate acetate were able to rapidly destroy autologous erythrocyte targets. Monocyte-mediated cytotoxicity was related to phorbol myristate acetate concentration and monocyte number. Purified preparations of lymphocytes were incapable of mediating erythrocyte lysis in this system. The ability of phorbol myristate acetate-stimulated monocytes to lyse erythrocyte targets was markedly impaired by catalase or superoxide dismutase but not by heat-inactivated enzymes or albumin. Despite a simultaneous requirement for superoxide anion and hydrogen peroxide in the cytotoxic event, a variety of hydroxyl radical and singlet oxygen scavengers did not effect cytolysis. However, tryptophan significantly inhibited cytotoxicity. The myeloperoxidase inhibitor cyanide enhanced erythrocyte destruction, whereas azide reduced it modestly. The inability of cyanide to reduce cytotoxicity coupled with the protective effect of superoxide dismutase suggests that cytotoxicity is independent of the classic myeloperoxidase system. We conclude that monocytes, stimulated with phorbol myristate acetate, generate superoxide anion and hydrogen peroxide, which together play an integral role in this cytotoxic mechanism.

Drug residues and endocrine disruptors in drinking water: risk for humans?

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Touraud, Evelyne; Roig, Benoit; Sumpter, John P; Coetsier, Clémence

2011-11-01

The presence of pharmaceuticals and endocrine disruptors in the environment raises many questions about risk to the environment and human health. Environmental exposure has been largely studied, providing to date a realistic picture of the degree of contamination of the environment by pharmaceuticals and hormones. Conversely, little information is available regarding human exposure. NSAIDS, carbamazepine, iodinated contrast media, β-blockers, antibiotics have been detected in drinking water, mostly in the range of ng/L. it is questioned if such concentrations may affect human health. Currently, no consensus among the scientific community exists on what risk, if any, pharmaceuticals and endocrine disruptors pose to human health. Future European research will focus, on one hand, on genotoxic and cytotoxic anti-cancer drugs and, on the other hand, on the induction of genetic resistance by antibiotics. This review does not aim to give a comprehensive overview of human health risk of drug residues and endocrine disruptors in drinking water but rather highlight important topics of discussion. Copyright © 2011. Published by Elsevier GmbH.

Comparative toxicity and endocrine disruption potential of urban and rural atmospheric organic PM1 in JEG-3 human placental cells.

Science.gov (United States)

van Drooge, Barend L; Marqueño, Anna; Grimalt, Joan O; Fernández, Pilar; Porte, Cinta

2017-11-01

Outdoor ambient air particulate matter and air pollution are related to adverse effects on human health. The present study assesses the cytotoxicity and ability to disrupt aromatase activity of organic PM 1 extracts from rural and urban areas at equivalent air volumes from 2 to 30 m 3 , in human placental JEG-3 cells. Samples were chemically analyzed for particle bounded organic compounds with endocrine disrupting potential, i.e. PAH, O-PAH, phthalate esters, but also for organic molecular tracer compounds for the emission source identification. Rural samples collected in winter were cytotoxic at the highest concentration tested and strongly inhibited aromatase activity in JEG-3 cells. No cytotoxicity was detected in summer samples from the rural site and the urban samples, while aromatase activity was moderately inhibited in these samples. In the urban area, the street site samples, collected close to intensive traffic, showed stronger inhibition of aromatase activity than the samples simultaneously collected at a roof site, 50 m above ground level. The cytotoxicity and endocrine disruption potential of the samples were linked to combustion products, i.e. PAH and O-PAH, especially from biomass burning in the rural site in winter. Copyright © 2017 Elsevier Ltd. All rights reserved.

Oxidative stress and the ageing endocrine system.

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Vitale, Giovanni; Salvioli, Stefano; Franceschi, Claudio

2013-04-01

Ageing is a process characterized by a progressive decline in cellular function, organismal fitness and increased risk of age-related diseases and death. Several hundred theories have attempted to explain this phenomenon. One of the most popular is the 'oxidative stress theory', originally termed the 'free radical theory'. The endocrine system seems to have a role in the modulation of oxidative stress; however, much less is known about the role that oxidative stress might have in the ageing of the endocrine system and the induction of age-related endocrine diseases. This Review outlines the interactions between hormones and oxidative metabolism and the potential effects of oxidative stress on ageing of endocrine organs. Many different mechanisms that link oxidative stress and ageing are discussed, all of which converge on the induction or regulation of inflammation. All these mechanisms, including cell senescence, mitochondrial dysfunction and microRNA dysregulation, as well as inflammation itself, could be targets of future studies aimed at clarifying the effects of oxidative stress on ageing of endocrine glands.

78 FR 57859 - Draft Guidance for Industry on Endocrine Disruption Potential of Drugs: Nonclinical Evaluation...

Science.gov (United States)

2013-09-20

... the endocrine system. This draft guidance also discusses factors to consider in determining the need... interfere with some aspect of the endocrine system of an organism or its progeny. Any component of the endocrine system can be a target of endocrine disruptors, although the systems most commonly affected...

Extending in silico mechanism-of-action analysis by annotating targets with pathways: application to cellular cytotoxicity readouts.

Science.gov (United States)

Liggi, Sonia; Drakakis, Georgios; Koutsoukas, Alexios; Cortes-Ciriano, Isidro; Martínez-Alonso, Patricia; Malliavin, Thérèse E; Velazquez-Campoy, Adrian; Brewerton, Suzanne C; Bodkin, Michael J; Evans, David A; Glen, Robert C; Carrodeguas, José Alberto; Bender, Andreas

2014-01-01

An in silico mechanism-of-action analysis protocol was developed, comprising molecule bioactivity profiling, annotation of predicted targets with pathways and calculation of enrichment factors to highlight targets and pathways more likely to be implicated in the studied phenotype. The method was applied to a cytotoxicity phenotypic endpoint, with enriched targets/pathways found to be statistically significant when compared with 100 random datasets. Application on a smaller apoptotic set (10 molecules) did not allowed to obtain statistically relevant results, suggesting that the protocol requires modification such as analysis of the most frequently predicted targets/annotated pathways. Pathway annotations improved the mechanism-of-action information gained by target prediction alone, allowing a better interpretation of the predictions and providing better mapping of targets onto pathways.

Cytotoxic of Ganoderma lucidum in Colon Cancer through Cyclooxygenase 2 (COX-2 as Its Molecular Target

Directory of Open Access Journals (Sweden)

Agustina Setiawati

2017-05-01

Full Text Available Many studies were designed explore chemopreventive activity of natural products on colon cancer especially addressing COX-2 as molecular target. Another promising source of natural product that potentially exhibit anticancer activity on colon cancer is Ganoderma lucidum. This study assessed selectivity of cytotoxic effect of G. lucidum extract on WiDr to Vero cells and investigated molecular mechanism on COX-2. G. lucidum ex-tract was prepared by reflux extraction method; in vitro anticancer was assayed by MTT method on WiDr and Vero cell line. This study applied apoptosis induction assay to observe cell death mechanism using double staining method; further COX-2 expression was stained by immunocytochemistry method. G. lucidum extract has cytotoxic effect on WiDr cells with IC50 135 µg/mL. However, the cytotoxic effect had low selectivity to-wards Vero cells with Selectivity Index (SI 3.66. The extract induced apoptosis and suppressed COX-2 ex-pression in WiDr cells. G. lucidum extract was potential to be developed as anticancer agent towards colon cancer.

Many Putative Endocrine Disruptors Inhibit Prostaglandin Synthesis

DEFF Research Database (Denmark)

Kristensen, David M.; Skalkam, Maria L.; Audouze, Karine Marie Laure

2011-01-01

Background: Prostaglandins (PGs) play key roles in development and maintenance of homeostasis of the adult body. Despite these important roles, it remains unclear whether the PG pathway is a target for endocrine disruption. However, several known endocrine disrupting compounds (EDCs) share a high...... suggest a hitherto unknown mode of action by EDCs through inhibition of the PG pathway and suggest new avenues to investigate effects of EDCs on reproductive and immunological disorders that have become increasingly common in recent decades....

The future of cytotoxic therapy: selective cytotoxicity based on biology is the key

International Nuclear Information System (INIS)

Bono, Johann S de; Tolcher, Anthony W; Rowinsky, Eric K

2003-01-01

Although mortality from breast cancer is decreasing, 15% or more of all patients ultimately develop incurable metastatic disease. It is hoped that new classes of target-based cytotoxic therapeutics will significantly improve the outcome for these patients. Many of these novel agents have displayed cytotoxic activity in preclinical and clinical evaluations, with little toxicity. Such preferential cytotoxicity against malignant tissues will remain tantamount to the Holy Grail in oncologic therapeutics because this portends improved patient tolerance and overall quality of life, and the capacity to deliver combination therapy. Combinations of such rationally designed target-based therapies are likely to be increasingly important in treating patients with breast carcinoma. The anticancer efficacy of these agents will, however, remain dependent on the involvement of the targets of these agents in the biology of the individual patient's disease. Results of DNA microarray analyses have raised high hopes that the analyses of RNA expression levels can successfully predict patient prognosis, and indicate that the ability to rapidly 'fingerprint' the oncogenic profile of a patient's tumor is now possible. It is hoped that these studies will support the identification of the molecules driving a tumor's growth, and the selection of the appropriate combination of targeted agents in the near future

A critical review of histopathological findings associated with endocrine and non-endocrine hepatic toxicity in fish models.

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Wolf, Jeffrey C; Wheeler, James R

2018-04-01

Although frequently examined as a target organ for non-endocrine toxicity, histopathological evaluation of the liver is becoming a routine component of endocrine disruption studies that utilize various fish species as test subjects. However, the interpretation of microscopic liver findings can be challenging, especially when attempting to distinguish adverse changes associated with endocrine disrupting substances from those caused by systemic or direct hepatic toxicity. The purpose of this project was to conduct a critical assessment of the available peer-reviewed and grey literature concerning the histopathologic effects of reproductive endocrine active substances (EAS) and non-endocrine acting substances in the livers of fish models, and to determine if liver histopathology can be used to reliably distinguish endocrine from non-endocrine etiologies. The results of this review suggest that few compound-specific histopathologic liver effects have been identified, among which are estrogen agonist-induced increases in hepatocyte basophilia and proteinaceous intravascular fluid in adult male teleosts, and potentially, decreased hepatocyte basophilia in female fish exposed to substances that possess androgenic, anti-estrogenic, or aromatase inhibitory activity. This review also used published standardized methodology to assess the credibility of the histopathology data in each of the 117 articles that reported liver effects of treatment, and consequently it was determined that in only 37% of those papers were the data considered either highly credible or credible. The outcome of this work highlights the value of histopathologic liver evaluation as an investigative tool for EAS studies, and provides information that may have implications for EAS hazard assessment. Copyright © 2018 The Author(s). Published by Elsevier B.V. All rights reserved.

Endocrine disruptors in female reproductive tract development and carcinogenesis

OpenAIRE

Ma, Liang

2009-01-01

Growing concerns over endocrine disrupting chemicals (EDCs) and their effects on human fetal development and adult health have promoted research into the underlying molecular mechanisms of endocrine disruption. Gene targeting technology has allowed insight into the genetic pathways governing reproductive tract development and how exposure to EDCs during a critical developmental window can alter reproductive tract development, potentially forming the basis for adult diseases. This review prima...

The peripheral GABAergic system as a target in endocrine disorders

NARCIS (Netherlands)

Gladkevich, A; Korf, J; Hakobyan, VP; Melkonyan, KV

2006-01-01

In addition to its well-recognized function as a cerebral inhibitory transmitter, less well established is the role of GABA in peripheral nervous and endocrine systems. We Summarize current evidence that GABA serves as a neurotransmitter or neuromodulator in the autonomic nervous system and as a

Impact of G protein-coupled receptor heteromers in endocrine systems.

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Jonas, K C; Hanyaloglu, A C

2017-07-05

The fine-tuning of endocrine homeostasis is regulated by dynamic receptor mediated processes. The superfamily of G protein-coupled receptors (GPCRs) have diverse roles in the modulation of all endocrine axes, thus understanding the mechanisms underpinning their functionality is paramount for treatment of endocrinopathies. Evidence over the last 20 years has highlighted homo and heteromerization as a key mode of mediating GPCR functional diversity. This review will discuss the concept of GPCR heteromerization and its relevance to endocrine function, detailing in vitro and in vivo evidence, and exploring current and potential pharmacological strategies for specific targeting of GPCR heteromers in endocrine heath and disease. Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.

Surgical treatment of pancreatic endocrine tumors in multiple endocrine neoplasia type 1

Directory of Open Access Journals (Sweden)

Marcel Cerqueira Cesar Machado

Full Text Available Surgical approaches to pancreatic endocrine tumors associated with multiple endocrine neoplasia type 1 may differ greatly from those applied to sporadic pancreatic endocrine tumors. Presurgical diagnosis of multiple endocrine neoplasia type 1 is therefore crucial to plan a proper intervention. Of note, hyperparathyroidism/multiple endocrine neoplasia type 1 should be surgically treated before pancreatic endocrine tumors/multiple endocrine neoplasia type 1 resection, apart from insulinoma. Non-functioning pancreatic endocrine tumors/multiple endocrine neoplasia type 1 >1 cm have a high risk of malignancy and should be treated by a pancreatic resection associated with lymphadenectomy. The vast majority of patients with gastrinoma/multiple endocrine neoplasia type 1 present with tumor lesions at the duodenum, so the surgery of choice is subtotal or total pancreatoduodenectomy followed by regional lymphadenectomy. The usual surgical treatment for insulinoma/multiple endocrine neoplasia type 1 is distal pancreatectomy up to the mesenteric vein with or without spleen preservation, associated with enucleation of tumor lesions in the pancreatic head. Surgical procedures for glucagonomas, somatostatinomas, and vipomas/ multiple endocrine neoplasia type 1 are similar to those applied to sporadic pancreatic endocrine tumors. Some of these surgical strategies for pancreatic endocrine tumors/multiple endocrine neoplasia type 1 still remain controversial as to their proper extension and timing. Furthermore, surgical resection of single hepatic metastasis secondary to pancreatic endocrine tumors/multiple endocrine neoplasia type 1 may be curative and even in multiple liver metastases surgical resection is possible. Hepatic trans-arterial chemo-embolization is usually associated with surgical resection. Liver transplantation may be needed for select cases. Finally, pre-surgical clinical and genetic diagnosis of multiple endocrine neoplasia type 1 syndrome and

GENERATION OF CYTOTOXIC LYMPHOCYTES IN MIXED LYMPHOCYTE REACTIONS

Science.gov (United States)

Forman, James; Möller, Göran

1973-01-01

Generation of cytotoxic effector cells by a unidirectional mixed lymphocyte reaction (MLR) in the mouse H-2 system was studied using labeled YAC (H-2a) leukemia cells as targets. The responding effector cell displayed a specific cytotoxic effect against target cells of the same H-2 genotype as the stimulating cell population. Killing of syngeneic H-2 cells was not observed, even when the labeled target cells were "innocent bystanders" in cultures where specific target cells were reintroduced. Similar results were found with spleen cells taken from mice sensitized in vivo 7 days earlier. The effector cell was not an adherent cell and was not activated by supernatants from MLR. The supernatants were not cytotoxic by themselves. When concanavalin A or phytohemagglutinin was added to the cytotoxic test system, target and effector cells were agglutinated. Under these conditions, killing of H-2a target cells was observed in mixed cultures where H-2a lymphocytes were also the effector cells. These findings indicate that specifically activated, probably thymus-derived lymphocytes, can kill nonspecifically once they have been activated and providing there is close contact between effector and target cells. Thus, specificity of T cell killing appears to be restricted to recognition and subsequent binding to the targets, the actual effector phase being nonspecific. PMID:4269560

Identification of Achaete-scute complex-like 1 (ASCL1) target genes and evaluation of DKK1 and TPH1 expression in pancreatic endocrine tumours

International Nuclear Information System (INIS)

Johansson, Térèse A; Westin, Gunnar; Skogseid, Britt

2009-01-01

ASCL1 role in pancreatic endocrine tumourigenesis has not been established. Recently it was suggested that ASCL1 negatively controls expression of the Wnt signalling antagonist DKK1. Notch signalling regulates expression of TPH1, the rate limiting enzyme in the biosyntesis of serotonin. Understanding the development and proliferation of pancreatic endocrine tumours (PETs) is essential for the development of new therapies. ASCL1 target genes in the pancreatic endocrine tumour cell line BON1 were identified by RNA interference and microarray expression analysis. Protein expressions of selected target genes in PETs were evaluated by immunohistochemistry. 158 annotated ASCL1 target genes were identified in BON1 cells, among them DKK1 and TPH1 that were negatively regulated by ASCL1. An inverse relation of ASCL1 to DKK1 protein expression was observed for 15 out of 22 tumours (68%). Nine tumours displayed low ASCL1/high DKK1 and six tumours high ASCL1/low DKK1 expression. Remaining PETs showed high ASCL1/high DKK1 (n = 4) or low ASCL1/low DKK1 (n = 3) expression. Nine of twelve analysed PETs (75%) showed TPH1 expression with no relation to ASCL1. A number of genes with potential importance for PET tumourigenesis have been identified. ASCL1 negatively regulated the Wnt signalling antagonist DKK1, and TPH1 expression in BON1 cells. In concordance with these findings DKK1 showed an inverse relation to ASCL1 expression in a subset of PETs, which may affect growth control by the Wnt signalling pathway

Endocrine autoimmune diseases and female infertility.

Science.gov (United States)

Sen, Aritro; Kushnir, Vitaly A; Barad, David H; Gleicher, Norbert

2014-01-01

An increasing body of evidence suggests that immune-mediated processes affect female reproductive success at multiple levels. Crosstalk between endocrine and immune systems regulates a large number of biological processes that affect target tissues, and this crosstalk involves gene expression, cytokine and/or lymphokine release and hormone action. In addition, endocrine-immune interactions have a major role in the implantation process of the fetal (paternally derived) semi-allograft, which requires a reprogramming process of the maternal immune system from rejection to temporary tolerance for the length of gestation. Usually, the female immune system is supportive of all of these processes and, therefore, facilitates reproductive success. Abnormalities of the female immune system, including autoimmunity, potentially interfere at multiple levels. The relevance of the immune system to female infertility is increasingly recognized by investigators, but clinically is often not adequately considered and is, therefore, underestimated. This Review summarizes the effect of individual autoimmune endocrine diseases on female fertility, and points towards selected developments expected in the near future.

Environmental endocrine disruptors: Effects on the human male reproductive system.

Science.gov (United States)

Sweeney, M F; Hasan, N; Soto, A M; Sonnenschein, C

2015-12-01

Incidences of altered development and neoplasia of male reproductive organs have increased during the last 50 years, as shown by epidemiological data. These data are associated with the increased presence of environmental chemicals, specifically "endocrine disruptors," that interfere with normal hormonal action. Much research has gone into testing the effects of specific endocrine disrupting chemicals (EDCs) on the development of male reproductive organs and endocrine-related cancers in both in vitro and in vivo models. Efforts have been made to bridge the accruing laboratory findings with the epidemiological data to draw conclusions regarding the relationship between EDCs, altered development and carcinogenesis. The ability of EDCs to predispose target fetal and adult tissues to neoplastic transformation is best explained under the framework of the tissue organization field theory of carcinogenesis (TOFT), which posits that carcinogenesis is development gone awry. Here, we focus on the available evidence, from both empirical and epidemiological studies, regarding the effects of EDCs on male reproductive development and carcinogenesis of endocrine target tissues. We also critique current research methodology utilized in the investigation of EDCs effects and outline what could possibly be done to address these obstacles moving forward.

Magnetic microgels for drug targeting applications: Physical–chemical properties and cytotoxicity evaluation

Energy Technology Data Exchange (ETDEWEB)

Turcu, Rodica, E-mail: rodica.turcu@itim-cj.ro [National Institute for Research and Development of Isotopic and Molecular Technologies, 65-103 Donath Street, 400293 Cluj-Napoca (Romania); Craciunescu, Izabell [National Institute for Research and Development of Isotopic and Molecular Technologies, 65-103 Donath Street, 400293 Cluj-Napoca (Romania); Garamus, Vasil M. [Helmholtz-Zentrum Geesthacht, Zentrum für Material- und Küstenforschung GmbH, 21502 Geesthacht (Germany); Janko, Christina; Lyer, Stefan; Tietze, Rainer; Alexiou, Christoph [ENT-Department, Else Kröner-Fresenius Stiftung-Professorship, Section for Experimental Oncology and Nanomedicine (SEON), University Hospital Erlangen (Germany); Vekas, Ladislau, E-mail: vekas@acad-tim.tm.edu.ro [Romanian Academy-Timisoara Branch, CFATR, Laboratory of Magnetic Fluids, Mihai Viteazul Street 24, 300223 Timisoara (Romania)

2015-04-15

Magnetoresponsive microgels with high saturation magnetization values have been obtained by a strategy based on the miniemulsion method using high colloidal stability organic carrier ferrofluid as primary material. Hydrophobic nanoparticles Fe{sub 3}O{sub 4}/oleic acid are densely packed into well-defined spherical nanoparticle clusters coated with polymers with sizes in the range 40–350 nm. Physical–chemical characteristics of magnetic microgels were investigated by TEM, SAXS, XPS and VSM measurements with the focus on the structure–properties relationship. The impact of magnetic microgels loaded with anticancer drug mitoxantrone (MTO) on the non-adherent human T cell leukemia line Jurkat was investigated in multiparameter flow cytometry. We showed that both MTO and microgel-loaded MTO penetrate into cells and both induce apoptosis and later secondary necrosis in a time- and dose dependent manner. In contrast, microgels without MTO are not cytotoxic in the corresponding concentrations. Our results show that MTO-loaded microgels are promising structures for application in magnetic drug targeting. - Highlights: • Densely packed spherical clusters of magnetic nanoparticles were obtained. • High magnetization microgels with superparamagnetic behavior are reported. • The facile and reproducible synthesis procedure applied is easy to be up-scaled. • The toxicity tests show that magnetic microgels are not cytotoxic. • We show that mitoxantrone loaded microgels induce death of Jurkat cells.

Fundamental studies on ADCC (antibody-dependent cell-mediated cytotoxicity) of human peripheral blood leukocytes using sheep red blood cells as target cells, and the effect of erythrophagocytosis

International Nuclear Information System (INIS)

Ichikawa, Yukinobu; Takaya, Masatoshi; Arimori, Shigeru

1979-01-01

We investigated antibody-dependent cell-mediated cytotoxicity (ADCC) of human peripheral blood leukocytes by using 51 Cr-labelled sheep red blood cells (SRBC) as target cells and anti-SRBC rabbit antibody. Lysis of SRBC was mediated by either human peripheral lymphoid cells or phagocytes (Monocytes and granulocytes). SRBC were useful as target cells in ADCC assay against human lymphoid cells, since decreased cytotoxic activity of phagocyte-contaminated crude lymphocyte fraction was recovered by elimination of contaminating phagocytes. The monocytes inhibited ADCC of lymphoid cells through phagocytosis of SRBC. This assay system may be useful for estimating not only Fc receptor-mediated cytotoxicity but also Fc receptor-mediated phagocytic activity of human peripheral blood leukocytes. (author)

DNA fragmentation: manifestation of target cell destruction mediated by cytotoxic T-cell lines, lymphotoxin-secreting helper T-cell clones, and cell-free lymphotoxin-containing supernatant

International Nuclear Information System (INIS)

Schmid, D.S.; Tite, J.P.; Ruddle, N.H.

1986-01-01

A Lyt-2 + , trinitrophenyl-specific, lymphotoxin-secreting, cytotoxic T-cell line, PCl 55, mediates the digestion of target cell DNA into discretely sized fragments. This phenomenon manifests itself within 30 min after effector cell encounter as measured by the release of 3 H counts from target cells prelabeled with [ 3 H]deoxythymidine and occurs even at very low effector to target cell ratios (0.25:1). A Lyt-1 + , ovalbumin-specific, lymphotoxin-secreting T-helper cell clone, 5.9.24, is also able to mediate fragmentation of target cell DNA over a time course essentially indistinguishable from the cytotoxic T lymphocyte-mediated hit. Cell-free lymphotoxin-containing supernatants also cause release of DNA from targets, although they require a longer time course, on the order of 24 hr. In contrast, lysis of cells by antibody plus complement or Triton X-100 does not result in DNA release even after extended periods of incubation (24 hr). All three treatments that result in the release of DNA from cells cause fragmentation of that DNA into discretely sized pieces that are multiples of 200 base pairs. The results thus suggest that cytotoxic T cells, lymphotoxin-secreting helper clones with cytolytic activity, and lymphotoxin all effect target cell destruction by means of a similar mechanism and that observed differences in time course and the absence of target cell specificity in killing mediated by lymphotoxin may simply reflect differences in the mode of toxin delivery

Endocrine Disrupting Chemicals (EDCs)

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... Center Pacientes y Cuidadores Hormones and Health The Endocrine System Hormones Endocrine Disrupting Chemicals (EDCs) Steroid and Hormone ... Hormones and Health › Endocrine Disrupting Chemicals (EDCs) The Endocrine System Hormones Endocrine Disrupting Chemicals (EDCs) EDCs Myth vs. ...

Testosterone-Fatty Acid esterification: a unique target for the endocrine toxicity of tributyltin to gastropods.

Science.gov (United States)

Leblanc, Gerald A; Gooding, Meredith P; Sternberg, Robin M

2005-01-01

Over the past thirty years, a global occurrence of sexual aberration has occurred whereby females among populations of prosobranch snails exhibit male sex characteristics. This condition, called imposex, has been causally associated with exposure to the biocide tributyltin. Tributyltin-exposed, imposex snails typically have elevated levels of testosterone which have led to the postulate that this endocrine dysfunction is responsible for imposex. This overview describes recent evidence that supports this postulate. Gastropods maintain circulating testosterone levels and administration of testosterone to females or castrates stimulates male sex differentiation in several snail species. Studies in the mud snail (Ilyanassa obsoleta) have shown that gastropods utilize a unique strategy for regulating free testosterone levels. Excess testosterone is converted to fatty acid esters by the action of a testosterone-inducible, high capacity/low affinity enzyme, acyl-CoA:testosterone acyl transferase, and stored within the organisms. Free testosterone levels are regulated during the reproductive cycle apparently due to changes in esterification/desterification suggesting that testosterone functions in the reproductive cycle of the organisms. Testosterone esterification provides a unique target in the testosterone regulatory machinery of snails that is altered by tributyltin. Indeed, imposex and free testosterone levels were elevated in field collected snails containing high tin levels, while testosterone-fatty acid ester pools were reduced in these organisms. These observations indicate that tributyltin elevates free testosterone by reducing the retention of testosterone as fatty acid-esters. This endocrine effect of tributyltin may be responsible for imposex.

Evaluation of cytotoxic and tumor targeting capability of (177)Lu-DOTATATE-nanoparticles: a trailblazing strategy in peptide receptor radionuclide therapy.

Science.gov (United States)

Arora, Geetanjali; Dubey, Priyanka; Shukla, Jaya; Ghosh, Sourabh; Bandopadhyaya, Gurupad

2016-06-01

We propose an innovative strategy of nanoparticle-mediated-peptide receptor radionuclide therapy (PRRT) employing PLGA-nanoparticles together with anti-β-hCG antibodies that can protect kidneys from radiation damage while simultaneously enhancing its tumor targeting and cytotoxic ability for somatostatin receptor (SSR) positive tumors. PEG-coated-(177)Lu-DOTATATE-PLGA-nanoparticles (PEG-LuD-NP) were formulated and characterized. In vitro toxicity of these particles was tested on human glioblastoma cell line U87MG over a radiation dose range of 19-78 Gy, using MTT assay and flow cytometry. To further enhance cytotoxicity and test the feasibility of active tumor targeting, apoptosis-inducing anti-β-hCG monoclonal antibodies were employed in vitro, after confirming expression of β-hCG on U87MG. In vivo tumor targeting ability of these particles, in comparison to uncoated particles and un-encapsulated (177)Lu-DOTATATE, was assessed by intravenous administration in tumor-induced wistar rats. Rats were first imaged in a gamma camera followed by euthanasia for organ extraction and counting in gamma counter. The particles were spherical in shape with mean diameter of 300 nm. Highest cytotoxicity that could be achieved with PEG-LuD-NP, on radio-resistant U87MG cells, was 35.8 % due to complex cellular response triggered by ionizing radiation. Interestingly, synergistic action of antibodies and PEG-LuD-NP doubled the cytotoxicity (80 %). PEG-LuD-NP showed the highest tumor uptake (4.3 ± 0.46 % ID/g) as compared to (177)Lu-DOTATATE (3.5 ± 0.31 %) and uncoated-(177)Lu-DOTATATE-nanoparticles (3.4 ± 0.35 %) in tumor-inoculated wistar rats (p targeting SSR positive tumors for enhanced cytoxicity and reduced renal radiation dose associated with conventional PRRT. To our knowledge of literature, this is the first study to establish in vitro and in vivo efficacy profile of nanoparticles in PRRT providing a stepping-stone for undergoing and future research

A Rat α-Fetoprotein Binding Activity Prediction Model to Facilitate Assessment of the Endocrine Disruption Potential of Environmental Chemicals.

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Hong, Huixiao; Shen, Jie; Ng, Hui Wen; Sakkiah, Sugunadevi; Ye, Hao; Ge, Weigong; Gong, Ping; Xiao, Wenming; Tong, Weida

2016-03-25

Endocrine disruptors such as polychlorinated biphenyls (PCBs), diethylstilbestrol (DES) and dichlorodiphenyltrichloroethane (DDT) are agents that interfere with the endocrine system and cause adverse health effects. Huge public health concern about endocrine disruptors has arisen. One of the mechanisms of endocrine disruption is through binding of endocrine disruptors with the hormone receptors in the target cells. Entrance of endocrine disruptors into target cells is the precondition of endocrine disruption. The binding capability of a chemical with proteins in the blood affects its entrance into the target cells and, thus, is very informative for the assessment of potential endocrine disruption of chemicals. α-fetoprotein is one of the major serum proteins that binds to a variety of chemicals such as estrogens. To better facilitate assessment of endocrine disruption of environmental chemicals, we developed a model for α-fetoprotein binding activity prediction using the novel pattern recognition method (Decision Forest) and the molecular descriptors calculated from two-dimensional structures by Mold² software. The predictive capability of the model has been evaluated through internal validation using 125 training chemicals (average balanced accuracy of 69%) and external validations using 22 chemicals (balanced accuracy of 71%). Prediction confidence analysis revealed the model performed much better at high prediction confidence. Our results indicate that the model is useful (when predictions are in high confidence) in endocrine disruption risk assessment of environmental chemicals though improvement by increasing number of training chemicals is needed.

Endocrine-disrupting chemicals: associated disorders and mechanisms of action.

Science.gov (United States)

De Coster, Sam; van Larebeke, Nicolas

2012-01-01

The incidence and/or prevalence of health problems associated with endocrine-disruption have increased. Many chemicals have endocrine-disrupting properties, including bisphenol A, some organochlorines, polybrominated flame retardants, perfluorinated substances, alkylphenols, phthalates, pesticides, polycyclic aromatic hydrocarbons, alkylphenols, solvents, and some household products including some cleaning products, air fresheners, hair dyes, cosmetics, and sunscreens. Even some metals were shown to have endocrine-disrupting properties. Many observations suggesting that endocrine disruptors do contribute to cancer, diabetes, obesity, the metabolic syndrome, and infertility are listed in this paper. An overview is presented of mechanisms contributing to endocrine disruption. Endocrine disruptors can act through classical nuclear receptors, but also through estrogen-related receptors, membrane-bound estrogen-receptors, and interaction with targets in the cytosol resulting in activation of the Src/Ras/Erk pathway or modulation of nitric oxide. In addition, changes in metabolism of endogenous hormones, cross-talk between genomic and nongenomic pathways, cross talk with estrogen receptors after binding on other receptors, interference with feedback regulation and neuroendocrine cells, changes in DNA methylation or histone modifications, and genomic instability by interference with the spindle figure can play a role. Also it was found that effects of receptor activation can differ in function of the ligand.

Endocrine-Disrupting Chemicals: Associated Disorders and Mechanisms of Action

Directory of Open Access Journals (Sweden)

Sam De Coster

2012-01-01

Full Text Available The incidence and/or prevalence of health problems associated with endocrine-disruption have increased. Many chemicals have endocrine-disrupting properties, including bisphenol A, some organochlorines, polybrominated flame retardants, perfluorinated substances, alkylphenols, phthalates, pesticides, polycyclic aromatic hydrocarbons, alkylphenols, solvents, and some household products including some cleaning products, air fresheners, hair dyes, cosmetics, and sunscreens. Even some metals were shown to have endocrine-disrupting properties. Many observations suggesting that endocrine disruptors do contribute to cancer, diabetes, obesity, the metabolic syndrome, and infertility are listed in this paper. An overview is presented of mechanisms contributing to endocrine disruption. Endocrine disruptors can act through classical nuclear receptors, but also through estrogen-related receptors, membrane-bound estrogen-receptors, and interaction with targets in the cytosol resulting in activation of the Src/Ras/Erk pathway or modulation of nitric oxide. In addition, changes in metabolism of endogenous hormones, cross-talk between genomic and nongenomic pathways, cross talk with estrogen receptors after binding on other receptors, interference with feedback regulation and neuroendocrine cells, changes in DNA methylation or histone modifications, and genomic instability by interference with the spindle figure can play a role. Also it was found that effects of receptor activation can differ in function of the ligand.

Immunologic Endocrine Disorders

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Michels, Aaron W.; Eisenbarth, George S.

2010-01-01

Autoimmunity affects multiple glands in the endocrine system. Animal models and human studies highlight the importance of alleles in HLA (human leukocyte antigen)-like molecules determining tissue specific targeting that with the loss of tolerance leads to organ specific autoimmunity. Disorders such as type 1A diabetes, Grave's disease, Hashimoto's thyroiditis, Addison's disease, and many others result from autoimmune mediated tissue destruction. Each of these disorders can be divided into stages beginning with genetic susceptibility, environmental triggers, active autoimmunity, and finally metabolic derangements with overt symptoms of disease. With an increased understanding of the immunogenetics and immunopathogenesis of endocrine autoimmune disorders, immunotherapies are becoming prevalent, especially in type 1A diabetes. Immunotherapies are being used more in multiple subspecialty fields to halt disease progression. While therapies for autoimmune disorders stop the progress of an immune response, immunomodulatory therapies for cancer and chronic infections can also provoke an unwanted immune response. As a result, there are now iatrogenic autoimmune disorders arising from the treatment of chronic viral infections and malignancies. PMID:20176260

In vitro and in vivo studies with [18F]fluorocholine on digestive tumoral cell lines and in an animal model of metastasized endocrine tumor

International Nuclear Information System (INIS)

Nejjari, Mimoun; Kryza, David; Poncet, Gilles; Roche, Colette; Perek, Nathalie; Chayvialle, Jean-Alain; Le Bars, Didier; Scoazec, Jean-Yves; Janier, Marc; Borson-Chazot, Francoise

2008-01-01

Purpose: The aim of this study was to investigate (a) in vitro the relationship between [ 18 F]fluorocholine ([ 18 F]FCH) uptake and cell growth in endocrine cell lines and (b) in vivo the uptake of [ 18 F]FCH by tumoral sites in an animal model of metastasized endocrine tumor. Methods: In vitro studies were conducted on three endocrine and two nonendocrine digestive tumoral cell lines. The proliferative ratio was estimated using the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay. The uptake of [ 18 F]FCH and that of [ 18 F]fluorodeoxyglucose ([ 18 F]FDG) were measured before and after cytotoxic therapy. [ 18 F]FCH biodistribution was studied in nude mice and in an endocrine xenografted mice model. Results: The [ 18 F]FCH uptake in tumoral cell lines was related to their proliferative capacities as measured by the MTT assay in basal conditions. After cytotoxic therapy, the IC 50 values calculated with the [ 18 F]FCH incorporation test were very close to those determined with the MTT assay. Biodistribution studies showed that [ 18 F]FCH was predominantly concentrated in the liver and kidney of nude mice. In the STC-1 xenografted animal model, the uptake of [ 18 F]FCH in the primary tumor was only 1.1%. On autoradiography and micro-positron emission tomography, there was no uptake of [ 18 F]FCH in liver metastases but there was a significant uptake of [ 18 F]FDG. Conclusions: In vitro studies suggested that the incorporation of [ 18 F]FCH in endocrine tumor cell lines was related to their growth capacities; however, in vivo studies conducted in an endocrine xenografted animal model showed an uptake of [ 18 F]FCH in hepatic metastases lower than that in normal liver cells. An influence of the microenvironment or a competition phenomenon for [ 18 F]FCH uptake between normal liver and endocrine tumor cells cannot be excluded

Endocrine disruptors and asthma-associated chemicals in consumer products.

Science.gov (United States)

Dodson, Robin E; Nishioka, Marcia; Standley, Laurel J; Perovich, Laura J; Brody, Julia Green; Rudel, Ruthann A

2012-07-01

Laboratory and human studies raise concerns about endocrine disruption and asthma resulting from exposure to chemicals in consumer products. Limited labeling or testing information is available to evaluate products as exposure sources. We analytically quantified endocrine disruptors and asthma-related chemicals in a range of cosmetics, personal care products, cleaners, sunscreens, and vinyl products. We also evaluated whether product labels provide information that can be used to select products without these chemicals. We selected 213 commercial products representing 50 product types. We tested 42 composited samples of high-market-share products, and we tested 43 alternative products identified using criteria expected to minimize target compounds. Analytes included parabens, phthalates, bisphenol A (BPA), triclosan, ethanolamines, alkylphenols, fragrances, glycol ethers, cyclosiloxanes, and ultraviolet (UV) filters. We detected 55 compounds, indicating a wide range of exposures from common products. Vinyl products contained > 10% bis(2-ethylhexyl) phthalate (DEHP) and could be an important source of DEHP in homes. In other products, the highest concentrations and numbers of detects were in the fragranced products (e.g., perfume, air fresheners, and dryer sheets) and in sunscreens. Some products that did not contain the well-known endocrine-disrupting phthalates contained other less-studied phthalates (dicyclohexyl phthalate, diisononyl phthalate, and di-n-propyl phthalate; also endocrine-disrupting compounds), suggesting a substitution. Many detected chemicals were not listed on product labels. Common products contain complex mixtures of EDCs and asthma-related compounds. Toxicological studies of these mixtures are needed to understand their biological activity. Regarding epidemiology, our findings raise concern about potential confounding from co-occurring chemicals and misclassification due to variability in product composition. Consumers should be able to avoid

Metabolic targets of endocrine disrupting chemicals assessed by cord blood transcriptome profiling

DEFF Research Database (Denmark)

Remy, Sylvie; Govarts, Eva; Wens, Britt

2016-01-01

Early life exposure to endocrine disrupting chemicals (EDCs) has been frequently associated with impaired perinatal growth, an important risk factor for later onset of metabolic disorders. We analyzed whether the cord blood transcriptome showed early indications of alterations in metabolic...

Pituitary autoantibodies in endocrine disorders

OpenAIRE

Bensing, Sophie

2005-01-01

Autoimmune endocrine disorders are characterised by the development of autoantibodies to specific autoantigens in the target organs. Lymphocytic hypophysitis (LyH) is a disease characterised by inflammation of the pituitary gland, often resulting in hypopituitarism. The aetiology of LyH is considered to be autoimmune. However, only a few pituitary autoantigens have so far been identified. Reliable autoantibody markers are requested in the diagnostic procedure of LyH to avoid...

SECONDARY (ENDOCRINE HYPERTENSION: LECTURE

Directory of Open Access Journals (Sweden)

M. Yu. Yukina

2016-01-01

Full Text Available Hypertension is a  very common disease with high morbidity and reduction in quality of life. Endocrine disorders are the most common cause of secondary hypertension affecting ~3% of the population. Primary aldosteronism can be the cause of endocrine hypertension more often than other endocrine disorders. Other less common causes of endocrine hypertension include Cushing syndrome, pheochromocytoma, thyroid disorders, and hyperparathyroidism. Endocrine hypertension is potentially curable if the underlying cause is identified and treated accordingly. Younger age at manifestation of resistance to multiple antihypertensive drugs, together with other clinical signs of an endocrine disorder, should raise the suspicion and prompt the appropriate evaluation.

Targeting tumour re-wiring by triple blockade of mTORC1, epidermal growth factor, and oestrogen receptor signalling pathways in endocrine-resistant breast cancer.

Science.gov (United States)

Ribas, Ricardo; Pancholi, Sunil; Rani, Aradhana; Schuster, Eugene; Guest, Stephanie K; Nikitorowicz-Buniak, Joanna; Simigdala, Nikiana; Thornhill, Allan; Avogadri-Connors, Francesca; Cutler, Richard E; Lalani, Alshad S; Dowsett, Mitch; Johnston, Stephen R; Martin, Lesley-Ann

2018-06-08

Endocrine therapies are the mainstay of treatment for oestrogen receptor (ER)-positive (ER + ) breast cancer (BC). However, resistance remains problematic largely due to enhanced cross-talk between ER and growth factor pathways, circumventing the need for steroid hormones. Previously, we reported the anti-proliferative effect of everolimus (RAD001-mTORC1 inhibitor) with endocrine therapy in resistance models; however, potential routes of escape from treatment via ERBB2/3 signalling were observed. We hypothesised that combined targeting of three cellular nodes (ER, ERBB, and mTORC1) may provide enhanced long-term clinical utility. A panel of ER + BC cell lines adapted to long-term oestrogen deprivation (LTED) and expressing ESR1 wt or ESR1 Y537S , modelling acquired resistance to an aromatase-inhibitor (AI), were treated in vitro with a combination of RAD001 and neratinib (pan-ERBB inhibitor) in the presence or absence of oestradiol (E2), tamoxifen (4-OHT), or fulvestrant (ICI182780). End points included proliferation, cell signalling, cell cycle, and effect on ER-mediated transactivation. An in-vivo model of AI resistance was treated with monotherapies and combinations to assess the efficacy in delaying tumour progression. RNA-seq analysis was performed to identify changes in global gene expression as a result of the indicated therapies. Here, we show RAD001 and neratinib (pan-ERBB inhibitor) caused a concentration-dependent decrease in proliferation, irrespective of the ESR1 mutation status. The combination of either agent with endocrine therapy further reduced proliferation but the maximum effect was observed with a triple combination of RAD001, neratinib, and endocrine therapy. In the absence of oestrogen, RAD001 caused a reduction in ER-mediated transcription in the majority of the cell lines, which associated with a decrease in recruitment of ER to an oestrogen-response element on the TFF1 promoter. Contrastingly, neratinib increased both ER

VAV3 mediates resistance to breast cancer endocrine therapy

NARCIS (Netherlands)

H. Aguilar (Helena); A. Urruticoechea (Ander); P. Halonen (Pasi); K. Kiyotani (Kazuma); T. Mushiroda (Taisei); X. Barril (Xavier); J. Serra-Musach (Jordi); A.B.M.M.K. Islam (Abul); L. Caizzi (Livia); L. Di Croce (Luciano); E. Nevedomskaya (Ekaterina); W. Zwart (Wilbert); J. Bostner (Josefine); E. Karlsson (Elin); G. Pérez Tenorio (Gizeh); T. Fornander (Tommy); D.C. Sgroi (Dennis); R. Garcia-Mata (Rafael); M.P.H.M. Jansen (Maurice); N. García (Nadia); N. Bonifaci (Núria); F. Climent (Fina); E. Soler (Eric); A. Rodríguez-Vida (Alejo); M. Gil (Miguel); J. Brunet (Joan); G. Martrat (Griselda); L. Gómez-Baldó (Laia); A.I. Extremera (Ana); J. Figueras; J. Balart (Josep); R. Clarke (Robert); K.L. Burnstein (Kerry); K.E. Carlson (Kathryn); J.A. Katzenellenbogen (John); M. Vizoso (Miguel); M. Esteller (Manel); A. Villanueva (Alberto); A.B. Rodríguez-Peña (Ana); X.R. Bustelo (Xosé); Y. Nakamura (Yusuke); H. Zembutsu (Hitoshi); O. Stål (Olle); R.L. Beijersbergen (Roderick); M.A. Pujana (Miguel)

2014-01-01

textabstractIntroduction: Endocrine therapies targeting cell proliferation and survival mediated by estrogen receptor α (ERα) are among the most effective systemic treatments for ERα-positive breast cancer. However, most tumors initially responsive to these therapies acquire resistance through

Upregulation of adhesion molecules on leukemia targets improves the efficacy of cytotoxic T cells transduced with chimeric anti-CD19 receptor.

Science.gov (United States)

Laurin, David; Marin, Virna; Biagi, Ettore; Pizzitola, Irene; Agostoni, Valentina; Gallot, Géraldine; Vié, Henri; Jacob, Marie Christine; Chaperot, Laurence; Aspord, Caroline; Plumas, Joël

2013-04-01

T lymphocytes engineered to express chimeric antigen receptors (CARs) interact directly with cell surface molecules, bypassing MHC antigen presentation dependence. We generated human anti-CD19ζ CAR cytotoxic T lymphocytes and cytokine-induced killer cells and studied their sensitivity to the expression of adhesion molecules for the killing of primary B-lineage acute lymphoblastic leukemia (B-ALL) targets. Despite a very low basal expression of surface adhesion molecules, B-ALL blasts were lysed by the anti-CD19ζ-CAR transduced effectors as expected. We next investigated the regulatory role of adhesion molecules during CAR-mediated cytolysis. The blocking of these accessory molecules strongly limited the chimeric effector's cytotoxicity. Thereafter, B-ALL cells surface adhesion molecule level expression was induced by IFN-γ or by the combined use of CD40L and IL-4 and the cells were submitted to anti-CD19ζ-CAR transduced effectors lysis. Upregulation of adhesion molecules expression by blasts potentiated their killing. The improved cytotoxicity observed was dependent on target surface expression of adhesion molecules, particularly CD54. Taken together, these results indicate that adhesion molecules, and principally CD54, are involved in the efficiency of recognition by effector chimeric ζ. These observations have potential implications for the design of immunotherapy treatment approaches for hematological malignancies and tumors based on the adoption of CAR effector cells.

Microchip screening platform for single cell assessment of NK cell cytotoxicity

Directory of Open Access Journals (Sweden)

Karolin eGuldevall

2016-04-01

Full Text Available Here we report a screening platform for assessment of the cytotoxic potential of individual natural killer (NK cells within larger populations. Human primary NK cells were distributed across a silicon-glass microchip containing 32 400 individual microwells loaded with target cells. Through fluorescence screening and automated image analysis the numbers of NK and live or dead target cells in each well could be assessed at different time points after initial mixing. Cytotoxicity was also studied by time-lapse live-cell imaging in microwells quantifying the killing potential of individual NK cells. Although most resting NK cells (≈75% were non-cytotoxic against the leukemia cell line K562, some NK cells were able to kill several (≥3 target cells within the 12 hours long experiment. In addition, the screening approach was adapted to increase the chance to find and evaluate serial killing NK cells. Even if the cytotoxic potential varied between donors it was evident that a small fraction of highly cytotoxic NK cells were responsible for a substantial portion of the killing. We demonstrate multiple assays where our platform can be used to enumerate and characterize cytotoxic cells, such as NK or T cells. This approach could find use in clinical applications, e.g. in the selection of donors for stem cell transplantation or generation of highly specific and cytotoxic cells for adoptive immunotherapy.

Microchip Screening Platform for Single Cell Assessment of NK Cell Cytotoxicity

Science.gov (United States)

Guldevall, Karolin; Brandt, Ludwig; Forslund, Elin; Olofsson, Karl; Frisk, Thomas W.; Olofsson, Per E.; Gustafsson, Karin; Manneberg, Otto; Vanherberghen, Bruno; Brismar, Hjalmar; Kärre, Klas; Uhlin, Michael; Önfelt, Björn

2016-01-01

Here, we report a screening platform for assessment of the cytotoxic potential of individual natural killer (NK) cells within larger populations. Human primary NK cells were distributed across a silicon–glass microchip containing 32,400 individual microwells loaded with target cells. Through fluorescence screening and automated image analysis, the numbers of NK and live or dead target cells in each well could be assessed at different time points after initial mixing. Cytotoxicity was also studied by time-lapse live-cell imaging in microwells quantifying the killing potential of individual NK cells. Although most resting NK cells (≈75%) were non-cytotoxic against the leukemia cell line K562, some NK cells were able to kill several (≥3) target cells within the 12-h long experiment. In addition, the screening approach was adapted to increase the chance to find and evaluate serial killing NK cells. Even if the cytotoxic potential varied between donors, it was evident that a small fraction of highly cytotoxic NK cells were responsible for a substantial portion of the killing. We demonstrate multiple assays where our platform can be used to enumerate and characterize cytotoxic cells, such as NK or T cells. This approach could find use in clinical applications, e.g., in the selection of donors for stem cell transplantation or generation of highly specific and cytotoxic cells for adoptive immunotherapy. PMID:27092139

Epicardial adipose tissue in endocrine and metabolic diseases.

Science.gov (United States)

Iacobellis, Gianluca

2014-05-01

Epicardial adipose tissue has recently emerged as new risk factor and active player in metabolic and cardiovascular diseases. Albeit its physiological and pathological roles are not completely understood, a body of evidence indicates that epicardial adipose tissue is a fat depot with peculiar and unique features. Epicardial fat is able to synthesize, produce, and secrete bioactive molecules which are then transported into the adjacent myocardium through vasocrine and/or paracrine pathways. Based on these evidences, epicardial adipose tissue can be considered an endocrine organ. Epicardial fat is also thought to provide direct heating to the myocardium and protect the heart during unfavorable hemodynamic conditions, such as ischemia or hypoxia. Epicardial fat has been suggested to play an independent role in the development and progression of obesity- and diabetes-related cardiac abnormalities. Clinically, the thickness of epicardial fat can be easily and accurately measured. Epicardial fat thickness can serve as marker of visceral adiposity and visceral fat changes during weight loss interventions and treatments with drugs targeting the fat. The potential of modulating the epicardial fat with targeted pharmacological agents can open new avenues in the pharmacotherapy of endocrine and metabolic diseases. This review article will provide Endocrine's reader with a focus on epicardial adipose tissue in endocrinology. Novel, established, but also speculative findings on epicardial fat will be discussed from the unexplored perspective of both clinical and basic Endocrinologist.

Next-generation sequencing for endocrine cancers: Recent advances and challenges.

Science.gov (United States)

Suresh, Padmanaban S; Venkatesh, Thejaswini; Tsutsumi, Rie; Shetty, Abhishek

2017-05-01

Contemporary molecular biology research tools have enriched numerous areas of biomedical research that address challenging diseases, including endocrine cancers (pituitary, thyroid, parathyroid, adrenal, testicular, ovarian, and neuroendocrine cancers). These tools have placed several intriguing clues before the scientific community. Endocrine cancers pose a major challenge in health care and research despite considerable attempts by researchers to understand their etiology. Microarray analyses have provided gene signatures from many cells, tissues, and organs that can differentiate healthy states from diseased ones, and even show patterns that correlate with stages of a disease. Microarray data can also elucidate the responses of endocrine tumors to therapeutic treatments. The rapid progress in next-generation sequencing methods has overcome many of the initial challenges of these technologies, and their advantages over microarray techniques have enabled them to emerge as valuable aids for clinical research applications (prognosis, identification of drug targets, etc.). A comprehensive review describing the recent advances in next-generation sequencing methods and their application in the evaluation of endocrine and endocrine-related cancers is lacking. The main purpose of this review is to illustrate the concepts that collectively constitute our current view of the possibilities offered by next-generation sequencing technological platforms, challenges to relevant applications, and perspectives on the future of clinical genetic testing of patients with endocrine tumors. We focus on recent discoveries in the use of next-generation sequencing methods for clinical diagnosis of endocrine tumors in patients and conclude with a discussion on persisting challenges and future objectives.

Endocrine resistance in breast cancer – an overview and update

Science.gov (United States)

Clarke, Robert; Tyson, John J.; Dixon, J. Michael

2015-01-01

Tumors that express detectable levels of the product of the ESR1 gene (estrogen receptor-α; ERα) represent the single largest molecular subtype of breast cancer. More women eventually die from ERα+ breast cancer than from either HER2+ disease (almost half of which also express ERα) and/or from triple negative breast cancer (ERα-negative, progesterone receptor-negative, and HER2-negative). Antiestrogens and aromatase inhibitors are largely indistinguishable from each other in their abilities to improve overall survival and almost 50% of ERα+ breast cancers will eventually fail one or more of these endocrine interventions. The precise reasons why these therapies fail in ERα+ breast cancer remain largely unknown. Pharmacogenetic explanations for Tamoxifen resistance are controversial. The role of ERα mutations in endocrine resistance remains unclear. Targeting the growth factors and oncogenes most strongly correlated with endocrine resistance has proven mostly disappointing in their abilities to improve overall survival substantially, particularly in the metastatic setting. Nonetheless, there are new concepts in endocrine resistance that integrate molecular signaling, cellular metabolism, and stress responses including endoplasmic reticulum stress and the unfolded protein response (UPR) that provide novel insights and suggest innovative therapeutic targets. Encouraging evidence that drug combinations with CDK4/CDK6 inhibitors can extend recurrence free survival may yet translate to improvements in overall survival. Whether the improvements seen with immunotherapy in other cancers can be achieved in breast cancer remains to be determined, particularly for ERα+ breast cancers. This review explores the basic mechanisms of resistance to endocrine therapies, concluding with some new insights from systems biology approaches further implicating autophagy and the UPR in detail, and a brief discussion of exciting new avenues and future prospects. PMID:26455641

Embryonic transcription factor SOX9 drives breast cancer endocrine resistance.

Science.gov (United States)

Jeselsohn, Rinath; Cornwell, MacIntosh; Pun, Matthew; Buchwalter, Gilles; Nguyen, Mai; Bango, Clyde; Huang, Ying; Kuang, Yanan; Paweletz, Cloud; Fu, Xiaoyong; Nardone, Agostina; De Angelis, Carmine; Detre, Simone; Dodson, Andrew; Mohammed, Hisham; Carroll, Jason S; Bowden, Michaela; Rao, Prakash; Long, Henry W; Li, Fugen; Dowsett, Mitchell; Schiff, Rachel; Brown, Myles

2017-05-30

The estrogen receptor (ER) drives the growth of most luminal breast cancers and is the primary target of endocrine therapy. Although ER blockade with drugs such as tamoxifen is very effective, a major clinical limitation is the development of endocrine resistance especially in the setting of metastatic disease. Preclinical and clinical observations suggest that even following the development of endocrine resistance, ER signaling continues to exert a pivotal role in tumor progression in the majority of cases. Through the analysis of the ER cistrome in tamoxifen-resistant breast cancer cells, we have uncovered a role for an RUNX2-ER complex that stimulates the transcription of a set of genes, including most notably the stem cell factor SOX9, that promote proliferation and a metastatic phenotype. We show that up-regulation of SOX9 is sufficient to cause relative endocrine resistance. The gain of SOX9 as an ER-regulated gene associated with tamoxifen resistance was validated in a unique set of clinical samples supporting the need for the development of improved ER antagonists.

Surgical strategies in endocrine tumors

NARCIS (Netherlands)

Schreinemakers, J.M.J.

2010-01-01

Endocrine surgery has become more custom-made throughout the years. Endocrine tumors can be sporadic or develop as part of familial syndromes. Several familial syndromes are known to cause endocrine tumors. The most common are multiple endocrine neoplasia (MEN) syndromes type 1, 2A and 2B. This

Endocrine myopathy: Case-based review

Directory of Open Access Journals (Sweden)

Babul Reddy Hanmayyagari

2016-01-01

Full Text Available Endocrine myopathy means muscle weakness in the presence of an abnormal endocrine state. Most of the endocrine disorders are associated with myopathy and it is usually reversible with correction of the underlying disturbance, though, there is an increasing knowledge of the metabolic effects of hormones, endocrine myopathy is a less recognized and often overlooked entity in clinical practice. Here, we describe this association in three of our patients, then, we discuss systematically about endocrine myopathy.

PSA-selective activation of cytotoxic human serine proteases within the tumor microenvironment as a therapeutic strategy to target prostate cancer.

Science.gov (United States)

Rogers, Oliver C; Anthony, Lizamma; Rosen, D Marc; Brennen, W Nathaniel; Denmeade, Samuel R

2018-04-27

Prostate cancer is the most diagnosed malignancy and the second leading cause of cancer-related death in American men. While localized therapy is highly curative, treatments for metastatic prostate cancer are largely palliative. Thus, new innovative therapies are needed to target metastatic tumors. Prostate-Specific Antigen (PSA) is a chymotrypsin-like protease with a unique substrate specificity that is secreted by both normal and malignant prostate epithelial cells. Previous studies demonstrated the presence of high levels (μM-mM) of enzymatically active PSA is present in the extracellular fluid of the prostate cancer microenvironment. Because of this, PSA is an attractive target for a protease activated pro-toxin therapeutic strategy. Because prostate cancers typically grow very slowly, a strategy employing a proliferation-independent cytotoxic payload is preferred. Recently, it was shown that the human protease Granzyme B (GZMB), at low micromolar concentrations in the extracellular space, can cleave an array of extracellular matrix (ECM) proteins thus perturbing cell growth, signaling, motility, and integrity. It is also well established that other human proteases such as trypsin can induce similar effects. Because both enzymes require N-terminal proteolytic activation, we propose to convert these proteins into PSA-activated cytotoxins. In this study, we examine the enzymatic and cell targeting parameters of these PSA-activated cytotoxic serine proteases. These pro-enzymes were activated robustly by PSA and induced ECM damage that led to the death of prostate cancer cells in vitro thus supporting the potential use of this strategy as means to target metastatic prostate cancers.

Overview of the Pathophysiological Implications of Organotins on the Endocrine System.

Science.gov (United States)

Marques, Vinicius Bermond; Faria, Rodrigo Alves; Dos Santos, Leonardo

2018-01-01

Organotins (OTs) are pollutants that are used widely by industry as disinfectants, pesticides, and most frequently as biocides in antifouling paints. This mini-review presents the main evidences from the literature about morphophysiological changes induced by OTs in the mammal endocrine system, focusing on the metabolism and reproductive control. Similar to other toxic compounds, the main effects with potential health risks to humans and experimental animals are not only related to dose and time of exposure but also to age, gender, and tissue/cell exposed. Regarding the underlying mechanisms, current literature indicates that OTs can directly damage endocrine glands, as well as interfere with neurohormonal control of endocrine function (i.e., in the hypothalamic-pituitary axis), altering hormone synthesis and/or bioavailability or activity of hormone receptors in the target cells. Importantly, OTs induces biochemical and morphological changes in gonads, abnormal steroidogenesis, both associated with reproductive dysfunctions such as irregular estrous cyclicity in female or spermatogenic disorders in male animals. Additionally, due to their role on endocrine systems predisposing to obesity, OTs are also included in the metabolism disrupting chemical hypothesis, either by central (e.g., accurate nucleus and lateral hypothalamus) or peripheral (e.g., adipose tissue) mechanisms. Thus, OTs should be indeed considered a major endocrine disruptor, being indispensable to understand the main toxic effects on the different tissues and its causative role for endocrine, metabolic, and reproductive dysfunctions observed.

Contribution of the Endocrine Perspective in the Evaluation of Endocrine Disrupting Chemical Effects

DEFF Research Database (Denmark)

Bourguignon, Jean-Pierre; Juul, Anders; Franssen, Delphine

2016-01-01

Debate makes science progress. In the field of endocrine disruption, endocrinology has brought up findings that substantiate a specific perspective on the definition of endocrine disrupting chemicals (EDCs), the role of the endocrine system and the endpoints of hormone and EDC actions among other...... issues. This paper aims at discussing the relevance of the endocrine perspective with regard to EDC effects on pubertal timing. Puberty involves particular sensitivity to environmental conditions. Reports about the advancing onset of puberty in several countries have led to the hypothesis...

Allogeneic major histocompatibility complex-mismatched equine bone marrow-derived mesenchymal stem cells are targeted for death by cytotoxic anti-major histocompatibility complex antibodies.

Science.gov (United States)

Berglund, A K; Schnabel, L V

2017-07-01

Allogeneic mesenchymal stem cells (MSCs) are a promising cell source for treating musculoskeletal injuries in horses. Controversy exists, however, over whether major histocompatibility complex (MHC)-mismatched MSCs are recognised by the recipient immune system and targeted for death by a cytotoxic antibody response. To determine if cytotoxic anti-MHC antibodies generated in vivo following MHC-mismatched MSC injections are capable of initiating complement-dependent cytotoxicity of MSCs. Experimental controlled study. Antisera previously collected at Days 0, 7, 14 and 21 post-injection from 4 horses injected with donor MHC-mismatched equine leucocyte antigen (ELA)-A2 haplotype MSCs and one control horse injected with donor MHC-matched ELA-A2 MSCs were utilised in this study. Antisera were incubated with ELA-A2 MSCs before adding complement in microcytotoxicity assays and cell death was analysed via eosin dye exclusion. ELA-A2 peripheral blood leucocytes (PBLs) were used in the assays as a positive control. Antisera from all 4 horses injected with MHC-mismatched MSCs contained antibodies that caused the death of ELA-A2 haplotype MSCs in the microcytotoxicity assays. In 2 of the 4 horses, antibodies were present as early as Day 7 post-injection. MSC death was consistently equivalent to that of ELA-A2 haplotype PBL death at all time points and antisera dilutions. Antisera from the control horse that was injected with MHC-matched MSCs did not contain cytotoxic ELA-A2 antibodies at any of the time points examined. This study examined MSC death in vitro only and utilized antisera from a small number of horses. The cytotoxic antibody response induced in recipient horses following injection with donor MHC-mismatched MSCs is capable of killing donor MSCs in vitro. These results suggest that the use of allogeneic MHC-mismatched MSCs must be cautioned against, not only for potential adverse events, but also for reduced therapeutic efficacy due to targeted MSC death. © 2016 The

Endocrine system: part 1.

Science.gov (United States)

Johnstone, Carolyn; Hendry, Charles; Farley, Alistair; McLafferty, Ella

2014-05-27

This article, which forms part of the life sciences series and is the first of two articles on the endocrine system, examines the structure and function of the organs of the endocrine system. It is important that nurses understand how the endocrine system works and its role in maintaining health. The role of the endocrine system and the types, actions and control of hormones are explored. The gross structure of the pituitary and thyroid glands are described along with relevant physiology. Several disorders of the thyroid gland are outlined. The second article examines growth hormone, the pancreas and adrenal glands.

Mitochondrial disease and endocrine dysfunction.

Science.gov (United States)

Chow, Jasmine; Rahman, Joyeeta; Achermann, John C; Dattani, Mehul T; Rahman, Shamima

2017-02-01

Mitochondria are critical organelles for endocrine health; steroid hormone biosynthesis occurs in these organelles and they provide energy in the form of ATP for hormone production and trafficking. Mitochondrial diseases are multisystem disorders that feature defective oxidative phosphorylation, and are characterized by enormous clinical, biochemical and genetic heterogeneity. To date, mitochondrial diseases have been found to result from >250 monogenic defects encoded across two genomes: the nuclear genome and the ancient circular mitochondrial genome located within mitochondria themselves. Endocrine dysfunction is often observed in genetic mitochondrial diseases and reflects decreased intracellular production or extracellular secretion of hormones. Diabetes mellitus is the most frequently described endocrine disturbance in patients with inherited mitochondrial diseases, but other endocrine manifestations in these patients can include growth hormone deficiency, hypogonadism, adrenal dysfunction, hypoparathyroidism and thyroid disease. Although mitochondrial endocrine dysfunction frequently occurs in the context of multisystem disease, some mitochondrial disorders are characterized by isolated endocrine involvement. Furthermore, additional monogenic mitochondrial endocrine diseases are anticipated to be revealed by the application of genome-wide next-generation sequencing approaches in the future. Understanding the mitochondrial basis of endocrine disturbance is key to developing innovative therapies for patients with mitochondrial diseases.

Metabolic and physiologic studies of nonimmune lymphoid cells cytotoxic for fibroblastic cells in vitro

International Nuclear Information System (INIS)

Mayhew, E.; Bennett, M.

1974-01-01

An in vitro reaction between mouse lymphoid cells and target fibroblastic cells in wells of microtest plates, which appears to simulate the in vivo rejection of hemopoietic allografts, has been analyzed for metabolic and physiologic requirements. Protein synthesis was required for only the first few hours of culture. Inhibition of RNA synthesis and alteration of cell surface charge with various agents were without obvious effects. Metabolic slowing at 4 0 C or deviation of the pH of the culture medium suppressed the reaction. Thymus cells, which are not cytotoxic in this system, significantly but not completely inhibited the cytotoxicity of lymph node cells. Antiserum directed against target cells specifically protected them from the cytotoxic lymphoid cells in the absence of complement. Precursors of cytotoxic lymphoid cells were radiosensitive, unlike the cytotoxic cells themselves. BALB/c anti-C57BL/6 spleen cell serum and 89 Sr both are able to prevent rejection of marrow allografts in vivo. Lymphoid cells incubated with this antiserum plus complement lost much of their cytotoxicity but were still effective at high ratios of aggressor to target cells. Lymphoid cells of mice treated with 89 Sr were effectively cytotoxic but lost practically all of their cytotoxicity after incubation with the antiserum plus complement. Thus, it appears that this reaction detects two different cytotoxic lymphoid cells, either of which can function in vitro. Both cell types may need to cooperate in vivo during marrow allograft rejections

Effect of radiotherapy on lymphocyte cytotoxicity in vitro

Energy Technology Data Exchange (ETDEWEB)

Wasserman, J; Melen, B [Central Microbiological Laboratory, Stockholm County Council (Sweden); Blomgren, H; Glas, U; Perlmann, P

1975-11-01

The cytotoxic functions of highly purified blood lymphocytes from patients with breast cancer were studied before and after radiotherapy. Addition of PHA or of rabbit antibodies to target cells (chicken erythrocytes) were chosen as two means of inducing lymphocyte cytotoxicity in vitro. The proportion of T and non-T lymphocytes was determined by means of E and EAC rosette tests. The antibody-induced cytotoxicity of lymphocytes decreased following radiotherapy while that mediated by PHA remained unchanged. There was some reduction in the percentage of EAC rosette-forming cells. These results, as well as earlier observations, suggest that the decrease in the peripheral blood of the proportion of lymphocytes with receptors for activated complement is responsible for changes in the antibody-mediated lymphocyte cytotoxicity.

PHA-induced cytotoxicity of human lymphocytes against adherent hela-cells

NARCIS (Netherlands)

Huges-Law, G.; de Gast, G. C.; The, T. Hauw

The conditions for a phytohaemagglutinin(PHA)-induced cytotoxicity test of human peripheral blood lymphocytes were investigated. [3H]thymidine prelabelled HeLa cells were used as target cells. Stimulation with 10 μl PHA/ml during 24 h gave the best measure of lymphocyte cytotoxic capacity.

Endocrine disruption: In silico interactions between phthalate plasticizers and corticosteroid binding globulin.

Science.gov (United States)

Sheikh, Ishfaq A; Beg, Mohd A

2017-12-01

Endocrine disruption is a phenomenon when a man-made or natural compound interferes with normal hormone function in human or animal body systems. Endocrine-disrupting compounds (EDCs) have assumed considerable importance as a result of industrial activity, mass production of synthetic chemicals and environmental pollution. Phthalate plasticizers are a group of chemicals used widely and diversely in industry especially in the plastic industry, and many of the phthalate compounds have endocrine-disrupting properties. Increasing evidence indicates that steroid nuclear receptors and steroid binding proteins are the main targets of endocrine disruption. Corticosteroid-binding globulin (CBG) is a steroid binding protein that binds and transports cortisol in the blood circulation and is a potential target for endocrine disruption. An imbalance of cortisol in the body leads to many health problems. Induced fit docking of nine important and environmentally relevant phthalate plasticizers (DMP, BBP, DBP, DIBP, DnHP, DEHP, DINP, DnOP, DIDP) showed interactions with 10-19 amino acid residues of CBG. Comparison of the interacting residues of CBG with phthalate ligands and cortisol showed an overlapping of the majority (53-82%) of residues for each phthalate. Five of nine phthalate compounds and cortisol shared a hydrogen bonding interaction with the Arg-252 residue of CBG. Long-chain phthalates, such as DEHP, DINP, DnOP and DIDP displayed a higher binding affinity and formed a number of interactions with CBG in comparison to short-chain phthalates. The similarity in structural binding characteristics of phthalate compounds and native ligand cortisol suggested potential competitive conflicts in CBG-cortisol binding function and possible disruption of cortisol and progesterone homeostasis. Copyright © 2017 John Wiley & Sons, Ltd.

EG-VEGF: a key endocrine factor in placental development.

Science.gov (United States)

Brouillet, Sophie; Hoffmann, Pascale; Feige, Jean-Jacques; Alfaidy, Nadia

2012-10-01

Endocrine gland-derived vascular endothelial growth factor (EG-VEGF), also named prokineticin 1, is the canonical member of the prokineticin family. Numerous reports suggest a direct involvement of this peptide in normal and pathological reproductive processes. Recent advances propose EG-VEGF as a key endocrine factor that controls many aspects of placental development and suggest its involvement in the development of preeclampsia (PE), the most threatening pathology of human pregnancy. This review describes the finely tuned action and regulation of EG-VEGF throughout human pregnancy, argues for its clinical relevance as a potential diagnostic marker of the onset of PE, and discusses future research directions for therapeutic targeting of EG-VEGF. Copyright © 2012 Elsevier Ltd. All rights reserved.

Genetics of Common Endocrine Disease: The Present and the Future.

Science.gov (United States)

Goodarzi, Mark O

2016-03-01

In honor of the 75th issue of the Journal of Clinical Endocrinology and Metabolism, the author was invited to present his perspectives on genetics in human endocrinology. This paper reviews what the field has achieved in the genetics of common endocrine disease, and offers predictions on where the field will move in the future and its impact on endocrine clinical practice. The October 2015 data release of the National Human Genome Research Institute-European Bioinformatics Institute (NHGRI-EBI) Catalog of Published Genome-wide Association Studies was queried regarding endocrinologic diseases and traits. PubMed searches were focused on genetic prediction of disease, genetic findings and drug targets, functional interrogation of genetic loci, use of genetics to subtype disease, missing heritability, systems genomics, and higher order chromatin structures as regulators of gene function. Nearly a quarter of genome wide association study findings concern endocrinologic diseases and traits. While these findings have not yet dramatically altered clinical care, genetics will have a major impact by providing the drug targets of tomorrow, facilitated by experimental and bioinformatic advances that will shorten the time from gene discovery to drug development. Use of genetic findings to subtype common endocrine disease will allow more precise prevention and treatment efforts. Future advances will allow us to move away from the common view of DNA as a string of letters, allowing exploration of higher order structure that likely explains much "missing heritability." The future will see a greater role of genetics at the bedside, with genetic epidemiologic discoveries leading not only to new treatments of endocrine disease, but also helping us prescribe the right drug to the right patients by allowing subclassification of common heterogeneous endocrine conditions. Future technological breakthroughs will reveal the heritable mysteries hidden in chromatin structure, leading to a

Overview of the Pathophysiological Implications of Organotins on the Endocrine System

Directory of Open Access Journals (Sweden)

Vinicius Bermond Marques

2018-03-01

Full Text Available Organotins (OTs are pollutants that are used widely by industry as disinfectants, pesticides, and most frequently as biocides in antifouling paints. This mini-review presents the main evidences from the literature about morphophysiological changes induced by OTs in the mammal endocrine system, focusing on the metabolism and reproductive control. Similar to other toxic compounds, the main effects with potential health risks to humans and experimental animals are not only related to dose and time of exposure but also to age, gender, and tissue/cell exposed. Regarding the underlying mechanisms, current literature indicates that OTs can directly damage endocrine glands, as well as interfere with neurohormonal control of endocrine function (i.e., in the hypothalamic–pituitary axis, altering hormone synthesis and/or bioavailability or activity of hormone receptors in the target cells. Importantly, OTs induces biochemical and morphological changes in gonads, abnormal steroidogenesis, both associated with reproductive dysfunctions such as irregular estrous cyclicity in female or spermatogenic disorders in male animals. Additionally, due to their role on endocrine systems predisposing to obesity, OTs are also included in the metabolism disrupting chemical hypothesis, either by central (e.g., accurate nucleus and lateral hypothalamus or peripheral (e.g., adipose tissue mechanisms. Thus, OTs should be indeed considered a major endocrine disruptor, being indispensable to understand the main toxic effects on the different tissues and its causative role for endocrine, metabolic, and reproductive dysfunctions observed.

Overview of the Pathophysiological Implications of Organotins on the Endocrine System

Science.gov (United States)

Marques, Vinicius Bermond; Faria, Rodrigo Alves; Dos Santos, Leonardo

2018-01-01

Organotins (OTs) are pollutants that are used widely by industry as disinfectants, pesticides, and most frequently as biocides in antifouling paints. This mini-review presents the main evidences from the literature about morphophysiological changes induced by OTs in the mammal endocrine system, focusing on the metabolism and reproductive control. Similar to other toxic compounds, the main effects with potential health risks to humans and experimental animals are not only related to dose and time of exposure but also to age, gender, and tissue/cell exposed. Regarding the underlying mechanisms, current literature indicates that OTs can directly damage endocrine glands, as well as interfere with neurohormonal control of endocrine function (i.e., in the hypothalamic–pituitary axis), altering hormone synthesis and/or bioavailability or activity of hormone receptors in the target cells. Importantly, OTs induces biochemical and morphological changes in gonads, abnormal steroidogenesis, both associated with reproductive dysfunctions such as irregular estrous cyclicity in female or spermatogenic disorders in male animals. Additionally, due to their role on endocrine systems predisposing to obesity, OTs are also included in the metabolism disrupting chemical hypothesis, either by central (e.g., accurate nucleus and lateral hypothalamus) or peripheral (e.g., adipose tissue) mechanisms. Thus, OTs should be indeed considered a major endocrine disruptor, being indispensable to understand the main toxic effects on the different tissues and its causative role for endocrine, metabolic, and reproductive dysfunctions observed. PMID:29615977

Receptor-targeted therapy of human experimental urinary bladder cancers with cytotoxic LH-RH analog AN-152 [AEZS- 108].

Science.gov (United States)

Szepeshazi, Karoly; Schally, Andrew V; Keller, Gunhild; Block, Norman L; Benten, Daniel; Halmos, Gabor; Szalontay, Luca; Vidaurre, Irving; Jaszberenyi, Miklos; Rick, Ferenc G

2012-07-01

Many bladder cancers progress to invasion with poor prognosis; new therapeutic methods are needed. We developed a cytotoxic LH-RH analog, AN-152 (AEZS-108) containing doxorubicin (DOX), for targeted therapy of cancers expressing LHRH receptors. We investigated the expression of LH-RH receptors in clinical bladder cancers and in HT-1376, J82, RT-4 and HT-1197 human bladder cancer lines. The effect of analog, AN-152, on growth of these tumor lines xenografted into nude mice was analyzed. Using molecular and functional assays, we also evaluated the differences between the effects of AN-152, and DOX alone. We demonstrated the expression of LH-RH receptors on 18 clinical bladder cancers by immunohistochemistry and on four human urinary bladder cancer lines HT-1376, J82, RT-4 and HT-1197 by Western blotting and binding assays. AN-152 powerfully inhibited growth of these bladder cancers in nude mice. AN-152 exerted greater effects than DOX and was less toxic. DOX activated strong multidrug resistance mechanisms in RT-4 and HT-1197 cancers, while AN-152 had no or less such effect. PCR assays and in vitro studies revealed differences in the action of AN-152 and DOX on the expression of genes involved in apoptosis. These results suggest that targeted cytotoxic LH-RH analog, AN-152 (AEZS- 108), should be examined for treatment of patients with LH-RH receptor positive invasive bladder cancers.

Insulin signaling in Caenorhabditis elegans regulates both endocrine-like and cell-autonomous outputs.

Science.gov (United States)

Iser, Wendy B; Gami, Minaxi S; Wolkow, Catherine A

2007-03-15

In C. elegans, insulin signaling affects development, lifespan and stress resistance. Several studies have shown that insulin signaling affects lifespan in an endocrine-like manner from different cells, while the major downstream target of insulin, the FOXO transcription factor encoded by daf-16, may act preferentially in intestinal cells to prolong lifespan. This discrepancy raised the possibility that insulin may have both endocrine and cell-intrinsic outputs. Here, we further investigated the types of cells capable of producing endocrine outputs of insulin and also identified a new cell-intrinsic insulin output. We found that insulin signaling within groups of neurons promoted wildtype lifespan, showing that the endocrine outputs of insulin were not restricted to specific cells. In contrast, DAF-16 appeared to have a greater effect on lifespan when expressed in a combination of tissues. These results suggest that insulin signaling may regulate DAF-16 through cell-intrinsic and endocrine pathways. We also found that an insulin-dependent response to fasting in intestinal cells was preferentially regulated by intestinal insulin signaling and was less responsive to insulin signaling from non-intestinal cells. Together, these results show that C. elegans insulin signaling has endocrine as well as tissue-specific outputs which could influence lifespan in a combinatorial fashion.

Human NK cells selective targeting of colon cancer-initiating cells: A role for natural cytotoxicity receptors and MHC class i molecules

KAUST Repository

Tallerico, Rossana

2013-01-23

Tumor cell populations have been recently proposed to be composed of two compartments: tumor-initiating cells characterized by a slow and asymmetrical growth, and the "differentiated" cancer cells with a fast and symmetrical growth. Cancer stem cells or cancer-initiating cells (CICs) play a crucial role in tumor recurrence. The resistance of CICs to drugs and irradiation often allows them to survive traditional therapy. NK cells are potent cytotoxic lymphocytes that can recognize tumor cells. In this study, we have analyzed the NK cell recognition of tumor target cells derived from the two cancer cell compartments of colon adenocarcinoma lesions. Our data demonstrate that freshly purified allogeneic NK cells can recognize and kill colorectal carcinoma- derived CICs whereas the non-CIC counterpart of the tumors (differentiated tumor cells), either autologous or allogeneic, is less susceptible to NK cells. This difference in the NK cell susceptibility correlates with higher expression on CICs of ligands for NKp30 and NKp44 in the natural cytotoxicity receptor (NCR) group of activating NK receptors. In contrast, CICs express lower levels of MHC class I, known to inhibit NK recognition, on their surface than do the "differentiated" tumor cells. These data have been validated by confocal microscopy where NCR ligands and MHC class I molecule membrane distribution have been analyzed. Moreover, NK cell receptor blockade in cytotoxicity assays demonstrates that NCRs play a major role in the recognition of CIC targets. This study strengthens the idea that biology-based therapy harnessing NK cells could be an attractive opportunity in solid tumors. Copyright © 2013 by The American Association of Immunologists, Inc. All rights reserved.

Human NK cells selective targeting of colon cancer-initiating cells: A role for natural cytotoxicity receptors and MHC class i molecules

KAUST Repository

Tallerico, Rossana; Todaro, Matilde; Di Franco, Simone; MacCalli, Cristina; Garofalo, Cinzia; Sottile, Rosa; Palmieri, Camillo; Tirinato, Luca; Pangigadde, Pradeepa N.; La Rocca, Rosanna; Mandelboim, Ofer; Stassi, Giorgio; Di Fabrizio, Enzo M.; Parmiani, Giorgio; Moretta, Alessandro; Dieli, Francesco; Kã rre, Klas; Carbone, Ennio

2013-01-01

Tumor cell populations have been recently proposed to be composed of two compartments: tumor-initiating cells characterized by a slow and asymmetrical growth, and the "differentiated" cancer cells with a fast and symmetrical growth. Cancer stem cells or cancer-initiating cells (CICs) play a crucial role in tumor recurrence. The resistance of CICs to drugs and irradiation often allows them to survive traditional therapy. NK cells are potent cytotoxic lymphocytes that can recognize tumor cells. In this study, we have analyzed the NK cell recognition of tumor target cells derived from the two cancer cell compartments of colon adenocarcinoma lesions. Our data demonstrate that freshly purified allogeneic NK cells can recognize and kill colorectal carcinoma- derived CICs whereas the non-CIC counterpart of the tumors (differentiated tumor cells), either autologous or allogeneic, is less susceptible to NK cells. This difference in the NK cell susceptibility correlates with higher expression on CICs of ligands for NKp30 and NKp44 in the natural cytotoxicity receptor (NCR) group of activating NK receptors. In contrast, CICs express lower levels of MHC class I, known to inhibit NK recognition, on their surface than do the "differentiated" tumor cells. These data have been validated by confocal microscopy where NCR ligands and MHC class I molecule membrane distribution have been analyzed. Moreover, NK cell receptor blockade in cytotoxicity assays demonstrates that NCRs play a major role in the recognition of CIC targets. This study strengthens the idea that biology-based therapy harnessing NK cells could be an attractive opportunity in solid tumors. Copyright © 2013 by The American Association of Immunologists, Inc. All rights reserved.

Sleep and the endocrine system.

Science.gov (United States)

Morgan, Dionne; Tsai, Sheila C

2015-07-01

In this article, the effect of sleep and sleep disorders on endocrine function and the influence of endocrine abnormalities on sleep are discussed. Sleep disruption and its associated endocrine consequences in the critically ill patient are also reviewed. Copyright © 2015 Elsevier Inc. All rights reserved.

[The immuno-endocrine system. A new endocrine theory: the problem of the packed transport].

Science.gov (United States)

Csaba, György

2011-05-15

Since the eighties of the last century hormone content was justified in immune cells (lymphocytes, granulocytes, monocytes, macrophages and mast cells), which produce, store and secrete these hormones. Although the amount of these materials in immune cells is relatively small, the mass of the producers (immune cells) is so large, that the phenomenon must be considered from endocrinological point of view, underlying the important differences between the "classical" and immuno-endocrine systems. Cells of the classic (built-in) endocrine system are mono-producers, while immune cells can synthesize many types of hormones (polyproducers). In addition, these cells can transport the whole hormone-producing machinery to the site of need, producing a local effect. This can be observed, for example, in the case of endorphin producing immune cells during inflammation and during early pregnancy around the chorionic villi. Hormone producing immune cells also have receptors for many hormones, so that they are poly-receivers. Via hormone producing and receiving capacity there is a bidirectional connection between the neuro-endocrine and immuno-endocrine systems. In addition, there is a network inside the immuno-endocrine system. The packed transport theory attempts to explain the mechanism and importance of the immuno-endocrine system.

DNA minor groove targeted alkylating agents based on bisbenzimidazole carriers: synthesis, cytotoxicity and sequence-specificity of DNA alkylation.

Science.gov (United States)

Smaill, J B; Fan, J Y; Denny, W A

1998-12-01

A series of bisbenzimidazoles bearing a variety of alkylating agents [ortho- and meta-mustards, imidazolebis(hydroxymethyl), imidazolebis(methylcarbamate) and pyrrolebis(hydroxymethyl)], appended by a propyl linker chain, were prepared and investigated for sequence-specificity of DNA alkylation and their cytotoxicity. Previous work has shown that, for para-aniline mustards, a propyl linker is optimal for cytotoxicity. Alkaline cleavage assays using a variety of different labelled oligonucleotides showed that the preferred sequences for adenine alkylation were 5'-TTTANANAANN and 5'-ATTANANAANN (underlined bases show the drug alkylation sites), with AT-rich sequences required on both the 5' and 3' sides of the alkylated adenine. The different aniline mustards showed little variation in alkylation pattern and similar efficiencies of DNA cross-link formation despite the changes in orientation and positioning of the mustard, suggesting that the propyl linker has some flexibility. The imidazole- and pyrrolebis(hydroxymethyl) alkylators showed no DNA strand cleavage following base treatment, indicating that no guanine or adenine N3 or N7 adducts were formed. Using the PCR-based polymerase stop assay, these alkylators showed PCR blocks at 5'-C*G sites (the * nucleotide indicates the blocked site), particularly at 5'-TAC*GA 5'-AGC*GGA, and 5'-AGCC*GGT sequences, caused by guanine 2-NH2 lesions on the opposite strand. Only the (more reactive) imidazolebis(methylcarbamoyl) and pyrrolebis(hydroxymethyl) alkylators demonstrated interstrand cross-linking ability. All of the bifunctional mustards showed large (approximately 100-fold) increases in cytotoxicity over chlorambucil, with the corresponding monofunctional mustards being 20- to 60-fold less cytotoxic. These results suggest that in the mustards the propyl linker provides sufficient flexibility to achieve delivery of the alkylator to favoured (adenine N3) sites in the minor groove, regardless of its exact geometry with

Endocrine emergencies in dogs and cats.

Science.gov (United States)

Koenig, Amie

2013-07-01

Success in treatment of endocrine emergencies is contingent on early recognition and treatment. Many endocrine diseases presenting emergently have nonspecific signs and symptoms. In addition, these endocrine crises are often precipitated by concurrent disease, further making early identification difficult. This article concentrates on recognition and emergency management of the most common endocrine crises in dogs and cats. Copyright © 2013 Elsevier Inc. All rights reserved.

The Transcription Factor Hobit Identifies Human Cytotoxic CD4(+) T Cells

NARCIS (Netherlands)

Oja, Anna E.; Vieira Braga, Felipe A.; Remmerswaal, Ester B. M.; Kragten, Natasja A. M.; Hertoghs, Kirsten M. L.; Zuo, Jianmin; Moss, Paul A.; van Lier, René A. W.; van Gisbergen, Klaas P. J. M.; Hombrink, Pleun

2017-01-01

The T cell lineage is commonly divided into CD4-expressing helper T cells that polarize immune responses through cytokine secretion and CD8-expressing cytotoxic T cells that eliminate infected target cells by virtue of the release of cytotoxic molecules. Recently, a population of CD4(+) T cells that

Endoplasmic reticulum targeting sequence enhances HBV-specific cytotoxic T lymphocytes induced by a CTL epitope-based DNA vaccine

International Nuclear Information System (INIS)

Xu Wei; Chu Yiwei; Zhang Ruihua; Xu Huanbin; Wang Ying; Xiong Sidong

2005-01-01

CD8 + T cells play a critical role in protective immunity against Hepatitis B Virus (HBV). Epitope-based DNA vaccines expressing HBV-dominant CTL epitopes can be used as candidate vaccines capable of inducing cytotoxic T Lymphocytes (CTL) responses. A plasmid DNA encoding a CTL epitope of HBV core antigen, HBc 18-27 , was constructed. Intramuscular immunization of C57BL/6 mice with this DNA vaccine resulted in successful induction of HBV-specific CTL responses. In order to promote transportation of the peptide into endoplasmic reticulum (ER) to bind to MHC class I molecules for optimal class I antigen presentation, an ER targeting sequence (ERTS) was fused with the C 18-27 encoding gene. ERTS fusion significantly enhanced specific CD8 + T cell responses in terms of CTL cytolysis as well as IFN-γ secretion. This enhancement was correlated with promoted epitope presentation on target cell surface. We report here an enhanced immunogenicity of an epitope-based DNA vaccine using an ER targeting signal sequence, which has significant implications for future design of therapeutic HBV vaccine

[The role of selenium in endocrine system diseases].

Science.gov (United States)

Balázs, Csaba; Rácz, Károly

2013-10-13

Oxygen derived free radicals, generated by a number of cellular reactions, include superoxide anion, hydrogen peroxide and hydroxyl radicals. They exert their cytotoxic effects mainly via peroxidation of the cell membrane resulting in the loss of membrane integrity. The essential trace element, selenium exerts complex effects on the endocrine systems, partly due to its antioxidant capacity. Well-characterized selenoproteins include iodothyronine deiodinases, glutathione peroxidases and thioredoxin reductases involved in thyroid hormone metabolism and protection from oxidative damage. The value of selenium supplementation in autoimmune thyroid disorders has been investigated and most studies confirmed the beneficial effect of selenium supplementation in Hashimoto's and Graves's diseases. Recently, selenium proved to be effective in mild inflammatory orbitopathy. There are a number of reports about the effect of selenium in diabetes mellitus, but the data are controversial as both insulin-like and diabetes-inducing effects of selenium have been described. Selenium was successfully used in both female and male infertility of autoimmune origin.

Testosterone conjugating activities in invertebrates: are they targets for endocrine disruptors?

Science.gov (United States)

Janer, G; Sternberg, R M; LeBlanc, G A; Porte, C

2005-02-10

processes can serve as targets for endocrine disrupting chemicals.

Reno-endocrinal disorders: A basic understanding of the molecular genetics

Directory of Open Access Journals (Sweden)

Sukhminder Jit Singh Bajwa

2012-01-01

Full Text Available The successful management of endocrine diseases is greatly helped by the complete understanding of the underlying pathology. The knowledge about the molecular genetics contributes immensely in the appropriate identification of the causative factors of the diseases and their subsequent management. The fields of nephrology and endocrinology are also interrelated to a large extent. Besides performing the secretory functions, the renal tissue also acts as target organ for many hormones such as antidiuretic hormone (ADH, atrial natriuretic peptides (ANP, and aldosterone. Understanding the molecular genetics of these hormones is important because the therapeutic interventions in many of these conditions is related to shared renal and endocrine functions, including the anemia of renal disease, chronic kidney disease, mineral bone disorders, and hypertension related to chronic kidney disease. Their understanding and in-depth knowledge is very essential in designing and formulating the therapeutic plans and innovating new management strategies. However, we still have to go a long way in order to completely understand the various confounding causative relationships between the pathology and disease of these reno-endocrinal manifestations.

[Arterial hypertension secondary to endocrine disorders].

Science.gov (United States)

Minder, Anna; Zulewski, Henryk

2015-06-01

Endocrine hypertension offers a potentially curative therapy if the underlying cause is identified and treated accordingly. In contrast to the high prevalence of arterial hypertension especially in the elderly, the classical endocrine causes remain a rare entity. Among patients with arterial hypertension the prevalence of Cushing's syndrome or pheochromocytoma is less than 1%. Primary hyperaldosteronism is more frequent with a reported prevalence of up to 9%. In order to avoid unnecessary, costly and potentially harmful evaluations and therapies due to the limited sensitivity and specificity of the critical endocrine tests it is mandatory to limit the exploration for endocrine causes to preselected patients with high pretest probability for an endocrine disorder. Younger age at manifestation of arterial hypertension or drug resistant hypertension together with other clinical signs of an endocrine disorder should raise the suspicion and prompt the appropriate evaluation.

[Dementia due to Endocrine Diseases].

Science.gov (United States)

Matsunaga, Akiko; Yoneda, Makoto

2016-04-01

Endocrine diseases affecting various organs, such as the pituitary gland, the thyroid, the parathyroid, the adrenal glands and the pancreas, occasionally cause dementia. While Alzheimer's disease (AD) is the main cause of dementia in the elderly and is untreatable, dementia caused by endocrine diseases is treatable in most cases. However, patients with dementia associated with endocrine diseases show memory impairments similar to those found in AD, often leading to misdiagnoses. Patients with endocrine diseases often present with other characteristic systemic and neuropsychiatric symptoms caused by altered hormone levels. Such neuropsychiatric symptoms include involuntary movements, depression, seizures, and muscle weakness. In these cases, abnormalities in imaging and blood or urine tests are helpful in making a differential diagnosis. As delays in the diagnosis and treatment of these patients may cause irreversible brain damage, it is imperative for clinicians to carefully exclude the possibility of latent endocrine diseases when treating patients with dementia.

Endocrine disorders in mitochondrial disease.

Science.gov (United States)

Schaefer, Andrew M; Walker, Mark; Turnbull, Douglass M; Taylor, Robert W

2013-10-15

Endocrine dysfunction in mitochondrial disease is commonplace, but predominantly restricted to disease of the endocrine pancreas resulting in diabetes mellitus. Other endocrine manifestations occur, but are relatively rare by comparison. In mitochondrial disease, neuromuscular symptoms often dominate the clinical phenotype, but it is of paramount importance to appreciate the multi-system nature of the disease, of which endocrine dysfunction may be a part. The numerous phenotypes attributable to pathogenic mutations in both the mitochondrial (mtDNA) and nuclear DNA creates a complex and heterogeneous catalogue of disease which can be difficult to navigate for novices and experts alike. In this article we provide an overview of the endocrine disorders associated with mitochondrial disease, the way in which the underlying mitochondrial disorder influences the clinical presentation, and how these factors influence subsequent management. Copyright © 2013 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

Intestinal endocrine cells in radiation enteritis

NARCIS (Netherlands)

Pietroletti, R.; Blaauwgeers, J. L.; Taat, C. W.; Simi, M.; Brummelkamp, W. H.; Becker, A. E.

1989-01-01

In this study, the intestinal endocrine cells were investigated in 13 surgical specimens affected by radiation enteritis. Endocrine cells were studied by means of Grimelius' silver staining and immunostaining for chromogranin, a general marker of endocrine cells. Positively stained cells were

Endocrine system and obesity.

Science.gov (United States)

Ashburn, Doyle D; Reed, Mary Jane

2010-10-01

Obesity is associated with significant alterations in endocrine function. An association with type 2 diabetes mellitus and dyslipidemia has been well documented. This article highlights the complexities of treating endocrine system disorders in obese patients. Copyright © 2010. Published by Elsevier Inc.

Chronology of endocrine differentiation and beta-cell neogenesis.

Science.gov (United States)

Miyatsuka, Takeshi

2016-01-01

Diabetes is a chronic and incurable disease, which results from absolute or relative insulin insufficiency. Therefore, pancreatic beta cells, which are the only type of cell that expresses insulin, is considered to be a potential target for the cure of diabetes. Although the findings regarding beta-cell neogenesis during pancreas development have been exploited to induce insulin-producing cells from non-beta cells, there are still many hurdles towards generating fully functional beta cells that can produce high levels of insulin and respond to physiological signals. To overcome these problems, a solid understanding of pancreas development and beta-cell formation is required, and several mouse models have been developed to reveal the unique features of each endocrine cell type at distinct developmental time points. Here I review our understanding of pancreas development and endocrine differentiation focusing on recent progresses in improving temporal cell labeling in vivo.

Endocrine active chemicals and endocrine disruption in Minnesota streams and lakes: implications for aquatic resources, 1994-2008

Science.gov (United States)

Lee, Kathy E.; Schoenfuss, Heiko L.; Barber, Larry B.; Writer, Jeff H.; Blazer, Vicki; Keisling, Richard L.; Ferrey, Mark L.

2010-01-01

The U.S. Geological Survey, in cooperation with St. Cloud State University, Minnesota Department of Health, Minnesota Pollution Control Agency, Minnesota Department of Natural Resources, Metropolitan Council Environmental Services, and the University of Minnesota, has conducted field monitoring studies and laboratory research to determine the presence of endocrine active chemicals and the incidence of endocrine disruption in Minnesota streams and lakes during 1994–2008. Endocrine active chemicals are chemicals that interfere with the natural regulation of endocrine systems, and may mimic or block the function of natural hormones in fish or other organisms. This interference commonly is referred to as endocrine disruption. Indicators of endocrine disruption in fish include vitellogenin (female egg yolk protein normally expressed in female fish) in male fish, oocytes present in male fish testes, reduced reproductive success, and changes in reproductive behavior.

Radiological imaging in endocrine hypertension

Directory of Open Access Journals (Sweden)

Chandan J Das

2011-01-01

Full Text Available While different generations of assays have played important role in elucidating causes of different endocrine disorders, radiological techniques are instrumental in localizing the pathology. This statement cannot be truer in any disease entity other than endocrine hypertension. This review makes an effort to highlight the role of different radiological modalities, especially ultrasonography, computed tomography and magnetic resonance imaging, in the evaluation of different causes of endocrine hypertension.

Spectrum of Endocrine Disorders in Central Ghana

Directory of Open Access Journals (Sweden)

Osei Sarfo-Kantanka

2017-01-01

Full Text Available Background. Although an increasing burden of endocrine disorders is recorded worldwide, the greatest increase is occurring in developing countries. However, the spectrum of these disorders is not well described in most developing countries. Objective. The objective of this study was to profile the frequency of endocrine disorders and their basic demographic characteristics in an endocrine outpatient clinic in Kumasi, central Ghana. Methods. A retrospective review was conducted on endocrine disorders seen over a five-year period between January 2011 and December 2015 at the outpatient endocrine clinic of Komfo Anokye Teaching Hospital. All medical records of patients seen at the endocrine clinic were reviewed by endocrinologists and all endocrinological diagnoses were classified according to ICD-10. Results. 3070 adults enrolled for care in the endocrine outpatient service between 2011 and 2015. This comprised 2056 females and 1014 males (female : male ratio of 2.0 : 1.0 with an overall median age of 54 (IQR, 41–64 years. The commonest primary endocrine disorders seen were diabetes, thyroid, and adrenal disorders at frequencies of 79.1%, 13.1%, and 2.2%, respectively. Conclusions. Type 2 diabetes and thyroid disorders represent by far the two commonest disorders seen at the endocrine clinic. The increased frequency and wide spectrum of endocrine disorders suggest the need for well-trained endocrinologists to improve the health of the population.

Efficiency of immunotoxin cytotoxicity is modulated by the intracellular itinerary.

Directory of Open Access Journals (Sweden)

Lori L Tortorella

Full Text Available Pseudomonas exotoxin-based immunotoxins, including LMB-2 (antiTac(F(v-PE38, are proposed to traffic to the trans-Golgi network (TGN and move by a retrograde pathway to the endoplasmic reticulum, where they undergo translocation to the cytoplasm, a step that is essential for cytotoxicity. The retrograde transport pathways used by LMB-2 are not completely understood, so it is unclear if transit through specific organelles is critical for maximal cytotoxic activity. In this study, we used Chinese hamster ovary (CHO cell lines that express chimeric constructs of CD25, the Tac antigen, attached to the cytoplasmic domain of the TGN-targeted transmembrane proteins, TGN38 and furin. These chimeras are both targeted to the TGN, but the itineraries they follow are quite different. LMB-2 was incubated with the two cell lines, and the efficiency of cell killing was determined using cell viability and cytotoxicity assays. LMB-2 that is targeted through the endocytic recycling compartment to the TGN via Tac-TGN38 kills the cells more efficiently than immunotoxins delivered through the late endosomes by Tac-furin. Although the processing to the 37 kDa active fragment was more efficient in Tac-furin cells than in Tac-TGN38 cells, this was not associated with enhanced cytotoxicity - presumably because the toxin was also degraded more rapidly in these cells. These data indicate that trafficking through specific organelles is an important factor modulating toxicity by LMB-2.

Towards an internationally harmonized test method for reproductive and developmental effects of endocrine disrupters in marine copepods

DEFF Research Database (Denmark)

Kusk, Kresten Ole; Wollenberger, Leah

2007-01-01

with marine copepods (Acartia tonsa, Nitocra spinipes, Tisbe battagliai, and Amphiascus tenuiremis). The present paper gives an overview on the endocrine system of crustaceans with special emphasis on development and reproduction, which are targets for endocrine disruption, and reviews available methods......New and updated methods to detect and characterize endocrine disrupting chemicals (EDCs) are urgently needed for the purpose of environmental risk assessment since these substances are often not detected using existing chronic toxicity tests. Numerous reports on the effects of EDCs on crustacean...... development and reproduction have been published and the development of life-cycle tests with crustaceans has been prioritized within the OECD work program for endocrine disrupter testing and assessment. As a result, Sweden, and Denmark initiated a proposal for development of a full life-cycle test...

The endoplasmic reticulum is a target organelle for trivalent dimethylarsinic acid (DMA{sup III})-induced cytotoxicity

Energy Technology Data Exchange (ETDEWEB)

Naranmandura, Hua, E-mail: narenman@zju.edu.cn [Department of Pharmacology, Toxicology, and Biochemical Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058 (China); Xu, Shi [Department of Pharmacology, Toxicology, and Biochemical Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058 (China); Koike, Shota [Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675 (Japan); Pan, Li Qiang [Department of Pharmacology, Toxicology, and Biochemical Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058 (China); Chen, Bin [Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030 (China); Wang, Yan Wei; Rehman, Kanwal; Wu, Bin [Department of Pharmacology, Toxicology, and Biochemical Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058 (China); Chen, Zhe [Zhejiang Hospital of Traditional Chinese Medicine, Zhejiang Chinese Medical University, Hangzhou (China); Suzuki, Noriyuki, E-mail: n-suzuki@p.chiba-u.ac.jp [Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675 (Japan)

2012-05-01

The purpose of present study was to characterize the endoplasmic reticulum stress and generation of ROS in rat liver RLC-16 cells by exposing to trivalent dimethylarsinous acid (DMA{sup III}) and compared with that of trivalent arsenite (iAs{sup III}) and monomethylarsonous acid (MMA{sup III}). Protein kinase-like endoplasmic reticulum kinase (PERK) phosphorylation was significantly induced in cells exposed to DMA{sup III}, while there was no change in phosphorylated PERK (P-PERK) detected in cells after exposure to iAs{sup III} or MMA{sup III}. The generation of reactive oxygen species (ROS) after DMA{sup III} exposure was found to take place specifically in the endoplasmic reticulum (ER), while previous reports showed that ROS was generated in mitochondria following exposure to MMA{sup III}. Meanwhile, cycloheximide (CHX) which is an inhibitor of protein biosynthesis strongly inhibited the DMA{sup III}-induced intracellular ROS generation in the ER and the phosphorylation of PERK, suggesting the induction of ER stress probably occurs through the inhibition of the protein folding process. Activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP) mRNA were induced by all three arsenic species, however, evidence suggested that they might be induced by different pathways in the case of iAs{sup III} and MMA{sup III}. In addition, ER resident molecular chaperone glucose-regulated protein78 (GRP78) was not affected by trivalent arsenicals, while it was induced in positive control only at high concentration (Thapsigargin;Tg), suggesting the GRP78 is less sensitive to low levels of ER stress. In summary, our findings demonstrate that the endoplasmic reticulum is a target organelle for DMA{sup III}-induced cytotoxicity. Highlights: ►ER is a target organelle for trivalent DMA{sup III}-induced cytotoxicity. ►Generation of ROS in ER can be induced specially by trivalent DMA{sup III}. ►ER-stress and generation of ROS are caused by the increase in

Mechanistic evaluation of endocrine disrupting chemicals

DEFF Research Database (Denmark)

Taxvig, Camilla

BACKGROUND: This PhD project is part of the research area concerning effects of endocrine disrupters at the National Food Institute at DTU in Denmark. Endocrine disrupting chemicals (EDCs) have proved to be important for improper development of the male reproductive organs and subsequent for the ...... metabolising system using liver S9 mixtures or hepatic rat microsomes could be a convenient method for the incorporation of metabolic aspects into in vitro testing for endocrine disrupting effects.......BACKGROUND: This PhD project is part of the research area concerning effects of endocrine disrupters at the National Food Institute at DTU in Denmark. Endocrine disrupting chemicals (EDCs) have proved to be important for improper development of the male reproductive organs and subsequent......, to be able to detect effects and predict mixture effects. In addition, a new hypothesis have emerge concerning a potential role of exposure to endocrine disrupting chemicals, and the development of obesity and obesity related diseases. AIM: This PhD project aimed to gain more information regarding...

What Is Men's Endocrine Health?

Science.gov (United States)

... Search form Search What is Men's Endocrine Health? Men's endocrine health incorporates physical activity and sound nutrition to maintain a strong body; however, a major emphasis includes male sexuality ...

Cystatin F as a regulator of immune cell cytotoxicity.

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Kos, Janko; Nanut, Milica Perišić; Prunk, Mateja; Sabotič, Jerica; Dautović, Esmeralda; Jewett, Anahid

2018-05-10

Cysteine cathepsins are lysosomal peptidases involved in the regulation of innate and adaptive immune responses. Among the diverse processes, regulation of granule-dependent cytotoxicity of cytotoxic T-lymphocytes (CTLs) and natural killer (NK) cells during cancer progression has recently gained significant attention. The function of cysteine cathepsins is regulated by endogenous cysteine protease inhibitors-cystatins. Whereas other cystatins are generally cytosolic or extracellular proteins, cystatin F is present in endosomes and lysosomes and is thus able to regulate the activity of its target directly. It is delivered to endosomal/lysosomal vesicles as an inactive, disulphide-linked dimer. Proteolytic cleavage of its N-terminal part leads to the monomer, the only form that is a potent inhibitor of cathepsins C, H and L, involved in the activation of granzymes and perforin. In NK cells and CTLs the levels of active cathepsin C and of granzyme B are dependent on the concentration of monomeric, active cystatin F. In tumour microenvironment, inactive dimeric cystatin F can be secreted from tumour cells or immune cells and further taken up by the cytotoxic cells. Subsequent monomerization and inhibition of cysteine cathepsins within the endosomal/lysosomal vesicles impairs granzyme and perforin activation, and provokes cell anergy. Further, the glycosylation pattern has been shown to be important in controlling secretion of cystatin F from target cells, as well as internalization by cytotoxic cells and trafficking to endosomal/lysosomal vesicles. Cystatin F is therefore an important mediator used by bystander cells to reduce NK and T-cell cytotoxicity.

Intestinal endocrine cells in radiation enteritis

International Nuclear Information System (INIS)

Pietroletti, R.; Blaauwgeers, J.L.; Taat, C.W.; Simi, M.; Brummelkamp, W.H.; Becker, A.E.

1989-01-01

In this study, the intestinal endocrine cells were investigated in 13 surgical specimens affected by radiation enteritis. Endocrine cells were studied by means of Grimelius' silver staining and immunostaining for chromogranin, a general marker of endocrine cells. Positively stained cells were quantified by counting their number per unit length of muscularis mucosa. Results in radiation enteritis were compared with matched control specimens by using Student's t test. Chromogranin immunostaining showed a statistically significant increase of endocrine cells in radiation enteritis specimens compared with controls both in small and large intestine (ileum, 67.5 +/- 23.5 cells per unit length of muscularis mucosa in radiation enteritis versus 17.0 +/- 6.1 in controls; colon, 40.9 +/- 13.7 cells per unit length of muscularis mucosa in radiation enteritis versus 9.5 +/- 4.1 in controls--p less than 0.005 in both instances). Increase of endocrine cells was demonstrated also by Grimelius' staining; however, without reaching statistical significance. It is not clear whether or not the increase of endocrine cells in radiation enteritis reported in this study is caused by a hyperplastic response or by a sparing phenomenon. We should consider that increased endocrine cells, when abnormally secreting their products, may be involved in some of the clinical features of radiation enteropathy. In addition, as intestinal endocrine cells produce trophic substances to the intestine, their increase could be responsible for the raised risk of developing carcinoma of the intestine in long standing radiation enteritis

Endocrine pathology: past, present and future.

Science.gov (United States)

Asa, Sylvia L; Mete, Ozgur

2018-01-01

Endocrine pathology is the subspecialty of diagnostic pathology which deals with the diagnosis and characterisation of neoplastic and non-neoplastic diseases of the endocrine system. This relatively young subspecialty was initially focused mainly on thyroid and parathyroid pathology, with some participants also involved in studies of the pituitary, the endocrine pancreas, and the adrenal glands. However, the endocrine system involves much more than these traditional endocrine organs and the discipline has grown to encompass lesions of the dispersed neuroendocrine cells, including neuroendocrine tumours (NETs) of the lungs, gastrointestinal tract, thymus, breast and prostate, as well as paraganglia throughout the body, not just in the adrenals. Indeed, the production of hormones is the hallmark of the endocrine system, and some aspects of gynecological/testicular, bone and liver pathology also fall into the realm of this specialty. Many of the lesions that are the focus of this discipline are increasing in incidence and their pathology is becoming more complex with increased understanding of molecular pathology and a high incidence of familial disease. The future of endocrine pathology will demand a depth of understanding of structure, function, prognosis and prediction as pathologists play a key role in the multidisciplinary care team of patients with endocrine diseases. It is anticipated that new technologies will allow increased subspecialisation in pathology and growth of this important area of expertise. Copyright © 2017 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.

Skin Manifestations of Endocrine Diseases.

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Demirkesen, Cuyan

2015-01-01

Endocrine diseases may result in changes in cutaneous function and morphology, which cause various skin manifestations, including nonspecific or pathognomonic signs. Some of these manifestations are already known dermatologic diseases with only increased frequency in this patient group. As a result the skin may the play role of a screen displaying endocrine disorders, either due to hormone excess or deficiency. Awareness of the skin manifestations may permit prompt and adequate approach to the patients, and therefore facilitate the early diagnosis of the endocrine disease and even be life saving. Some of these manifestations may be recognized clinically, but sometimes they need to be confirmed histopathologically. In this article, many endocrine diseases and their associated skin lesions will be reviewed briefly.

Endocrine regulation of the reproduction in crustaceans: Identification of potential targets for toxicants and environmental contaminants

Czech Academy of Sciences Publication Activity Database

Mazurová, E.; Hilscherová, Klára; Triebskorn, R.; Kohler, H.R.; Maršálek, Blahoslav; Bláha, Luděk

2008-01-01

Roč. 63, č. 2 (2008), s. 139-150 ISSN 0006-3088 Institutional research plan: CEZ:AV0Z60050516 Keywords : crustaceans * reproduction * endocrine disruption Subject RIV: EF - Botanics Impact factor: 0.406, year: 2008

Analyzing endocrine system conservation and evolution.

Science.gov (United States)

Bonett, Ronald M

2016-08-01

Analyzing variation in rates of evolution can provide important insights into the factors that constrain trait evolution, as well as those that promote diversification. Metazoan endocrine systems exhibit apparent variation in evolutionary rates of their constituent components at multiple levels, yet relatively few studies have quantified these patterns and analyzed them in a phylogenetic context. This may be in part due to historical and current data limitations for many endocrine components and taxonomic groups. However, recent technological advancements such as high-throughput sequencing provide the opportunity to collect large-scale comparative data sets for even non-model species. Such ventures will produce a fertile data landscape for evolutionary analyses of nucleic acid and amino acid based endocrine components. Here I summarize evolutionary rate analyses that can be applied to categorical and continuous endocrine traits, and also those for nucleic acid and protein-based components. I emphasize analyses that could be used to test whether other variables (e.g., ecology, ontogenetic timing of expression, etc.) are related to patterns of rate variation and endocrine component diversification. The application of phylogenetic-based rate analyses to comparative endocrine data will greatly enhance our understanding of the factors that have shaped endocrine system evolution. Copyright © 2016 Elsevier Inc. All rights reserved.

Consensus models to predict endocrine disruption for all ...

Science.gov (United States)

Humans are potentially exposed to tens of thousands of man-made chemicals in the environment. It is well known that some environmental chemicals mimic natural hormones and thus have the potential to be endocrine disruptors. Most of these environmental chemicals have never been tested for their ability to disrupt the endocrine system, in particular, their ability to interact with the estrogen receptor. EPA needs tools to prioritize thousands of chemicals, for instance in the Endocrine Disruptor Screening Program (EDSP). Collaborative Estrogen Receptor Activity Prediction Project (CERAPP) was intended to be a demonstration of the use of predictive computational models on HTS data including ToxCast and Tox21 assays to prioritize a large chemical universe of 32464 unique structures for one specific molecular target – the estrogen receptor. CERAPP combined multiple computational models for prediction of estrogen receptor activity, and used the predicted results to build a unique consensus model. Models were developed in collaboration between 17 groups in the U.S. and Europe and applied to predict the common set of chemicals. Structure-based techniques such as docking and several QSAR modeling approaches were employed, mostly using a common training set of 1677 compounds provided by U.S. EPA, to build a total of 42 classification models and 8 regression models for binding, agonist and antagonist activity. All predictions were evaluated on ToxCast data and on an exte

Celiac disease and endocrine autoimmunity.

Science.gov (United States)

Kahaly, George J; Schuppan, Detlef

2015-01-01

Celiac disease (CD) is a small-intestinal inflammatory disease that is triggered by the ingestion of the storage proteins (gluten) of wheat, barley and rye. Endocrine autoimmunity is prevalent in patients with CD and their relatives. The genes that predispose to endocrine autoimmune diseases, e.g. type 1 diabetes, autoimmune thyroid diseases, and Addison's disease, i.e. DR3-DQ2 and DR4-DQ8, are also the major genetic determinants of CD, which is the best understood HLA-linked disease. Thus, up to 30% of first-degree relatives both of patients with CD and/or endocrine autoimmunity are affected by the other disease. In CD, certain gluten proteins bind with high affinity to HLA-DQ2 or -DQ8 in the small-intestinal mucosa, to activate gluten-specific T cells which are instrumental in the destruction of the resorptive villi. Here, the autoantigen tissue transglutaminase increases the T cell response by generating deamidated gluten peptides that bind more strongly to DQ2 or DQ8. Classical symptoms such as diarrhea and consequences of malabsorption like anemia and osteoporosis are often absent in patients with (screening-detected) CD, but this absence does not significantly affect these patients' incidence of endocrine autoimmunity. Moreover, once autoimmunity is established, a gluten-free diet is not able to induce remission. However, ongoing studies attempt to address how far a gluten-free diet may prevent or retard the development of CD and endocrine autoimmunity in children at risk. The close relationship between CD and endocrine autoimmunity warrants a broader immune genetic and endocrine screening of CD patients and their relatives. © 2015 S. Karger AG, Basel.

Construction and application of a bovine immune-endocrine cDNA microarray.

Science.gov (United States)

Tao, Wenjing; Mallard, Bonnie; Karrow, Niel; Bridle, Byram

2004-09-01

A variety of commercial DNA arrays specific for humans and rodents are widely available; however, microarrays containing well-characterized genes to study pathway-specific gene expression are not as accessible for domestic animals, such as cattle, sheep and pigs. Therefore, a small-scale application-targeted bovine immune-endocrine cDNA array was developed to evaluate genetic pathways involved in the immune-endocrine axis of cattle during periods of altered homeostasis provoked by physiological or environmental stressors, such as infection, vaccination or disease. For this purpose, 167 cDNA sequences corresponding to immune, endocrine and inflammatory response genes were collected and categorized. Positive controls included 5 housekeeping genes (glyceraldehydes-3-phosphate dehydrogenase, hypoxanthine phosphoribosyltransferase, ribosomal protein L19, beta-actin, beta2-microglobulin) and bovine genomic DNA. Negative controls were a bacterial gene (Rhodococcus equi 17-kDa virulence-associated protein) and a partial sequence of the plasmid pACYC177. In addition, RNA extracted from un-stimulated, as well as superantigen (Staphylococcus aureus enterotoxin-A, S. aureus Cowan Pansorbin Cells) and mitogen-stimulated (LPS, ConA) bovine blood leukocytes was mixed, reverse transcribed and PCR amplified using gene-specific primers. The endocrine-associated genes were amplified from cDNA derived from un-stimulated bovine hypothalamus, pituitary, adrenal and thyroid gland tissues. The array was constructed in 4 repeating grids of 180 duplicated spots by coupling the PCR amplified 213-630 bp gene fragments onto poly-l-lysine coated glass slides. The bovine immune-endocrine arrays were standardized and preliminary gene expression profiles generated using Cy3 and Cy5 labelled cDNA from un-stimulated and ConA (5 microg/ml) stimulated PBMC of 4 healthy Holstein cows (2-4 replicate arrays/cow) in a time course study. Mononuclear cell-derived cytokine and chemokine (IL-2, IL-1alpha

A case report of mixed acinar-endocrine carcinoma of the pancreas treated with S-1 chemotherapy: Does it work or induce endocrine differentiation?

Science.gov (United States)

Yokode, Masataka; Itai, Ryosuke; Yamashita, Yukimasa; Zen, Yoh

2017-11-01

Acinar cell carcinomas (ACCs) and mixed acinar-endocrine carcinomas (MAECs) of the pancreas are rare, accounting for only 1% of pancreatic tumors. Although both typically present at an advanced stage, chemotherapeutic regimes have not yet been standardized. A 65-year-old man presented with a large mass in the pancreatic tail with multiple liver metastases. He was initially treated with gemcitabine for suspected ductal carcinoma of the pancreas, but no response was observed. S-1, administered as second-line chemotherapy, showed an approximately 38% reduction in the size of the primary tumor and metastatic deposits with therapeutic effects being maintained for 12 months. When the tumor progressed again, he underwent a percutaneous liver biopsy, which led to the diagnosis of MAEC. Combination therapy with cisplatin and etoposide targeting the endocrine component was administered, and this was based on the endocrine component potentially being less sensitive to S-1 than the ACC element. However, therapy was stopped due to the development of neutropenia, and the patient is currently receiving best supportive care. Given the previous studies suggested that S-1 is more effective for ACCs than gemcitabine, MAECs may also respond to S-1 chemotherapy, similar to ACCs. Another potential interpretation is that S-1 was effective when the condition was ACC, and eventually showed decreased effectiveness when the condition shifted to MAEC. Future studies are needed to conclude whether S-1 chemotherapy truly works against MAECs or induces endocrine differentiation in ACCs as a part of the drug-resistance process.

A flow-cytometric NK-cytotoxicity assay adapted for use in rat repeated dose toxicity studies

International Nuclear Information System (INIS)

Marcusson-Staahl, Maritha; Cederbrant, Karin

2003-01-01

A recent regulatory document for immunotoxicity testing of new pharmaceutical drugs includes cytotoxic natural killer (NK)-cell function as a required parameter in repeated dose toxicity studies. The classical 51 Cr-release assay is the conventional test for cytotoxicity testing but several drawbacks with this assay has increased the demand for new reliable test systems. Here, we describe the optimisation of a flow-cytometric cytotoxicity assay especially adapted for regulatory rat studies in drug development. The test principle is based on target cell labelling with 5-(6)-carboxy-fluorescein succinimidyl ester (CFSE) and subsequent DNA-labelling with propidium iodide (PI) for identification of target cells with compromised cell membranes. The results are expressed as percentage of dead targets on a cell-to-cell basis. The final format of the assay includes 0.5 ml peripheral blood, 1.25x10 5 effector cells per sample, and collection of 500 target events by flow-cytometry. When NKR-P1+ cells were removed from the effector cell population by magnetic depletion the relative proportion decreased from 6 to 0.08%. The corresponding cytotoxic activity decreased from 68 to 8%. Also, the cytotoxic activity showed a significant and positive correlation with the proportion of NK-cells present in the effector cell suspension. Thus, the cytotoxicity measured is almost exclusively exerted by NK-cells. The current flow-cytometric test benefits from using peripheral blood as a source for effector cells since it will not conflict with the use of spleen for histopathological investigations in repeated dose toxicity studies. Additionally, since only a minimal number of effector cells are required per sample repeated testing of the same animal is enabled

Recent advances in nuclear medicine in endocrine oncology.

Science.gov (United States)

Luster, Markus; Pfestroff, Andreas; Verburg, Frederik A

2017-01-01

The purpose is to review recent advances concerning the role of nuclear medicine in endocrine oncology. For I therapy of thyroid cancer a thyrotropin (TSH) more than 30 mU/l has for many years been deemed a condition sine qua non. However, new data show that patients with lower TSH levels at the time of ablation have the same rate of successful ablation as those with TSH more than 30 mU/l.I-124 combined integrated positron emission tomography and computed X-ray tomography was shown to be highly accurate in predicting findings on posttherapy radioiodine scanning and was shown to have a high prognostic power.In neuroendocrine tumors, long-term complication rates of peptide receptor radionuclide therapy were reported. Furthermore first preclinical and clinical results of peptide receptor radionuclide therapy with somatostatin receptor antagonists were published.In nuclear medicine, prostate-specific membrane antigen (PSMA)-targeted radionuclide imaging and therapy is of interest. PSMA was shown to also be expressed in neoplasms of the thyroid, the adrenal glands and neuroendocrine tumors. Further individualization of thyroid cancer patient care by means of I-124-positron emission tomography and computed X-ray tomography-based selection of the therapeutic strategy is possible. I therapy might not require as intensive TSH stimulation as thought previously. For endocrine-related malignancies PSMA targeting deserves further investigation.

Preparation of Conjugates of Cytotoxic Lupane Triterpenes with Biotin.

Science.gov (United States)

Soural, Miroslav; Hodon, Jiri; Dickinson, Niall J; Sidova, Veronika; Gurska, Sona; Dzubak, Petr; Hajduch, Marian; Sarek, Jan; Urban, Milan

2015-12-16

To better understand the mechanism of action of antitumor triterpenes, we are developing methods to identify their molecular targets. A promising method is based on combination of quantitative proteomics with SILAC and uses active compounds anchored to magnetic beads via biotin-streptavidin interaction. We developed a simple and fast solid-phase synthetic technique to connect terpenes to biotin through a linker. Betulinic acid was biotinylated from three different conjugation sites for use as a standard validation tool since many molecular targets of this triterpene are already known. Then, a set of four other cytotoxic triterpenoids was biotinylated. Biotinylated terpenes were similarly cytotoxic to their nonbiotinylated parents, which suggests that the target identification should not be influenced by linker or biotin. The developed solid-phase synthetic approach is the first attempt to use solid-phase synthesis to connect active triterpenes to biotin and is applicable as a general procedure for routine conjugation of triterpenes with other molecules of choice.

Your Endocrine System (For Kids)

Science.gov (United States)

... Kids / Your Endocrine System Print en español Tu sistema endocrino You might say endocrine (say: EN-doh- ... of Use Notice of Nondiscrimination Visit the Nemours Web site. Note: All information on KidsHealth® is for ...

Molecular Targets for Targeted Radionuclide Therapy

International Nuclear Information System (INIS)

Mather, S.J.

2009-01-01

Molecular targeted radionuclide cancer therapy is becoming of increasing importance, especially for disseminated diseases. Systemic chemotherapies often lack selectivity while targeted radionuclide therapy has important advantages as the radioactive cytotoxic unit of the targeting vector is specifically directed to the cancer, sparing normal tissues. The principle strategy to improve cancer selectivity is to couple therapeutic agents to tumour-targeting vectors. In targeted radionuclide therapy (TRT), the cytotoxic portion of the conjugates normally contains a therapeutic radiometal immobilised by a bifunctional chelator. The aim is therefore to use as ligand-targeted therapeutics vectors coupled to Auger-, alpha- and/or beta-emitting radionuclides. An advantage of using radiation instead of chemotherapeutics as the cytotoxic agent is the so called 'crossfire effect'. This allows sterilisation of tumour cells that are not directly targeted due to heterogeneity in target molecule expression or inhomogeneous vector delivery. However, before the targeting ligands can be selected, the target molecule on the tumour has to be selected. It should be uniquely expressed, or at least highly overexpressed, on or in the target cells relative to normal tissues. The target should be easily accessible for ligand delivery and should not be shed or down- regulated after ligand binding. An important property of a receptor (or antigen) is its potential to be internalized upon binding of the ligand. This provides an active uptake mechanism and allows the therapeutic agent to be trapped within the tumour cells. Molecular targets of current interest include: Receptors: G-protein coupled receptors are overexpressed on many major human tumours. The prototype of these receptors are somatostatin receptors which show very high density in neuroendocrine tumours, but there are many other most interesting receptors to be applied for TRT. The targeting ligands for these receptors are

Differential gene expression patterns in developing sexually dimorphic rat brain regions exposed to antiandrogenic, estrogenic, or complex endocrine disruptor mixtures: glutamatergic synapses as target.

Science.gov (United States)

Lichtensteiger, Walter; Bassetti-Gaille, Catherine; Faass, Oliver; Axelstad, Marta; Boberg, Julie; Christiansen, Sofie; Rehrauer, Hubert; Georgijevic, Jelena Kühn; Hass, Ulla; Kortenkamp, Andreas; Schlumpf, Margret

2015-04-01

The study addressed the question whether gene expression patterns induced by different mixtures of endocrine disrupting chemicals (EDCs) administered in a higher dose range, corresponding to 450×, 200×, and 100× high-end human exposure levels, could be characterized in developing brain with respect to endocrine activity of mixture components, and which developmental processes were preferentially targeted. Three EDC mixtures, A-Mix (anti-androgenic mixture) with 8 antiandrogenic chemicals (di-n-butylphthalate, diethylhexylphthalate, vinclozolin, prochloraz, procymidone, linuron, epoxiconazole, and DDE), E-Mix (estrogenic mixture) with 4 estrogenic chemicals (bisphenol A, 4-methylbenzylidene camphor, 2-ethylhexyl 4-methoxycinnamate, and butylparaben), a complex mixture, AEP-Mix, containing the components of A-Mix and E-Mix plus paracetamol, and paracetamol alone, were administered by oral gavage to rat dams from gestation day 7 until weaning. General developmental endpoints were not affected by EDC mixtures or paracetamol. Gene expression was analyzed on postnatal day 6, during sexual brain differentiation, by exon microarray in medial preoptic area in the high-dose group, and by real-time RT-PCR in medial preoptic area and ventromedial hypothalamus in all dose groups. Expression patterns were mixture, sex, and region specific. Effects of the analgesic drug paracetamol, which exhibits antiandrogenic activity in peripheral systems, differed from those of A-Mix. All mixtures had a strong, mixture-specific impact on genes encoding for components of excitatory glutamatergic synapses and genes controlling migration and pathfinding of glutamatergic and GABAergic neurons, as well as genes linked with increased risk of autism spectrum disorders. Because development of glutamatergic synapses is regulated by sex steroids also in hippocampus, this may represent a general target of ECD mixtures.

[Disperse endocrine system and APUD concept].

Science.gov (United States)

Mil'to, I V; Sukhodolo, I V; Gereng, E A; Shamardina, L A

2011-01-01

This review describes the problems of disperse endocrine system and APUD-system morphology, summarizes some debatable issues of single endocrine cell biology. The data presented refer to the history of both systems discovery, morphological methods of their study, developmental sources, their structural organization and physiological roles of their cells. The significance of single endocrine cells in the regulation of the organism functions is discussed.

Restoring Ovarian Endocrine Function with Encapsulated Ovarian Allograft in Immune Competent Mice.

Science.gov (United States)

David, Anu; Day, James Ronald; Cichon, Alexa Leigh; Lefferts, Adam; Cascalho, Marilia; Shikanov, Ariella

2017-07-01

Premature ovarian insufficiency (POI) is a major complication of cytotoxic treatments due to extreme ovarian sensitivity to chemotherapy and radiation. In pediatric cancer patients modern therapy has improved the long-term survival to over 80% in the United States. However, these cancer survivors face long-term health problems related to treatment toxicity. In female cancer survivors POI leads to sterility, along with the consequences of estrogen deficiency such as premature osteopenia, muscle wasting, accelerated cardiovascular diseases and a vast array of other health and developmental problems. These long-lasting effects are particularly significant for young girls reaching puberty. As such, restoring ovarian endocrine function is paramount in this population. In the present study, we evaluated the feasibility of restoring ovarian endocrine function in ovariectomized mice by transplanting syngeneic and allogeneic ovarian tissue encapsulated in alginate capsules or TheraCyte ® . Histological analysis of the implants retrieved after 7 and 30 days' post implantation showed follicular development up to the secondary and antral stages in both syngeneic and allogeneic implants. Implantation of syngeneic and allogeneic ovarian grafts encapsulated in TheraCyte devices restored ovarian endocrine function, which was confirmed by decreased serum FSH levels from 60 to 70 ng/mL in ovariectomized mice to 30-40 ng/mL 30 days after implantation. Absence of allo-MHC-specific IgG and IgM antibodies in the sera of implanted mice with allogeneic ovarian tissue encapsulated in TheraCyte indicate that the implants did not evoke an allo-immune response, while the allogeneic controls were rejected 21 days after implantation. Our results show that TheraCyte effectively isolates the graft from immune recognition but also supports follicular growth.

Interleukin-2 activation of cytotoxic cells in postmastectomy seroma.

Science.gov (United States)

Gercel-Taylor, C; Hoffman, J P; Taylor, D D; Owens, K J; Eisenberg, B L

1996-02-15

Lymphocytes were isolated from breast seroma fluids and used to study the mechanism of activation of cytotoxic lymphocytes and possible role of immunological potentiation following surgery in breast cancer patients. Single or serial samples were obtained from patients who had undergone mastectomy or lumpectomy with axillary node dissection. Lymphocytes were activated with rIL-2 (interleukin-2) and their cytotoxic activity was studied against Daudi and K562 cells and against a breast tumor line (SKBr-3). All of the patients (21/21) responded to IL-2 stimulation by significant activation of cytotoxic activity. The unstimulated cytotoxic activity of these cells against NK targets was low with less than 10% specific release in cytotoxicity assays. In simultaneous experiments, autologous seroma fluid was included during activation of lymphocytes to study possible regulatory molecules that may be present. In 17/21 patients, the presence of their seroma fluid, during the activation period, enhanced or did not effect the cytotoxic potential of their lymphocytes; inhibition was observed when seroma fluids from 4/21 patients were included. Analysis of the cytotoxic population derived from combined IL-2 and seroma treatments indicates the presence of cells with increased expression of CD56, and CD2, as well as in some cases CD16 expression. Cytotoxic lymphocytes derived from IL-2 and seroma treatments appeared to be more effective killers. Modulation of CD2 expression with seroma alone appeared to result in the generation of this highly cytotoxic population. This study demonstrates the role of CD2 expression in the effectiveness of LAK cell killing and also potential benefit of an immunotherapeutic approach to the postoperative treatment of carcinoma of the breast.

Clinical activity of fulvestrant in metastatic breast cancer previously treated with endocrine therapy and/or chemotherapy.

Science.gov (United States)

Heo, Mi Hwa; Kim, Hee Kyung; Lee, Hansang; Kim, Ji-Yeon; Ahn, Jin-Seok; Im, Young-Hyuck; Park, Yeon Hee

2018-03-16

We conducted a retrospective analysis of the clinical activity of fulvestrant in postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC) previously treated with endocrine therapy and/or chemotherapy. We reviewed the medical records of all patients with MBC treated at Samsung Medical Center between January 2009 and August 2016. Patients received fulvestrant 250 mg intramuscularly every 28 days (from January 2009 to November 2010) or 500 mg intramuscularly every 28 days (from December 2010 to August 2016). Tumor responses were assessed every 8 weeks and at the end of treatment, as well as when disease progression was suspected. A total of 84 patients were included in this study. A median of two previous endocrine treatments had been performed; 79% of the patients had received two or more endocrine treatments. Forty-five patients (54%) had been treated with chemotherapy for MBC before the fulvestrant treatment course. Visceral metastasis was found in 49 patients (58%). The estimated median progression-free survival and overall survival were 4.4 months (95% confidence interval [CI], 3.4 to 5.5) and 32.5 months (95% CI, 17.6 to 47.4), respectively. The disease control rate was 40.5% (95% CI, 30.5 to 51.5); partial response was observed in 16% of the patients and stable disease was observed in 25% of the patients. The most frequently reported adverse reactions were mild-to-moderate grade myalgia (10.5% of the patients), injection site pain (7%), and fatigue (7%). Fulvestrant was generally well tolerated. Fulvestrant showed encouraging clinical activity and favorable feasibility in postmenopausal women with MBC who had been treated with multiple endocrine therapies and/or cytotoxic chemotherapies.

Endocrine effects of chemicals: aspects of hazard identification and human health risk assessment.

Science.gov (United States)

Dekant, Wolfgang; Colnot, Thomas

2013-12-16

Hazard and risk assessment of chemicals with endocrine activity is hotly debated due to claimed non-monotonous dose-response curves in the low-dose region. In hazard identification a clear definition of "endocrine disruptors" (EDs) is required; this should be based on the WHO/IPCS definition of EDs and on adverse effects demonstrated in intact animals or humans. Therefore, endocrine effects are a mode of action potentially resulting in adverse effects; any classification should not be based on a mode of action, but on adverse effects. In addition, when relying on adverse effects, most effects reported in the low-dose region will not qualify for hazard identification since most have little relation to an adverse effect. Non-monotonous dose-response curves that had been postulated from limited, exploratory studies could also not be reproduced in targeted studies with elaborate quality assurance. Therefore, regulatory agencies or advisory bodies continue to apply the safety-factor method or the concept of "margin-of-exposure" based on no observed adverse effect levels (NOAELs) in the risk assessment of chemicals with weak hormonal activity. Consistent with this approach, tolerable levels regarding human exposure have been defined for such chemicals. To conclusively support non-monotonous dose-response curves, targeted experiments with a sufficient number of animals, determination of adverse endpoints, adequate statistics and quality control would be required. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Pha-induced T-cell cytotoxity. Mechanism and application in haemodialysis and renal transplant patients.

NARCIS (Netherlands)

Huges-Wirawan, Gladys Ratna Widhi Indrati

1978-01-01

This thesis describes a method to measure PHA-incluced cytotoxicity of human lymphocytes (nonspecific T-cell cytotoxicity), using 3H-thymidine prelabelled target cells (HeLa cells). The method has some advantages over the widely used 51Cr-release assay. Its application in two clinical conditions is

BRD4-targeted therapy induces Myc-independent cytotoxicity in Gnaq/11-mutatant uveal melanoma cells.

Science.gov (United States)

Ambrosini, Grazia; Sawle, Ashley D; Musi, Elgilda; Schwartz, Gary K

2015-10-20

Uveal melanoma (UM) is an aggressive intraocular malignancy with limited therapeutic options. Both primary and metastatic UM are characterized by oncogenic mutations in the G-protein alpha subunit q and 11. Furthermore, nearly 40% of UM has amplification of the chromosomal arm 8q and monosomy of chromosome 3, with consequent anomalies of MYC copy number. Chromatin regulators have become attractive targets for cancer therapy. In particular, the bromodomain and extra-terminal (BET) inhibitor JQ1 has shown selective inhibition of c-Myc expression with antiproliferative activity in hematopoietic and solid tumors. Here we provide evidence that JQ1 had cytotoxic activity in UM cell lines carrying Gnaq/11 mutations, while in cells without the mutations had little effects. Using microarray analysis, we identified a large subset of genes modulated by JQ1 involved in the regulation of cell cycle, apoptosis and DNA repair. Further analysis of selected genes determined that the concomitant silencing of Bcl-xL and Rad51 represented the minimal requirement to mimic the apoptotic effects of JQ1 in the mutant cells, independently of c-Myc. In addition, administration of JQ1 to mouse xenograft models of Gnaq-mutant UM resulted in significant inhibition of tumor growth.Collectively, our results define BRD4 targeting as a novel therapeutic intervention against UM with Gnaq/Gna11 mutations.

Novel drugs that target the estrogen-related receptor alpha: their therapeutic potential in breast cancer

Energy Technology Data Exchange (ETDEWEB)

May, Felicity EB, E-mail: F.E.B.May@ncl.ac.uk [Northern Institute for Cancer Research and Department of Pathology, Faculty of Medical Sciences, University of Newcastle upon Tyne, Newcastle upon Tyne (United Kingdom)

2014-05-23

The incidence of breast cancer continues to rise: 1.7 million women were diagnosed with and 521,000 women died from breast cancer in 2012. This review considers first current treatment options: surgery; radiotherapy; and systemic endocrine, anti-biological, and cytotoxic therapies. Clinical management includes prevention, early detection by screening, treatment with curative intent, management of chronic disease, and palliative control of advanced breast cancer. Next, the potential of novel drugs that target DNA repair, growth factor dependence, intracellular and intercellular signal transduction, and cell cycle are considered. Estrogen-related receptor alpha has attracted attention as a therapeutic target in triple-negative breast cancers with de novo resistance to, and in breast cancers with acquired resistance to, endocrine therapies such as antiestrogens and aromatase inhibitors. Estrogen-related receptor alpha is an orphan receptor and transcription factor. Its activity is regulated by coregulator proteins and posttranslational modification. It is an energy sensor that controls adaptation to energy demand and may facilitate glycolytic metabolism and mitochondrial oxidative respiration in breast cancer cells. Estrogen-related receptor alpha increases breast cancer cell migration, proliferation, and tumor development. It is expressed at high levels in estrogen receptor-negative tumors, and is proposed to activate estrogen-responsive genes in endocrine-resistant tumors. The structures and functions of the ligand-binding domains of estrogen receptor alpha and estrogen-related receptor alpha, their ability to bind estrogens, phytoestrogens, and synthetic ligands, and the effects of ligand agonists, antagonists, and inverse agonists on biological activity, are evaluated. Synthetic ligands of estrogen-related receptor alpha have activity in preclinical models of metabolic disorders, diabetes, osteoporosis, and oncology. The clinical settings in which these novel

Novel drugs that target the estrogen-related receptor alpha: their therapeutic potential in breast cancer

International Nuclear Information System (INIS)

May, Felicity EB

2014-01-01

The incidence of breast cancer continues to rise: 1.7 million women were diagnosed with and 521,000 women died from breast cancer in 2012. This review considers first current treatment options: surgery; radiotherapy; and systemic endocrine, anti-biological, and cytotoxic therapies. Clinical management includes prevention, early detection by screening, treatment with curative intent, management of chronic disease, and palliative control of advanced breast cancer. Next, the potential of novel drugs that target DNA repair, growth factor dependence, intracellular and intercellular signal transduction, and cell cycle are considered. Estrogen-related receptor alpha has attracted attention as a therapeutic target in triple-negative breast cancers with de novo resistance to, and in breast cancers with acquired resistance to, endocrine therapies such as antiestrogens and aromatase inhibitors. Estrogen-related receptor alpha is an orphan receptor and transcription factor. Its activity is regulated by coregulator proteins and posttranslational modification. It is an energy sensor that controls adaptation to energy demand and may facilitate glycolytic metabolism and mitochondrial oxidative respiration in breast cancer cells. Estrogen-related receptor alpha increases breast cancer cell migration, proliferation, and tumor development. It is expressed at high levels in estrogen receptor-negative tumors, and is proposed to activate estrogen-responsive genes in endocrine-resistant tumors. The structures and functions of the ligand-binding domains of estrogen receptor alpha and estrogen-related receptor alpha, their ability to bind estrogens, phytoestrogens, and synthetic ligands, and the effects of ligand agonists, antagonists, and inverse agonists on biological activity, are evaluated. Synthetic ligands of estrogen-related receptor alpha have activity in preclinical models of metabolic disorders, diabetes, osteoporosis, and oncology. The clinical settings in which these novel

Sarcopenia and Age-Related Endocrine Function

Directory of Open Access Journals (Sweden)

Kunihiro Sakuma

2012-01-01

Full Text Available Sarcopenia, the age-related loss of skeletal muscle, is characterized by a deterioration of muscle quantity and quality leading to a gradual slowing of movement, a decline in strength and power, and an increased risk of fall-related injuries. Since sarcopenia is largely attributed to various molecular mediators affecting fiber size, mitochondrial homeostasis, and apoptosis, numerous targets exist for drug discovery. In this paper, we summarize the current understanding of the endocrine contribution to sarcopenia and provide an update on hormonal intervention to try to improve endocrine defects. Myostatin inhibition seems to be the most interesting strategy for attenuating sarcopenia other than resistance training with amino acid supplementation. Testosterone supplementation in large amounts and at low frequency improves muscle defects with aging but has several side effects. Although IGF-I is a potent regulator of muscle mass, its therapeutic use has not had a positive effect probably due to local IGF-I resistance. Treatment with ghrelin may ameliorate the muscle atrophy elicited by age-dependent decreases in growth hormone. Ghrelin is an interesting candidate because it is orally active, avoiding the need for injections. A more comprehensive knowledge of vitamin-D-related mechanisms is needed to utilize this nutrient to prevent sarcopenia.

Endocrine Dysregulation in Anorexia Nervosa Update

Science.gov (United States)

2011-01-01

Context: Anorexia nervosa is a primary psychiatric disorder with serious endocrine consequences, including dysregulation of the gonadal, adrenal, and GH axes, and severe bone loss. This Update reviews recent advances in the understanding of the endocrine dysregulation observed in this state of chronic starvation, as well as the mechanisms underlying the disease itself. Evidence Acquisition: Findings of this update are based on a PubMed search and the author's knowledge of this field. Evidence Synthesis: Recent studies have provided insights into the mechanisms underlying endocrine dysregulation in states of chronic starvation as well as the etiology of anorexia nervosa itself. This includes a more complex understanding of the pathophysiologic bases of hypogonadism, hypercortisolemia, GH resistance, appetite regulation, and bone loss. Nevertheless, the etiology of the disease remains largely unknown, and effective therapies for the endocrine complications and for the disease itself are lacking. Conclusions: Despite significant progress in the field, further research is needed to elucidate the mechanisms underlying the development of anorexia nervosa and its endocrine complications. Such investigations promise to yield important advances in the therapeutic approach to this disease as well as to the understanding of the regulation of endocrine function, skeletal biology, and appetite regulation. PMID:21976742

Vitamin A, endocrine tissues and hormones: interplay and interactions

Directory of Open Access Journals (Sweden)

J Brossaud

2017-09-01

Full Text Available Vitamin A (retinol is a micronutrient critical for cell proliferation and differentiation. In adults, vitamin A and metabolites such as retinoic acid (RA play major roles in vision, immune and brain functions and tissue remodelling and metabolism. This review presents the physiological interactions of retinoids and endocrine tissues and hormonal systems. Two endocrine systems have been particularly studied. In the pituitary, retinoids target the corticotrophs with a possible therapeutic use in corticotropinomas. In the thyroid, retinoids interfere with iodine metabolism and vitamin A deficiency aggravates thyroid dysfunction caused by iodine-deficient diets. Retinoids use in thyroid cancer appears less promising than expected. Recent and still controversial studies investigated the relations between retinoids and metabolic syndrome. Indeed, retinoids contribute to pancreatic development and modify fat and glucose metabolism. However, more detailed studies are needed before planning any therapeutic use. Finally, retinoids probably play more minor roles in adrenal and gonads development and function apart from their major effects on spermatogenesis.

Executive Summary to EDC-2: The Endocrine Society's Second Scientific Statement on Endocrine-Disrupting Chemicals.

Science.gov (United States)

Gore, A C; Chappell, V A; Fenton, S E; Flaws, J A; Nadal, A; Prins, G S; Toppari, J; Zoeller, R T

2015-12-01

This Executive Summary to the Endocrine Society's second Scientific Statement on environmental endocrine-disrupting chemicals (EDCs) provides a synthesis of the key points of the complete statement. The full Scientific Statement represents a comprehensive review of the literature on seven topics for which there is strong mechanistic, experimental, animal, and epidemiological evidence for endocrine disruption, namely: obesity and diabetes, female reproduction, male reproduction, hormone-sensitive cancers in females, prostate cancer, thyroid, and neurodevelopment and neuroendocrine systems. EDCs such as bisphenol A, phthalates, pesticides, persistent organic pollutants such as polychlorinated biphenyls, polybrominated diethyl ethers, and dioxins were emphasized because these chemicals had the greatest depth and breadth of available information. The Statement also included thorough coverage of studies of developmental exposures to EDCs, especially in the fetus and infant, because these are critical life stages during which perturbations of hormones can increase the probability of a disease or dysfunction later in life. A conclusion of the Statement is that publications over the past 5 years have led to a much fuller understanding of the endocrine principles by which EDCs act, including nonmonotonic dose-responses, low-dose effects, and developmental vulnerability. These findings will prove useful to researchers, physicians, and other healthcare providers in translating the science of endocrine disruption to improved public health.

Endocrine and metabolic disorders associated with human immune deficiency virus infection.

Science.gov (United States)

Unachukwu, C N; Uchenna, D I; Young, E E

2009-01-01

Many reports have described endocrine and metabolic disorders in the human immunodeficiency virus (HIV) infection. This article reviewed various reports in the literature in order to increase the awareness and thus the need for early intervention when necessary. Data were obtained from MEDLINE, Google search and otherjournals on 'HIV, Endocrinopathies/Metabolic Disorders' from 1985 till 2007. Studies related to HIV associated endocrinopathies and metabolic disorders in the last two decades were reviewed. Information on epidemiology, pathogenesis, diagnosis and treatment of the target organ endocrinopathies and metabolic disorders in HIV/AIDS were extracted from relevant literature. Endocrine and metabolic disturbances occur in the course of HIV infection. Pathogenesis includes direct infection of endocrine glands by HIV or opportunistic organisms, infiltration by neoplasms and side effects of drugs. Adrenal insufficiency is the commonest HIV endocrinopathy with cytomegalovirus adrenalitis occurring in 40-88% of cases. Thyroid dysfunction may occur as euthyroid sick syndrome or sub-clinical hypothyroidism. Hypogonadotrophic dysfunction accounts for 75% of HIV-associated hypogonadism, with prolonged amenorrhoea being three times more likely in the women. Pancreatic dysfunction may result in hypoglycaemia or diabetes mellitus (DM). Highly active antiretroviral therapy (HAART) especially protease inhibitors has been noted to result in insulin resistance and lipodystrophy. Virtually every endocrine organ is involved in the course of HIV infection. Detailed endocrinological and metabolic evaluation and appropriate treatment is necessary in the optimal management of patients with HIV infection in our environment.

Radiotherapy for unresectable endocrine pancreatic carcinomas

International Nuclear Information System (INIS)

Tennvall, J.; Ljungberg, O.; Ahren, B.; Gustavsson, A.; Nillson, L.O.

1992-01-01

Surgery, when possible, is the treatment of choice for the uncommon endocrine tumours of pancreas. Unresectable cases are usually treated with cytostatic drugs or α-interferon. We describe a patient with unresectable, locally advanced endocrine pancreatic carcinoma (measuring 5 x 5 x 6 cm) that was totally cured by external radiation therapy only (40 Gy). This case together with four cases in the literature indicate that external radiation therapy should be considered in locally unresectable endocrine pancreatic carcinomas. (author)

Gold(III) bis(thiosemicarbazonate) compounds in breast cancer cells: Cytotoxicity and thioredoxin reductase targeting.

Science.gov (United States)

Rodríguez-Fanjul, Vanessa; López-Torres, Elena; Mendiola, M Antonia; Pizarro, Ana María

2018-03-25

Gold(III) compounds have received increasing attention in cancer research. Three gold complexes of general formula [Au III L]Cl, where L is benzil bis(thiosemicarbazonate), compound 1, benzil bis(4-methyl-3-thiosemicarbazonate), compound 2, or benzil bis(4-cyclohexyl-3-thiosemicarbazonate), compound 3, have been synthesized and fully characterized, including the X-ray crystal structure of compound 3, confirming square-planar geometry around the gold(III) centre. Compound 1 showed moderate cytotoxicity and accumulation in MCF7 breast cancer cells but did not inhibit thioredoxin reductase (TrxR) activity and did not induce reactive oxygen species (ROS) production. Compound 2, the least cytotoxic, was found to be capable of modestly inhibiting TrxR activity and produced low levels of ROS in the MCF7 cell line. The most cytotoxic compound, 3, had the highest cellular accumulation and its distribution pattern showed a clear preference for the cytosol and mitochondria of MCF7 cells. It readily hampered intracellular TrxR activity leading to a dramatic alteration of the cellular redox state and to the induction of cell death. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Changes in Actin Organization During the Cytotoxic Process

NARCIS (Netherlands)

Radosevic, K.; Radosevic, Katarina; van Leeuwen, Anne Marie T.; Segers-Nolten, Gezina M.J.; Figdor, Carl; de Grooth, B.G.; Greve, Jan

1994-01-01

Changes in organization of F-actin during the cytotoxic process between NK and K562 cells have been observed and studied using confpcal laser scanning microscopy and quantitative fluorescence microscopy. An increase in F-actin content and orientation of F-actin towards the target cell have been

Sexually dimorphic gene regulation in brain as a target for endocrine disrupters: Developmental exposure of rats to 4-methylbenzylidene camphor

International Nuclear Information System (INIS)

Maerkel, Kirsten; Durrer, Stefan; Henseler, Manuel; Schlumpf, Margret; Lichtensteiger, Walter

2007-01-01

The developing neuroendocrine brain represents a potential target for endocrine active chemicals. The UV filter 4-methylbenzylidene camphor (4-MBC) exhibits estrogenic activity, but also interferes with the thyroid axis. We investigated effects of pre- and postnatal exposure to 4-MBC in the same rat offspring at brain and reproductive organ levels. 4-MBC (7, 24, 47 mg/kg/day) was administered in chow to the parent generation before mating, during gestation and lactation, and to the offspring until adulthood. mRNA of estrogen target genes involved in control of sexual behavior and gonadal functions was measured by real-time RT-PCR in ventromedial hypothalamic nucleus (VMH) and medial preoptic area (MPO) of adult offspring. 4-MBC exposure affected mRNA levels of ER alpha, progesterone receptor (PR), preproenkephalin (PPE) and insulin-like growth factor-I (IGF-I) in a sex- and region-specific manner. In order to assess possible changes in sensitivity of target genes to estrogens, offspring were gonadectomized on day 70, injected with estradiol (E2, 10 or 50 μg/kg s.c.) or vehicle on day 84, and sacrificed 6 h later. The acute induction of PR mRNA, and repression (at 6 h) of PPE mRNA by E2 was enhanced by 4-MBC in male and female VMH and female MPO, whereas male MPO exhibited reduced responsiveness of both genes. Steroid receptor coactivator SRC-1 mRNA levels were increased in female VMH and MPO. The data indicate profound sex- and region-specific alterations in the regulation of estrogen target genes at brain level. Effect patterns in baseline and E2-induced gene expression differ from those in uterus and prostate

Pesticides Provoke Endocrine Disruption A Review

International Nuclear Information System (INIS)

Aly, M.A.S.

2006-01-01

Increasing numbers of environmental chemicals,including pesticides, have the ability to produce endocrine disruption by various mechanisms. such substances may affect hormone secretion from an endocrine gland and may alter the rate of hormone elimination from the body. environmental chemicals may also disrupt regulatory feedback mechanisms that exist between two endocrine organs; or may interact with a hormone receptor either by mimicking or antagonizing the actions of the natural hormone. these chemicals are referred to endocrine disruptive chemicals (EDC's). EDC's act to alter the blood hormone levels or the subsequent action of hormones . the use of radioimmunoassay(RIA) constitutes a superior and unrivalled tool for the determination and quantification of hormones.the endocrine system participates in virtually all important functions of an organism, such as sexual differentiation before birth, sexual maturation during puberty, reproduction in adulthood, growth, metabolism, digestion, cardiovascular function and excretion. hormones are also implicated in the etiology of certain cancers of hormone- dependent tissues, such as those of the breast, uterus, and prostate gland. therefore, endocrine disruption can potentially produce widespread effects. scientists should not stick to the past belief which presumes that pesticides have limited effect on some hormones. A paradigm shift in which a wider vision of understanding of the wholesome complex effects of pesticides on the whole body rather than a narrow limited understanding should take place

Antibody-dependent cellular cytotoxicity and skin disease

International Nuclear Information System (INIS)

Norris, D.A.; Lee, L.A.

1985-01-01

Antibody dependent cellular cytotoxicity (ADCC) is a recently described mechanism of immunologic lysis in which cellular targets sensitized by specific antibodies are efficiently and selectively lysed by Fc receptor (FcR) bearing nonspecific effectors. Immunoglobulins of various classes (IgG, IgM, IgA, IgE) and various cellular effectors (large granular lymphocytes, monocyte/macrophages, T lymphocytes, neutrophils, and eosinophils) can induce ADCC in vitro, and the importance of ADCC in vivo is being tested experimentally in resistance to viral, bacterial, and parasitic infection, in tumor surveillance, in allograft rejection, and in inflammatory diseases. There is much indirect evidence that ADCC may be the mechanism of damage of different cellular targets in skin diseases, but the best direct evidence concerns immunologic keratinocyte damage, especially in cutaneous lupus erythematosus (LE). The authors have shown that keratinocytes of several species are highly susceptible to lymphocyte and monocyte-mediated ADCC, but not to neutrophil or eosinophil ADCC in vitro using two different cytotoxicity assays. In contrast, complement was a relatively ineffective mediator of lysis of metabolically intact keratinocyte targets. Patients with certain cutaneous lupus syndromes have serum antibodies capable of inducing monocyte and lymphocyte ADCC of targets coated with extractable nuclear antigens. The authors have shown that these antigens apparently move to the cell membrane of keratinocytes in vitro following ultraviolet irradiation. In an animal model, they have shown that antibodies to SSA/Ro bind to human keratinocytes in vivo, especially after ultraviolet irradiation

Conformational targeting of fibrillar polyglutamine proteins in live cells escalates aggregation and cytotoxicity.

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Erik Kvam

2009-05-01

Full Text Available Misfolding- and aggregation-prone proteins underlying Parkinson's, Huntington's and Machado-Joseph diseases, namely alpha-synuclein, huntingtin, and ataxin-3 respectively, adopt numerous intracellular conformations during pathogenesis, including globular intermediates and insoluble amyloid-like fibrils. Such conformational diversity has complicated research into amyloid-associated intracellular dysfunction and neurodegeneration. To this end, recombinant single-chain Fv antibodies (scFvs are compelling molecular tools that can be selected against specific protein conformations, and expressed inside cells as intrabodies, for investigative and therapeutic purposes.Using atomic force microscopy (AFM and live-cell fluorescence microscopy, we report that a human scFv selected against the fibrillar form of alpha-synuclein targets isomorphic conformations of misfolded polyglutamine proteins. When expressed in the cytoplasm of striatal cells, this conformation-specific intrabody co-localizes with intracellular aggregates of misfolded ataxin-3 and a pathological fragment of huntingtin, and enhances the aggregation propensity of both disease-linked polyglutamine proteins. Using this intrabody as a tool for modulating the kinetics of amyloidogenesis, we show that escalating aggregate formation of a pathologic huntingtin fragment is not cytoprotective in striatal cells, but rather heightens oxidative stress and cell death as detected by flow cytometry. Instead, cellular protection is achieved by suppressing aggregation using a previously described intrabody that binds to the amyloidogenic N-terminus of huntingtin. Analogous cytotoxic results are observed following conformational targeting of normal or polyglutamine-expanded human ataxin-3, which partially aggregate through non-polyglutamine domains.These findings validate that the rate of aggregation modulates polyglutamine-mediated intracellular dysfunction, and caution that molecules designed to

Endocrine Diseases

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... Syndrome (PCOS) Pregnancy and Thyroid Disease Primary Hyperparathyroidism Prolactinoma Thyroid Tests Turner Syndrome Contact Us The National ... Management Liver Disease Urologic Diseases Endocrine Diseases Diet & Nutrition Blood Diseases Diagnostic Tests La información de la ...

Genome-wide identification of genetic determinants for the cytotoxicity of perifosine

Directory of Open Access Journals (Sweden)

Zhang Wei

2008-09-01

Full Text Available Abstract Perifosine belongs to the class of alkylphospholipid analogues, which act primarily at the cell membrane, thereby targeting signal transduction pathways. In phase I/II clinical trials, perifosine has induced tumour regression and caused disease stabilisation in a variety of tumour types. The genetic determinants responsible for its cytotoxicity have not been comprehensively studied, however. We performed a genome-wide analysis to identify genes whose expression levels or genotypic variation were correlated with the cytotoxicity of perifosine, using public databases on the US National Cancer Institute (NCI-60 human cancer cell lines. For demonstrating drug specificity, the NCI Standard Agent Database (including 171 drugs acting through a variety of mechanisms was used as a control. We identified agents with similar cytotoxicity profiles to that of perifosine in compounds used in the NCI drug screen. Furthermore, Gene Ontology and pathway analyses were carried out on genes more likely to be perifosine specific. The results suggested that genes correlated with perifosine cytotoxicity are connected by certain known pathways that lead to the mitogen-activated protein kinase signalling pathway and apoptosis. Biological processes such as 'response to stress', 'inflammatory response' and 'ubiquitin cycle' were enriched among these genes. Three single nucleotide polymorphisms (SNPs located in CACNA2DI and EXOC4 were found to be correlated with perifosine cytotoxicity. Our results provided a manageable list of genes whose expression levels or genotypic variation were strongly correlated with the cytotoxcity of perifosine. These genes could be targets for further studies using candidate-gene approaches. The results also provided insights into the pharmacodynamics of perifosine.

Serine esterase and hemolytic activity in human cloned cytotoxic T lymphocytes

OpenAIRE

1988-01-01

Target cell lysis by most murine cytotoxic T lymphocytes appears to be mediated by a complement (C9)-like protein called perforin, contained in high-density cytoplasmic granules. These granules also contain high levels of serine esterase activity, which may also play a role in cytolysis. Analysis of 17 cloned human cytotoxic T lymphocytes revealed the presence of serine esterase that is very similar to its murine counterpart in substrate and inhibitor specificities, pH optimum, and molecular ...

Endocrine Disruptors (Chapter 14) in Mammalian Toxicology Book

Science.gov (United States)

Endocrine disrupting chemicals (EDCs) are exogenous substances that alter endocrine system function(s) and consequently cause adverse health effects in intact organisms or its progeny. The endocrine system is important for a wide range of biological processes, from normal cell si...

Interrelationships of radiation, viruses, and the immune response in radium-induced tumors. Part III. Lymphocyte cytotoxicity to osteosarcoma cells in vitro

International Nuclear Information System (INIS)

Menon, M.; Lloyd, E.L.; Mitchen, J.L.

Lymphocytes from patients carrying a body burden greater than 0.3 μCi 226 Ra were tested for specific cytotoxicity to four different osteosarcoma cell lines, as well as normal human fibroblasts. Cytotoxicity indices (defined as the ratio of the number of target cells remaining, after treatment with the patients' lymphocytes, relative to the values obtained with normal control subjects) have been calculated. With one exception, no cytotoxicity was observed. This is in agreement with the fact that no fresh osteosarcomas were diagnosed. The patient in whom cytotoxicity was observed was suffering from inflammation of the hip joint at the time of the first test. When the test was repeated 10 months later, no cytotoxicity was observed. No significant nonspecific cytotoxicity was observed using lymphocytes taken from four normal control subjects with any of the target cell lines used. (U.S.)

Adipose Type One Innate Lymphoid Cells Regulate Macrophage Homeostasis through Targeted Cytotoxicity.

Science.gov (United States)

Boulenouar, Selma; Michelet, Xavier; Duquette, Danielle; Alvarez, David; Hogan, Andrew E; Dold, Christina; O'Connor, Donal; Stutte, Suzanne; Tavakkoli, Ali; Winters, Desmond; Exley, Mark A; O'Shea, Donal; Brenner, Michael B; von Andrian, Ulrich; Lynch, Lydia

2017-02-21

Adipose tissue has a dynamic immune system that adapts to changes in diet and maintains homeostatic tissue remodeling. Adipose type 1 innate lymphoid cells (AT1-ILCs) promote pro-inflammatory macrophages in obesity, but little is known about their functions at steady state. Here we found that human and murine adipose tissue harbor heterogeneous populations of AT1-ILCs. Experiments using parabiotic mice fed a high-fat diet (HFD) showed differential trafficking of AT1-ILCs, particularly in response to short- and long-term HFD and diet restriction. At steady state, AT1-ILCs displayed cytotoxic activity toward adipose tissue macrophages (ATMs). Depletion of AT1-ILCs and perforin deficiency resulted in alterations in the ratio of inflammatory to anti-inflammatory ATMs, and adoptive transfer of AT1-ILCs exacerbated metabolic disorder. Diet-induced obesity impaired AT1-ILC killing ability. Our findings reveal a role for AT1-ILCs in regulating ATM homeostasis through cytotoxicity and suggest that this function is relevant in both homeostasis and metabolic disease. Copyright © 2017 Elsevier Inc. All rights reserved.

Once and for all, LXRα and LXRβ are gatekeepers of the endocrine system.

Science.gov (United States)

Maqdasy, Salwan; Trousson, Amalia; Tauveron, Igor; Volle, David H; Baron, Silvère; Lobaccaro, Jean-Marc A

2016-06-01

Liver X receptors (LXRs) α and β are nuclear receptors whose transcriptional activity is regulated by oxysterols, the oxidized forms of cholesterol. Described in the late 1990s as lipid sensors, both LXRs regulate cholesterol and fatty acid homeostasis. Over the years, deep phenotypic analyses of mouse models deficient for LXRα and/or LXRβ have pointed out various other physiological functions including glucose homeostasis, immunology, and neuroprotection. This review enlightens the "endocrine" functions of LXRs; they deeply impact plasma glucose directly and by modulating insulin signaling, renin-angiotensin-aldosterone axis, thyroid and pituitary hormone levels, and bone homeostasis. Besides, LXR signaling is also involved in adrenal physiology, steroid synthesis, and male and female reproduction. Hence, LXRs are definitely involved in the endocrine system and could thus be considered as endocrine receptors, even though oxysterols do not fully correspond to the definition of hormones. Finally, because they are ligand-regulated transcription factors, LXRs are potential pharmacological targets with promising beneficial metabolic effects. Copyright © 2016 Elsevier Ltd. All rights reserved.

Effect of Endocrine Disruptor Pesticides: A Review

Directory of Open Access Journals (Sweden)

Benoit Roig

2011-06-01

Full Text Available Endocrine disrupting chemicals (EDC are compounds that alter the normal functioning of the endocrine system of both wildlife and humans. A huge number of chemicals have been identified as endocrine disruptors, among them several pesticides. Pesticides are used to kill unwanted organisms in crops, public areas, homes and gardens, and parasites in medicine. Human are exposed to pesticides due to their occupations or through dietary and environmental exposure (water, soil, air. For several years, there have been enquiries about the impact of environmental factors on the occurrence of human pathologies. This paper reviews the current knowledge of the potential impacts of endocrine disruptor pesticides on human health.

Cytotoxic CD4 T Cells—Friend or Foe during Viral Infection?

Science.gov (United States)

Juno, Jennifer A.; van Bockel, David; Kent, Stephen J.; Kelleher, Anthony D.; Zaunders, John J.; Munier, C. Mee Ling

2017-01-01

CD4 T cells with cytotoxic function were once thought to be an artifact due to long-term in vitro cultures but have in more recent years become accepted and reported in the literature in response to a number of viral infections. In this review, we focus on cytotoxic CD4 T cells in the context of human viral infections and in some infections that affect mice and non-human primates. We examine the effector mechanisms used by cytotoxic CD4 cells, the phenotypes that describe this population, and the transcription factors and pathways that lead to their induction following infection. We further consider the cells that are the predominant targets of this effector subset and describe the viral infections in which CD4 cytotoxic T lymphocytes have been shown to play a protective or pathologic role. Cytotoxic CD4 T cells are detected in the circulation at much higher levels than previously realized and are now recognized to have an important role in the immune response to viral infections. PMID:28167943

Endocrine system: part 2.

Science.gov (United States)

Hendry, Charles; Farley, Alistair; McLafferty, Ella; Johnstone, Carolyn

2014-06-03

This article, the last in the life sciences series, is the second of two articles on the endocrine system. It discusses human growth hormone, the pancreas and adrenal glands. The relationships between hormones and their unique functions are also explored. It is important that nurses understand how the endocrine system works and its role in maintaining health to provide effective care to patients. Several disorders caused by human growth hormone or that affect the pancreas and adrenal glands are examined.

Intrinsic imperfections of endocrine replacement therapy

NARCIS (Netherlands)

Romijn, J. A.; Smit, J. W. A.; Lamberts, S. W. J.

2003-01-01

Hormonal substitution therapy has been extremely successful, with respect to morbidity and mortality, in the treatment of the major syndromes of endocrine insufficiency. However, many patients treated for endocrine insufficiencies still suffer from more or less vague complaints and a decreased

EDCs DataBank: 3D-Structure database of endocrine disrupting chemicals.

Science.gov (United States)

Montes-Grajales, Diana; Olivero-Verbel, Jesus

2015-01-02

Endocrine disrupting chemicals (EDCs) are a group of compounds that affect the endocrine system, frequently found in everyday products and epidemiologically associated with several diseases. The purpose of this work was to develop EDCs DataBank, the only database of EDCs with three-dimensional structures. This database was built on MySQL using the EU list of potential endocrine disruptors and TEDX list. It contains the three-dimensional structures available on PubChem, as well as a wide variety of information from different databases and text mining tools, useful for almost any kind of research regarding EDCs. The web platform was developed employing HTML, CSS and PHP languages, with dynamic contents in a graphic environment, facilitating information analysis. Currently EDCs DataBank has 615 molecules, including pesticides, natural and industrial products, cosmetics, drugs and food additives, among other low molecular weight xenobiotics. Therefore, this database can be used to study the toxicological effects of these molecules, or to develop pharmaceuticals targeting hormone receptors, through docking studies, high-throughput virtual screening and ligand-protein interaction analysis. EDCs DataBank is totally user-friendly and the 3D-structures of the molecules can be downloaded in several formats. This database is freely available at http://edcs.unicartagena.edu.co. Copyright © 2014. Published by Elsevier Ireland Ltd.

ENDOCRINE OPHTHALMOPATHY: ETIOLOGY, PATHOGENESIS, CLINICAL PICTURE, DIAGNOSIS

Directory of Open Access Journals (Sweden)

Nikonova L. V.

2018-03-01

Full Text Available The relevance of the study of endocrine ophthalmopathy is due to the high prevalence of this disease and a high risk of developing impaired vision that leads to disability of patients. This lecture presents the main genetic, immunological, clinical manifestations of endocrine ophthalmopathy in order to improve the diagnosis and treatment of this pathology. The clinical picture of endocrine ophthalmopathy is various, unique for every patient and depends on the activity and severity of the process, which requires combined etiopathogenetic therapy. The importance of timely diagnosis for endocrine ophthalmopathy with an assessment of the activity of the process for choosing the right tactics for managing patients is very high.

Clinical evaluation of radiotherapy for endocrine ophthalmopathy

International Nuclear Information System (INIS)

Okada, Kayoko; Oshitani, Takashi; Mieda, Chieko

1990-01-01

Ten patients with severe endocrine ophthalmopathy were treated by radiotherapy at Hyogo Medical Center for Adults from May 1984 to February 1988. All but one of the patients had poorly responded to previous systemic or topical corticosteroid therapy. The target of the radiotherapy was both retrobulbar tissues. The radiation field used was about 4 x 4 cm, excluding the pituitary gland and the brain, and was angled 5deg posteriorly to avoid the contralateral lens. A total of 2000 cGy was given to each patient over a 2 week-period. Eight of the ten patients showed some response, with 5 of them (50%) having a good to excellent response. Treatment was more effective for soft tissue changes, proptosis and keratopathy, while myopathy was less responsive. As for the duration of the eye signs and symptoms, those of a shorter duration (less than 12 months) responded better. It was also noted that the degree of the eye muscle enlargement on the pre-treatment orbital CT scan was directly correlated to the results of the treatment. Although three of the patients experienced transient headache, there were no serious acute reactions or long term complications. In conclusion, retrobulbar radiotherapy is a well-tolerated, safe and effective treatment for sever endocrine ophthalmopathy. (author)

Clinical evaluation of radiotherapy for endocrine ophthalmopathy

Energy Technology Data Exchange (ETDEWEB)

Okada, Kayoko; Oshitani, Takashi; Mieda, Chieko (Hyogo Medical Center for Adults, Hyogo (Japan)) (and others)

1990-06-01

Ten patients with severe endocrine ophthalmopathy were treated by radiotherapy at Hyogo Medical Center for Adults from May 1984 to February 1988. All but one of the patients had poorly responded to previous systemic or topical corticosteroid therapy. The target of the radiotherapy was both retrobulbar tissues. The radiation field used was about 4 x 4 cm, excluding the pituitary gland and the brain, and was angled 5deg posteriorly to avoid the contralateral lens. A total of 2000 cGy was given to each patient over a 2 week-period. Eight of the ten patients showed some response, with 5 of them (50%) having a good to excellent response. Treatment was more effective for soft tissue changes, proptosis and keratopathy, while myopathy was less responsive. As for the duration of the eye signs and symptoms, those of a shorter duration (less than 12 months) responded better. It was also noted that the degree of the eye muscle enlargement on the pre-treatment orbital CT scan was directly correlated to the results of the treatment. Although three of the patients experienced transient headache, there were no serious acute reactions or long term complications. In conclusion, retrobulbar radiotherapy is a well-tolerated, safe and effective treatment for sever endocrine ophthalmopathy. (author).

Food odors trigger an endocrine response that affects food ingestion and metabolism.

Science.gov (United States)

Lushchak, Oleh V; Carlsson, Mikael A; Nässel, Dick R

2015-08-01

Food odors stimulate appetite and innate food-seeking behavior in hungry animals. The smell of food also induces salivation and release of gastric acid and insulin. Conversely, sustained odor exposure may induce satiation. We demonstrate novel effects of food odors on food ingestion, metabolism and endocrine signaling in Drosophila melanogaster. Acute exposure to attractive vinegar odor triggers a rapid and transient increase in circulating glucose, and a rapid upregulation of genes encoding the glucagon-like hormone adipokinetic hormone (AKH), four insulin-like peptides (DILPs) and some target genes in peripheral tissues. Sustained exposure to food odors, however, decreases food intake. Hunger-induced strengthening of synaptic signaling from olfactory sensory neurons (OSNs) to brain neurons increases food-seeking behavior, and conversely fed flies display reduced food odor sensitivity and feeding. We show that increasing the strength of OSN signaling chronically by genetic manipulation of local peptide neuromodulation reduces feeding, elevates carbohydrates and diminishes lipids. Furthermore, constitutively strengthened odor sensitivity altered gene transcripts for AKH, DILPs and some of their targets. Thus, we show that food odor can induce a transient anticipatory endocrine response, and that boosted sensitivity to this odor affects food intake, as well as metabolism and hormonal signaling.

Analysis of the Effects of Cell Stress and Cytotoxicity on In ...

Science.gov (United States)

Chemical toxicity can arise from disruption of specific biomolecular functions or through more generalized cell stress and cytotoxicity-mediated processes. Here, concentration-dependent responses of 1063 chemicals including pharmaceuticals, natural products, pesticidals, consumer, and industrial chemicals across a diverse battery of 821 in vitro assay endpoints from 7 high-throughput assay technology platforms were analyzed in order to better distinguish between these types of activities. Both cell-based and cell-free assays showed a rapid increase in the frequency of responses at concentrations where cell stress / cytotoxicity responses were observed in cell-based assays. Chemicals that were positive on at least two viability/cytotoxicity assays within the concentration range tested (typically up to 100 M) activated a median of 12% of assay endpoints while those that were not cytotoxic in this concentration range activated 1.3% of the assays endpoints. The results suggest that activity can be broadly divided into: (1) specific biomolecular interactions against one or more targets (e.g., receptors or enzymes) at concentrations below which overt cytotoxicity-associated activity is observed; and (2) activity associated with cell stress or cytotoxicity, which may result from triggering of specific cell stress pathways, chemical reactivity, physico-chemical disruption of proteins or membranes, or broad low-affinity non-covalent interactions. Chemicals showing a g

The eunuchs of India: An endocrine eye opener

Directory of Open Access Journals (Sweden)

Sanjay Kalra

2012-01-01

Full Text Available There are established guidelines for the endocrine and overall treatment of transsexual persons. These guidelines provide information about the optimal endocrine management of male-to-female and female-to-male transsexual persons. India has a large community of eunuchs, also known as hijras, who are men with gender identity disorders. While this community has been studied from a social and medical point of new, no endocrine work has been done in them. This exploratory article tries to discuss the endocrine status, health, and management of the eunuchs.

Respiratory manifestations in endocrine diseases

OpenAIRE

LENCU, CODRU?A; ALEXESCU, TEODORA; PETRULEA, MIRELA; LENCU, MONICA

2016-01-01

The control mechanisms of respiration as a vital function are complex: voluntary ? cortical, and involuntary ? metabolic, neural, emotional and endocrine. Hormones and hypothalamic neuropeptides (that act as neurotrasmitters and neuromodulators in the central nervous system) play a role in the regulation of respiration and in bronchopulmonary morphology. This article presents respiratory manifestations in adult endocrine diseases that evolve with hormone deficit or hypersecretion. In hyperthy...

Multistage model for the action of cytotoxic T lymphocytes in multicellular conjugates

International Nuclear Information System (INIS)

Macken, C.A.; Perelson, A.S.

1984-01-01

The authors propose a multistage stochastic model to explain data on the kinetics of target cell lysis by cytotoxic T lymphocytes in multicellular conjugates. A novel feature of this model is that the authors explicitly consider both the lethal hitting stage and the target cell disintegration stage of the cytolytic process. Further, the authors allow for the possibility that target cell disintegration is itself a complex process composed of many events. The comparison of this model with the data of other investigators suggests that cytotoxic T cells deliver lethal hits at random to undamage target cells. Having received a lethal hit, the target cell disintegrates over a variable length of time. The disintegration times of target cells from different conjugates appear to be randomly distributed and to be consistent with a model in which disintegration occurs by at least two major, sequential, rate-limiting events. For conjugates containing one lymphocyte and multiple target cells, the mean rate at which a lethally hit target cell disintegrates is found to be independent of the total number of target cells in the conjugate. This model predicts that in such multicellular conjugates, individual target cells lyse one by one, on average at approximately 30-min intervals, thus agreeing closely with previously reported experimental observations. 35 references, 3 figures, 2 tables

Targeted enzyme prodrug therapies.

Science.gov (United States)

Schellmann, N; Deckert, P M; Bachran, D; Fuchs, H; Bachran, C

2010-09-01

The cure of cancer is still a formidable challenge in medical science. Long-known modalities including surgery, chemotherapy and radiotherapy are successful in a number of cases; however, invasive, metastasized and inaccessible tumors still pose an unresolved and ongoing problem. Targeted therapies designed to locate, detect and specifically kill tumor cells have been developed in the past three decades as an alternative to treat troublesome cancers. Most of these therapies are either based on antibody-dependent cellular cytotoxicity, targeted delivery of cytotoxic drugs or tumor site-specific activation of prodrugs. The latter is a two-step procedure. In the first step, a selected enzyme is accumulated in the tumor by guiding the enzyme or its gene to the neoplastic cells. In the second step, a harmless prodrug is applied and specifically converted by this enzyme into a cytotoxic drug only at the tumor site. A number of targeting systems, enzymes and prodrugs were investigated and improved since the concept was first envisioned in 1974. This review presents a concise overview on the history and latest developments in targeted therapies for cancer treatment. We cover the relevant technologies such as antibody-directed enzyme prodrug therapy (ADEPT), gene-directed enzyme prodrug therapy (GDEPT) as well as related therapies such as clostridial- (CDEPT) and polymer-directed enzyme prodrug therapy (PDEPT) with emphasis on prodrug-converting enzymes, prodrugs and drugs.

Psychosocial approach to endocrine disease.

Science.gov (United States)

Sonino, Nicoletta; Tomba, Elena; Fava, Giovanni A

2007-01-01

In recent years, there has been growing interest in the psychosocial aspects of endocrine disease, such as the role of life stress in the pathogenesis of some conditions, their association with affective disorders, and the presence of residual symptoms after adequate treatment. In clinical endocrinology, exploration of psychosocial antecedents may elucidate the temporal relationships between life events and symptom onset, as it has been shown to be relevant for pituitary (Cushing's disease, hyperprolactinemia) or thyroid (Graves' disease) conditions, as well as the role of allostatic load, linked to chronic stress, in uncovering a person's vulnerability. After endocrine abnormalities are established, they are frequently associated with a wide range of psychological symptoms: at times, such symptoms reach the level of psychiatric illness (mainly mood and anxiety disorders); at other times, however, they can only be identified by the subclinical forms of assessment provided by the Diagnostic Criteria for Psychosomatic Research (DCPR). Indeed, in a population study, the majority of patients suffered from at least one of the three DCPR syndromes considered: irritable mood, demoralization, persistent somatization. In particular, irritable mood was found to occur in 46% of 146 patients successfully treated for endocrine conditions, a rate similar to that found in cardiology and higher than in oncology and gastroenterology. Long-standing endocrine disorders may imply a degree of irreversibility of the pathological process and induce highly individualized affective responses. In patients who showed persistence or even worsening of psychological distress upon proper endocrine treatment, the value of appropriate psychiatric interventions was underscored. As it happened in other fields of clinical medicine, a conceptual shift from a merely biomedical care to a psychosomatic consideration of the person and his/her quality of life appears to be necessary for improving

Cloning of the relative genes of endocrine exophthalmos

International Nuclear Information System (INIS)

Zheng, JG

2004-01-01

Aim: In order to clarify the pathogenesis of endocrine exophthalmos, and lay foundations for finding the new functions of its relative genes, the cloning of its relative genes was carried out. Methods: The thyroid tissues of 10 hyperthyroidism patients, 5 of them with endocrine exophthalmos and 5 without that, were obtained. Their mRNA were collected respectively by using Quick Prep Micro mRNA purification kit. Then the same amount of the mRNA from 5 patients with endocrine exophthalmos was added into an eppendorf tube to form a mRNA pool. And that of the 5 patients without endocrine exophthalmos was also prepared as the other pool. As a model, the pool was used to synthesize the single and double chains of cDNA through SMART Tm PCR cDNA Synthesis Kit. The double chains cDNA from the endocrine exophthalmos patients, being used as tester, and that from the patients without endocrine exophthalmos, being used as driver, were digested by restriction endonucleases Hae III to get the fragments which was less than 500 bases. The tester cDNA was ligated with adapt or 1 or 2 respectively. Then the subtractive suppressive hybridization was performed between tester and driver cDNA. And the efficacies of subtraction were measured. The differential genes between the thyroid tissues of endocrine exophthalmos and the thyroid tissues without endocrine exophthalmos were obtained through two cycles of subtractive hybridization and two cycles PCR. The differential genes were cloned into the vector of pT-Adv, and then transformed into E.coliDH5a. 48 white clonies were selected to build the subtractive suppressive library of the relative genes of endocrine exophthalmos. The primer 2 was applied for the colony PCR of the relative genes. The amplified genes were obtained and purified by using Quaqwich Spine PCR Purification Kit. According to the principle of random primer, the double chains cDNA from the thyroid tissues with or without endocrine exophthalmos were digested by Hae III

A novel multiparametric flow cytometry-based cytotoxicity assay simultaneously immunophenotypes effector cells: Comparisons to a 4 h 51Cr-release assay

OpenAIRE

Kim, GG; Donnenberg, VS; Donnenberg, AD; Gooding, W; Whiteside, TL

2007-01-01

Natural killer (NK) cell- or T cell-mediated cytotoxicity traditionally is measured in 4-16h 51Cr-release assays (CRA). A new four-color flow cytometry-based cytotoxicity assay (FCC) was developed to simultaneously measure NK cell cytotoxicity and NK cell phenotype (CD3−CD16+CD56+). Target cells, K562 or Daudi, were labeled with Cell Tracker Orange (CTO) prior to the addition of effector cells. Following co-incubation, 7 amino-actinomycin D (7-AAD) was added to measure death of target cells. ...

IgM-mediated opsonization and cytotoxicity in the shark.

Science.gov (United States)

McKinney, E C; Flajnik, M F

1997-02-01

Two types of cytotoxic reactions have been observed using cells from the nurse shark: spontaneous cytotoxicity mediated by cells of the macrophage lineage and antibody-dependent killing carried out by a different effector cell population. Previous data showed that removal of phagocytic cells using iron particles abolished macrophage-mediated killing, but not antibody-dependent reactions. The current study used single cell assays and showed that the effector of antibody-driven reactions was the neutrophil. Surprisingly, the mechanism of killing was shown to be phagocytosis mediated by both 7S and 19S immunoglobulin M (IgM). Reactions proceeded with as little as 0.01 microg of purified 19S or 7S IgM and were complete within 4-6 h. In contrast, purified immunoglobulin did not adsorb to macrophages and had no effect on target cell binding or cytotoxicity. Pretreatment of cells with cytochalasin D abolished the phagocytic reaction, but not spontaneous cytotoxicity. These data show that antibody-mediated killing results from opsonization and phagocytosis; the mechanism of macrophage killing is currently unknown. In addition, these data show that the shark neutrophil, not the macrophage lineage, carries a receptor for Fc mu.

Scintigraphic imaging of endocrine organs

International Nuclear Information System (INIS)

Gross, M.D.; Shapiro, B.; Thrall, J.H.; Freitas, J.E.; Beierwaltes, W.H.

1984-01-01

The nuclear medicine approach to the portrayal of endocrine organs is unique; the scintigraphic images provide not only anatomic and localization information, but in many instances allow a quantitative assessment of organ function. The ability to image endocrine glands is based upon the design of radionuclides and radiopharmaceuticals with characteristics to take advantage of many unique and specific biochemical and advantage of many unique and specific biochemical and metabolic functions of these tissues. The recent introduction of new radiopharmaceutical and tracers has provided the consulting endocrinologist with imaging procedures that allow localization and functional characterization not available by other single, noninvasive diagnostic modalities. This review will serve as an update of the available techniques to image and quantitate the function of the endocrine glands using the nuclear medicine approach

PET and endocrine tumors

International Nuclear Information System (INIS)

Rigo, P.; Belhocine, T.; Hustinx, R.; Foidart-Willems, J.

2000-01-01

The authors review the main indications of PET examination, and specifically of 18 FDG, in the assessment of endocrine tumors: of the thyroid, of the parathyroid, of the adrenal and of the pituitary glands. Neuroendocrine tumors, gastro-entero-pancreatic or carcinoid tumors are also under the scope. Usually, the most differentiated tumors show only poor uptake of the FDG as they have a weak metabolic and proliferative activity. In the assessment of endocrine tumors, FDG-PET should be used only after most specific nuclear examinations been performed. (author)

Structural requirements for bioactivation of anticonvulsants to cytotoxic metabolites in vitro.

Science.gov (United States)

Riley, R J; Kitteringham, N R; Park, B K

1989-01-01

The formation of cytotoxic metabolites from the anticonvulsants phenytoin and carbamazepine was investigated in vitro using a hepatic microsomal enzyme system and human mononuclear leucocytes as target cells. Both drugs were metabolised to cytotoxic products. In order to assess the structural requirements for this bioactivation, a series of structurally related compounds was investigated. It was found that molecules which contain either an amide function or an aryl ring may undergo activation in vitro, but only the metabolism-dependent toxicity of the latter is potentiated by pre-treatment of the target cells with an epoxide hydrolase inhibitor. Taken collectively, these data are consistent with the concept that reactive epoxide metabolites of both phenytoin and carbamazepine may produce toxicity in individuals with an inherited deficiency in epoxide hydrolase. PMID:2590607

Update on endocrine disturbances in anorexia nervosa

DEFF Research Database (Denmark)

Støving, R K; Hangaard, J; Hagen, C

2001-01-01

The marked endocrine changes that occur in anorexia nervosa have aroused a great deal of interest, and over the last decade much research has been conducted in this field. The endocrine disturbances are not specific to this disorder, as they also occur in starvation states secondary to other causes...... of the large body of literature concerning endocrine aspects of anorexia nervosa with the main focus on the latest results, which provide leads for potential etiological theories....

Diagnosis and pathology of endocrine diseases

International Nuclear Information System (INIS)

Shriver, B.D.

1988-01-01

This book contains 22 papers under the headings of Diagnosis and Pathology of endocrine diseases. Topics covered include: Laboratory tests in the diagnosis and management of thyroid disorders, Pathology of thyroid diseases, Diagnosis of adrenourtical disease, Radiologic techniques in evaluating endocrine disorders; and the Pituitary and adrenal glands

Diagnosis and pathology of endocrine diseases

Energy Technology Data Exchange (ETDEWEB)

Shriver, B.D.

1988-01-01

This book contains 22 papers under the headings of Diagnosis and Pathology of endocrine diseases. Topics covered include: Laboratory tests in the diagnosis and management of thyroid disorders, Pathology of thyroid diseases, Diagnosis of adrenourtical disease, Radiologic techniques in evaluating endocrine disorders; and the Pituitary and adrenal glands.

Endocrine pancreatic function changes after acute pancreatitis.

Science.gov (United States)

Wu, Deqing; Xu, Yaping; Zeng, Yue; Wang, Xingpeng

2011-10-01

This study aimed to investigate the impairment of pancreatic endocrine function and the associated risk factors after acute pancreatitis (AP). Fifty-nine patients were subjected to tests of pancreatic function after an attack of pancreatitis. The mean time after the event was 3.5 years. Pancreatic endocrine function was evaluated by fasting blood glucose (FBG), glycosylated hemoglobin, fasting blood insulin, and C-peptide. Homeostasis model assessment was used to evaluate insulin resistance and islet β-cell function. Pancreatic exocrine function was evaluated by fecal elastase 1. Factors that could influence endocrine function were also investigated. Nineteen patients (32%) were found to have elevated FBG, whereas 5 (8%) had abnormal glycosylated hemoglobin levels. The levels of FBG, fasting blood insulin, and C-peptide were higher in patients than in controls (P endocrine insufficiency. Pancreatic exocrine functional impairment was found at the same time. Endocrine functional impairment with insulin resistance was found in patients after AP. Obesity, hyperlipidemia, and diabetes-related symptoms increased the likelihood of developing functional impairment after AP.

Calcein AM release-based cytotoxic cell assay for fish leucocytes.

Science.gov (United States)

Iwanowicz, Luke R; Densmore, Christine L; Ottinger, Christopher A

2004-02-01

A non-specific cytotoxic cell assay for fish is presented that is based on the release of the activated fluorochrome calcein AM from lysed carp epithelioma papulosum cyprini (EPC) cells. To establish the suitability of treating EPC cells with calcein AM the uptake and spontaneous release of the calcein AM by the EPC cells was evaluated. Incubation of 5 microM calcein AM in culture medium with 1x10(5)EPC cells well(-1)for a minimum of 3 h provided sufficient labelling. Spontaneous release of fluorescence from the labelled EPC cells during 10 h of post labelling incubation ranged from 30 to 39% of the total observed fluorescence. Cytotoxic activity of trout leucocytes was evaluated at three leucocyte to target cell ratios (10:1, 2:1 and 1:1) following incubation (4, 6, 8, and 10 h) with calcein AM-labelled EPC cells at 15 degrees C. In some instances, the monoclonal antibody specific for the NCC surface receptor NCCRP-1 (MAb5C.6) was included in the cultures. The activity of NCC cells was significantly inhibited in the presence of 0.25 microg well(-1)of MAb5C.6 relative to no antibody (Pcytotoxic cell activity of approximately 18% was observed following 8 h of incubation at the 2:1 and 1:1 leucocyte to target cell ratios. Percent cytotoxic cell activity using calcein AM was similar to values reported for rainbow trout leucocytes using the 51Cr-release assay.

Endocrine Dysfunctions in Patients with Inherited Metabolic Diseases.

Science.gov (United States)

Erdöl, Şahin; Sağlam, Halil

2016-09-01

Inherited metabolic diseases (IMDs) can affect many organ systems, including the endocrine system. There are limited data regarding endocrine dysfunctions related to IMDs in adults, however, no data exist in pediatric patients with IMDs. The aim of this study was to investigate endocrine dysfunctions in patients with IMDs by assessing their demographic, clinical, and laboratory data. Data were obtained retrospectively from the medical reports of patients with IMDs who were followed by the division of pediatric metabolism and nutrition between June 2011 and November 2013. In total, 260 patients [139 males (53%) and 121 females (47%)] with an IMD diagnosis were included in the study. The mean age of the patients was 5.94 (range; 0.08 to 49) years and 95.8% (249 of 260 patients) were in the pediatric age group. Growth status was evaluated in 258 patients and of them, 27 (10.5%) had growth failure, all cases of which were attributed to non-endocrine reasons. There was a significant correlation between growth failure and serum albumin levels below 3.5 g/dL (p=0.002). Only three of 260 (1.1%) patients had endocrine dysfunction. Of these, one with lecithin-cholesterol acyltransferase deficiency and another with Kearns-Sayre syndrome had diabetes, and one with glycerol kinase deficiency had glucocorticoid deficiency. Endocrine dysfunction in patients with IMDs is relatively rare. For this reason, there is no need to conduct routine endocrine evaluations in most patients with IMDs unless a careful and detailed history and a physical examination point to an endocrine dysfunction.

Endocrine potency of wastewater: Contents of endocrine disrupting chemicals and effects measured by in vivo and in vitro assays

DEFF Research Database (Denmark)

Kusk, Kresten Ole; Krüger, Tanja; Long, Manhai

2011-01-01

chemical analysis and a battery of bioassays. Influent samples, collected at the first STP grate, and effluent samples, collected after the sewage treatment, were extracted using solid phase extraction. Extracts were analyzed for the content of a range of industrial chemicals with endocrine disrupting...... properties: phthalate metabolites, parabens, industrial phenols, ultraviolet screens, and natural and synthetic steroid estrogens. The endocrine disrupting bioactivity and toxicity of the extracts were analyzed in cell culture assay for the potency to affect the function of the estrogen, androgen, aryl......Industrial and municipal effluents are important sources of endocrine disrupting compounds (EDCs) discharged into the aquatic environment. This study investigated the endocrine potency of wastewater and the cleaning efficiency of two typical urban Danish sewage treatment plants (STPs), using...

Cytotoxic effects and aromatase inhibition by xenobiotic endocrine disrupters alone and in combination

International Nuclear Information System (INIS)

Benachour, Nora; Moslemi, Safa; Sipahutar, Herbert; Seralini, Gilles-Eric

2007-01-01

Xenobiotics may cause long-term adverse effects in humans, especially at the embryonic level, raising questions about their levels of exposure, combined effects, and crucial endpoints. We are interested in the possible interactions between xenobiotic endocrine disrupters, cellular viability and androgen metabolism. Accordingly, we tested aroclor 1254 (A1254), atrazine (AZ), o,p'-DDT, vinclozolin (VZ), p,p'-DDE, bisphenol A (BPA), chlordecone (CD), nonylphenol (NP), tributylin oxide (TBTO), and diethylstilbestrol (DES) for cellular toxicity against human embryonic 293 cells, and activity against cellular aromatase, but also on placental microsomes and on the purified equine enzyme. Cellular viability was affected in 24 h by all the xenobiotics with a threshold at 50 μM (except for TBTO and DES, 10 μM threshold), and aromatase was inhibited at non-toxic doses. In combination synergism was observed reducing the threshold values of toxicity to 4-10 μM, and aromatase activity by 50% in some cases. In placental microsomes the most active xenobiotics rapidly inhibited microsomal aromatase in a manner independent of NADPH metabolism. Prolonged exposures to low doses in cells generally amplified by 50 times aromatase inhibition. These xenobiotics may act by inhibition of the active site or by allosteric effects on the enzyme. Bioaccumulation is a feature of some xenobiotics, especially chlordecone, DDT and DDE, and low level chronic exposures can also affect cell signaling mechanisms. This new information about the mechanism of action of these xenobiotics will assist in improved molecular design with a view to providing safer compounds for use in the (human) environment

CTL lysis: there is a hyperbolic relation of killing rate to exocytosable granzyme A for highly cytotoxic murine cytotoxic T lymphocytes.

Science.gov (United States)

Poe, M; Wu, J K; Talento, A; Koo, G C

1996-06-10

The lysis of susceptible targets by efficient cytotoxic T lymphocytes (CTL) increases both with time and with the ratio of CTL to target. Simple methods for calculating a killing rate constant from the time dependence of killing and for calculating the relation of the killing rate constant to the concentration of exocytosable granzyme A are given. Application of these methods to the killing of target cells by the highly efficient mouse CTL AR1 is presented. AR1 needed granzyme A for efficient killing. AR1 contained sufficient exocytosable granzyme A to kill at about 80% of the rate possible at infinite exocytosable granzyme A.

Purinergic signaling pathways in endocrine system.

Science.gov (United States)

Bjelobaba, Ivana; Janjic, Marija M; Stojilkovic, Stanko S

2015-09-01

Adenosine-5'-triphosphate is released by neuroendocrine, endocrine, and other cell types and acts as an extracellular agonist for ligand-gated P2X cationic channels and G protein-coupled P2Y receptors in numerous organs and tissues, including the endocrine system. The breakdown of ATP by ectonucleotidases not only terminates its extracellular messenger functions, but also provides a pathway for the generation of two additional agonists: adenosine 5'-diphosphate, acting via some P2Y receptors, and adenosine, a native agonist for G protein-coupled adenosine receptors, also expressed in the endocrine system. This article provides a review of purinergic signaling pathways in the hypothalamic magnocellular neurosecretory cells and neurohypophysis, hypothalamic parvocellular neuroendocrine system, adenohypophysis, and effector glands organized in five axes: hypothalamic-pituitary-gonadal, hypothalamic-pituitary-thyroid, hypothalamic-pituitary-adrenal, hypothalamic-pituitary-growth hormone, and hypothalamic-pituitary-prolactin. We attempted to summarize current knowledge of purinergic receptor subtypes expressed in the endocrine system, including their roles in intracellular signaling, hormone secretion, and other cell functions. We also briefly review the release mechanism for adenosine-5'-triphosphate by neuroendocrine, endocrine and surrounding cells, the enzymes involved in adenosine-5'-triphosphate hydrolysis to adenosine-5'-diphosphate and adenosine, and the relevance of this pathway for sequential activation of receptors and termination of signaling. Published by Elsevier B.V.

Purinergic Signaling Pathways in Endocrine System

Science.gov (United States)

Bjelobaba, Ivana; Janjic, Marija M.; Stojilkovic, Stanko S.

2015-01-01

Adenosine-5′-triphosphate is released by neuroendocrine, endocrine, and other cell types and acts as an extracellular agonist for ligand-gated P2X cationic channels and G protein-coupled P2Y receptors in numerous organs and tissues, including the endocrine system. The breakdown of ATP by ectonucleotidases not only terminates its extracellular messenger functions, but also provides a pathway for the generation of two additional agonists: adenosine 5′-diphosphate, acting via some P2Y receptors, and adenosine, a native agonist for G protein-coupled adenosine receptors, also expressed in the endocrine system. This article provides a review of purinergic signaling pathways in the hypothalamic magnocellular neurosecretory cells and neurohypophysis, hypothalamic parvocellular neuroendocrine system, adenohypophysis, and effector glands organized in five axes: hypothalamic-pituitary-gonadal, hypothalamic-pituitary-thyroid, hypothalamic-pituitary-adrenal, hypothalamic-pituitary-growth hormone, and hypothalamic-pituitary-prolactin. We attempted to summarize current knowledge of purinergic receptor subtypes expressed in the endocrine system, including their roles in intracellular signaling, hormone secretion, and other cell functions. We also briefly review the release mechanism for adenosine-5′-triphosphate by neuroendocrine, endocrine and surrounding cells, the enzymes involved in adenosine-5′-triphosphate hydrolysis to adenosine-5′-diphosphate and adenosine, and the relevance of this pathway for sequential activation of receptors and termination of signaling. PMID:25960051

Pediatric endocrine surgery development

Directory of Open Access Journals (Sweden)

Ivan I. Dedov

2017-12-01

Full Text Available Department of pediatric surgery at the Endocrinology Research Centre has been around for nearly two years. During operation, surgical treatment has received more than 500 patients with various endocrine disorders. The article discusses modern diagnostic approaches and surgical options for diseases included in the new direction of pediatric surgery – endocrine surgery in children. There are discussions about options for radical treatment of Graves disease in children, positive and negative aspects of surgical and radioactive iodine treatment. Is own stats of postoperative hyperparathyroidism. Is proposed to optimize the algorithm of actions in identifying thyroid nodules in children. In primary hyperparathyroidism, the emphasis is on the complexity of the postoperative management of patients related to the feature of children’s age in determining the severity of the reactions on the water-electrolyte disorders. Separately reviewed the literature of the adrenal glands diseases in children, demonstrating their own clinical cases which required surgical intervention. The authors describe the possibilities of modern neurosurgical equipment in the Endocrinology Research Centre in operations on the pituitary gland in children. Patients of different age groups performed transnasal transsphenoidal removal of tumors of the chiasm-sellar region using endoscopic assistance. The article also cited research data of pancreas diseases and their surgical treatment. Much attention is paid to the gender section of endocrine surgery in children. Discusses the tactics in disorders of sex development, gonadal tumors in children, diseases of the breast. In conclusion outlines the prospects for the development of endocrine surgery in children.

Alterations in polyadenylation and its implications for endocrine disease

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Anders eRehfeld

2013-05-01

Full Text Available IntroductionPolyadenylation is the process in which the pre-mRNA is cleaved at the poly(A site and a poly(A tail is added - a process necessary for normal mRNA formation. Genes with multiple poly(A sites can undergo alternative polyadenylation, producing distinct mRNA isoforms with different 3’ untranslated regions (3’ UTRs and in some cases different coding regions. Two thirds of all human genes undergo alternative polyadenylation. The efficiency of the polyadenylation process regulates gene expression and alternative polyadenylation plays an important part in post-transcriptional regulation, as the 3’ UTR contains various cis-elements associated with post-transcriptional regulation, such as target sites for microRNAs and RNA-binding proteins.Implications of alterations in polyadenylation for endocrine diseaseAlterations in polyadenylation have been found to be causative of neonatal diabetes and IPEX (immune dysfunction, polyendocrinopathy, enteropathy, X-linked and to be associated with type I and II diabetes, pre-eclampsia, fragile X-associated premature ovarian insufficiency, ectopic Cushing syndrome and many cancer diseases, including several types of endocrine tumor diseases.PerspectivesRecent developments in high-throughput sequencing have made it possible to characterize polyadenylation genome-wide. Antisense elements inhibiting or enhancing specific poly(A site usage can induce desired alterations in polyadenylation, and thus hold the promise of new therapeutic approaches. SummaryThis review gives a detailed description of alterations in polyadenylation in endocrine disease, an overview of the current literature on polyadenylation and summarizes the clinical implications of the current state of research in this field.

Immune Response to Recombinant Adenovirus in Humans: Capsid Components from Viral Input Are Targets for Vector-Specific Cytotoxic T Lymphocytes

Science.gov (United States)

Molinier-Frenkel, Valérie; Gahery-Segard, Hanne; Mehtali, Majid; Le Boulaire, Christophe; Ribault, Sébastien; Boulanger, Pierre; Tursz, Thomas; Guillet, Jean-Gérard; Farace, Françoise

2000-01-01

We previously demonstrated that a single injection of 109 PFU of recombinant adenovirus into patients induces strong vector-specific immune responses (H. Gahéry-Ségard, V. Molinier-Frenkel, C. Le Boulaire, P. Saulnier, P. Opolon, R. Lengagne, E. Gautier, A. Le Cesne, L. Zitvogel, A. Venet, C. Schatz, M. Courtney, T. Le Chevalier, T. Tursz, J.-G. Guillet, and F. Farace, J. Clin. Investig. 100:2218–2226, 1997). In the present study we analyzed the mechanism of vector recognition by cytotoxic T lymphocytes (CTL). CD8+ CTL lines were derived from two patients and maintained in long-term cultures. Target cell infections with E1-deleted and E1-plus E2-deleted adenoviruses, as well as transcription-blocking experiments with actinomycin D, revealed that host T-cell recognition did not require viral gene transcription. Target cells treated with brefeldin A were not lysed, indicating that viral input protein-derived peptides are associated with HLA class I molecules. Using recombinant capsid component-loaded targets, we observed that the three major proteins could be recognized. These results raise the question of the use of multideleted adenoviruses for gene therapy in the quest to diminish antivector CTL responses. PMID:10906225

Tumor-Selective Cytotoxicity of Nitidine Results from Its Rapid Accumulation into Mitochondria

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Hironori Iwasaki

2017-01-01

Full Text Available We identified a nitidine- (NTD- accumulating organelle and evaluated the net cytotoxicity of accumulated NTD. To evaluate tumor cell selectivity of the drug, we evaluated its selective cytotoxicity against 39 human cancer cell lines (JFCR39 panel, and the profile was compared with those of known anticancer drugs. Organelle specificity of NTD was visualized using organelle-targeted fluorescent proteins. Real-time analysis of cell growth, proliferation, and cytotoxicity was performed using the xCELLigence system. Selectivity of NTD in the JFCR39 panel was evaluated. Mitochondria-specific accumulation of NTD was observed. Real-time cytotoxicity analysis suggested that the mechanism of NTD-induced cell death is independent of the cell cycle. Short-term treatment indicated that this cytotoxicity only resulted from the accumulation of NTD into the mitochondria. The results from the JFCR39 panel indicated that NTD-mediated cytotoxicity resulted from unique mechanisms compared with those of other known anticancer drugs. These results suggested that the cytotoxicity of NTD is only induced by its accumulation in mitochondria. The drug triggered mitochondrial dysfunction in less than 2 h. Similarity analysis of the selectivity of NTD in 39 tumor cell lines strongly supported the unique tumor cell specificity of NTD. Thus, these features indicate that NTD may be a promising antitumor drug for new combination chemotherapies.

Precommitment low-level Neurog3 expression defines a long-lived mitotic endocrine-biased progenitor pool that drives production of endocrine-committed cells

Science.gov (United States)

Bechard, Matthew E.; Bankaitis, Eric D.; Hipkens, Susan B.; Ustione, Alessandro; Piston, David W.; Yang, Yu-Ping; Magnuson, Mark A.; Wright, Christopher V.E.

2016-01-01

The current model for endocrine cell specification in the pancreas invokes high-level production of the transcription factor Neurogenin 3 (Neurog3) in Sox9+ bipotent epithelial cells as the trigger for endocrine commitment, cell cycle exit, and rapid delamination toward proto-islet clusters. This model posits a transient Neurog3 expression state and short epithelial residence period. We show, however, that a Neurog3TA.LO cell population, defined as Neurog3 transcriptionally active and Sox9+ and often containing nonimmunodetectable Neurog3 protein, has a relatively high mitotic index and prolonged epithelial residency. We propose that this endocrine-biased mitotic progenitor state is functionally separated from a pro-ductal pool and endows them with long-term capacity to make endocrine fate-directed progeny. A novel BAC transgenic Neurog3 reporter detected two types of mitotic behavior in Sox9+ Neurog3TA.LO progenitors, associated with progenitor pool maintenance or derivation of endocrine-committed Neurog3HI cells, respectively. Moreover, limiting Neurog3 expression dramatically increased the proportional representation of Sox9+ Neurog3TA.LO progenitors, with a doubling of its mitotic index relative to normal Neurog3 expression, suggesting that low Neurog3 expression is a defining feature of this cycling endocrine-biased state. We propose that Sox9+ Neurog3TA.LO endocrine-biased progenitors feed production of Neurog3HI endocrine-committed cells during pancreas organogenesis. PMID:27585590

Endocrine Disrupting Chemicals and Disease Susceptibility

Science.gov (United States)

Schug, Thaddeus T.; Janesick, Amanda; Blumberg, Bruce; Heindel, Jerrold J.

2011-01-01

Environmental chemicals have significant impacts on biological systems. Chemical exposures during early stages of development can disrupt normal patterns of development and thus dramatically alter disease susceptibility later in life. Endocrine disrupting chemicals (EDCs) interfere with the body's endocrine system and produce adverse developmental, reproductive, neurological, cardiovascular, metabolic and immune effects in humans. A wide range of substances, both natural and man-made, are thought to cause endocrine disruption, including pharmaceuticals, dioxin and dioxin-like compounds, polychlorinated biphenyls, DDT and other pesticides, and components of plastics such as bisphenol A (BPA) and phthalates. EDCs are found in many everyday products– including plastic bottles, metal food cans, detergents, flame retardants, food additives, toys, cosmetics, and pesticides. EDCs interfere with the synthesis, secretion, transport, activity, or elimination of natural hormones. This interference can block or mimic hormone action, causing a wide range of effects. This review focuses on the mechanisms and modes of action by which EDCs alter hormone signaling. It also includes brief overviews of select disease endpoints associated with endocrine disruption. PMID:21899826

Classification of human natural killer cells based on migration behavior and cytotoxic response.

Science.gov (United States)

Vanherberghen, Bruno; Olofsson, Per E; Forslund, Elin; Sternberg-Simon, Michal; Khorshidi, Mohammad Ali; Pacouret, Simon; Guldevall, Karolin; Enqvist, Monika; Malmberg, Karl-Johan; Mehr, Ramit; Önfelt, Björn

2013-02-21

Despite intense scrutiny of the molecular interactions between natural killer (NK) and target cells, few studies have been devoted to dissection of the basic functional heterogeneity in individual NK cell behavior. Using a microchip-based, time-lapse imaging approach allowing the entire contact history of each NK cell to be recorded, in the present study, we were able to quantify how the cytotoxic response varied between individual NK cells. Strikingly, approximately half of the NK cells did not kill any target cells at all, whereas a minority of NK cells was responsible for a majority of the target cell deaths. These dynamic cytotoxicity data allowed categorization of NK cells into 5 distinct classes. A small but particularly active subclass of NK cells killed several target cells in a consecutive fashion. These "serial killers" delivered their lytic hits faster and induced faster target cell death than other NK cells. Fast, necrotic target cell death was correlated with the amount of perforin released by the NK cells. Our data are consistent with a model in which a small fraction of NK cells drives tumor elimination and inflammation.

WNT4 mediates estrogen receptor signaling and endocrine resistance in invasive lobular carcinoma cell lines.

Science.gov (United States)

Sikora, Matthew J; Jacobsen, Britta M; Levine, Kevin; Chen, Jian; Davidson, Nancy E; Lee, Adrian V; Alexander, Caroline M; Oesterreich, Steffi

2016-09-20

critical role in estrogen-induced growth that may also mediate endocrine resistance. WNT4 signaling may represent a novel target to modulate endocrine response specifically for patients with ILC.

Arterial and venous thrombosis in endocrine diseases

NARCIS (Netherlands)

van Zaane, Bregje; Stuijver, Danka J. F.; Squizzato, Alessandro; Gerdes, Victor E. A.

2013-01-01

Endocrine diseases have been associated with cardiovascular events. Both altered coagulation and fibrinolysis markers and thrombotic disorders have been described in several endocrine diseases. This review summarizes the evidence on the influence of thyroid diseases, cortisol excess and deficiency,

Case series

African Journals Online (AJOL)

5 sept. 2012 ... 2000;4(5):415-418. This article on PubMed. 24. Azim HA Jr, Peccatori FA, Pavlidis N. Treatment of the pregnant mother with cancer: a systematic review on the use of cytotoxic, endocrine, targeted agents and immunotherapy during pregnancy. Part I: Solid tumors. Cancer Treat Rev. 2010 Apr;36(2):101-9.

Reproductive toxicity of the endocrine disrupters vinclozolin and bisphenol A in the terrestrial isopod Porcellio scaber (Latreille, 1804).

NARCIS (Netherlands)

Lemos, M.F.L.; van Gestel, C.A.M.; Soares, A.M.V.M.

2010-01-01

Endocrine Disruptor Compounds (EDCs) have been largely studied concerning their effects on vertebrates. Nevertheless, invertebrates as targets for these chemicals have been neglected and few studies are available. Specifically for edaphic invertebrates, data concerning the effects of EDCs is

Impact of diffusion barriers to small cytotoxic molecules on the efficacy of immunotherapy in breast cancer.

Directory of Open Access Journals (Sweden)

Hiranmoy Das

Full Text Available Molecular-focused cancer therapies, e.g., molecularly targeted therapy and immunotherapy, so far demonstrate only limited efficacy in cancer patients. We hypothesize that underestimating the role of biophysical factors that impact the delivery of drugs or cytotoxic cells to the target sites (for associated preferential cytotoxicity or cell signaling modulation may be responsible for the poor clinical outcome. Therefore, instead of focusing exclusively on the investigation of molecular mechanisms in cancer cells, convection-diffusion of cytotoxic molecules and migration of cancer-killing cells within tumor tissue should be taken into account to improve therapeutic effectiveness. To test this hypothesis, we have developed a mathematical model of the interstitial diffusion and uptake of small cytotoxic molecules secreted by T-cells, which is capable of predicting breast cancer growth inhibition as measured both in vitro and in vivo. Our analysis shows that diffusion barriers of cytotoxic molecules conspire with γδ T-cell scarcity in tissue to limit the inhibitory effects of γδ T-cells on cancer cells. This may increase the necessary ratios of γδ T-cells to cancer cells within tissue to unrealistic values for having an intended therapeutic effect, and decrease the effectiveness of the immunotherapeutic treatment.

A RNA-DNA Hybrid Aptamer for Nanoparticle-Based Prostate Tumor Targeted Drug Delivery

Directory of Open Access Journals (Sweden)

John C. Leach

2016-03-01

Full Text Available The side effects of radio- and chemo-therapy pose long-term challenges on a cancer patient’s health. It is, therefore, highly desirable to develop more effective therapies that can specifically target carcinoma cells without damaging normal and healthy cells. Tremendous efforts have been made in the past to develop targeted drug delivery systems for solid cancer treatment. In this study, a new aptamer, A10-3-J1, which recognizes the extracellular domain of the prostate specific membrane antigen (PSMA, was designed. A super paramagnetic iron oxide nanoparticle-aptamer-doxorubicin (SPIO-Apt-Dox was fabricated and employed as a targeted drug delivery platform for cancer therapy. This DNA RNA hybridized aptamer antitumor agent was able to enhance the cytotoxicity of targeted cells while minimizing collateral damage to non-targeted cells. This SPIO-Apt-Dox nanoparticle has specificity to PSMA+ prostate cancer cells. Aptamer inhibited nonspecific uptake of membrane-permeable doxorubic to the non-target cells, leading to reduced untargeted cytotoxicity and endocytic uptake while enhancing targeted cytotoxicity and endocytic uptake. The experimental results indicate that the drug delivery platform can yield statistically significant effectiveness being more cytotoxic to the targeted cells as opposed to the non-targeted cells.

Cytotoxicity Testing: Cell Experiments

Science.gov (United States)

Grünert, Renate; Westendorf, Aron; Buczkowska, Magdalena; Hänsch, Mareike; Grüunert, Sybil; Bednarski, Patrick J.

Screening for new anticancer agents has traditionally been done with in vitro cell culture methods. Even in the genomic era of target-driven drug design, screening for cytotoxic activity is still a standard tool in the search for new anticancer agents, especially if the mode of action of a substance is not yet known. A wide variety of cell culture methods with unique end-points are available for testing the anticancer potential of a substance. Each has its advantages and disadvantages, which must be weighed in the decision to use a particular method. Often several complementary methods are used to gain information on the mode of action of a substance.

Celastrol targets mitochondrial respiratory chain complex I to induce reactive oxygen species-dependent cytotoxicity in tumor cells

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Xu Yuanji

2011-05-01

Full Text Available Abstract Background Celastrol is an active ingredient of the traditional Chinese medicinal plant Tripterygium Wilfordii, which exhibits significant antitumor activity in different cancer models in vitro and in vivo; however, the lack of information on the target and mechanism of action of this compound have impeded its clinical application. In this study, we sought to determine the mode of action of celastrol by focusing on the processes that mediate its anticancer activity. Methods The downregulation of heat shock protein 90 (HSP90 client proteins, phosphorylation of c-Jun NH2-terminal kinase (JNK, and cleavage of PARP, caspase 9 and caspase 3 were detected by western blotting. The accumulation of reactive oxygen species (ROS was analyzed by flow cytometry and fluorescence microscopy. Cell cycle progression, mitochondrial membrane potential (MMP and apoptosis were determined by flow cytometry. Absorption spectroscopy was used to determine the activity of mitochondrial respiratory chain (MRC complexes. Results Celastrol induced ROS accumulation, G2-M phase blockage, apoptosis and necrosis in H1299 and HepG2 cells in a dose-dependent manner. N-acetylcysteine (NAC, an antioxidative agent, inhibited celastrol-induced ROS accumulation and cytotoxicity. JNK phosphorylation induced by celastrol was suppressed by NAC and JNK inhibitor SP600125 (SP. Moreover, SP significantly inhibited celastrol-induced loss of MMP, cleavage of PARP, caspase 9 and caspase 3, mitochondrial translocation of Bad, cytoplasmic release of cytochrome c, and cell death. However, SP did not inhibit celastrol-induced ROS accumulation. Celastrol downregulated HSP90 client proteins but did not disrupt the interaction between HSP90 and cdc37. NAC completely inhibited celastrol-induced decrease of HSP90 client proteins, catalase and thioredoxin. The activity of MRC complex I was completely inhibited in H1299 cells treated with 6 μM celastrol in the absence and presence of NAC

Endocrine Abnormalities in Patients with Chronic Kidney Disease.

Science.gov (United States)

Kuczera, Piotr; Adamczak, Marcin; Wiecek, Andrzej

2015-01-01

In patients with chronic kidney disease the alterations of the endocrine system may arise from several causes. The kidney is the site of degradation as well as synthesis of many different hormones. Moreover, a number of concomitant pathological conditions such as inflammation, metabolic acidosis and malnutrition may participate in the pathogenesis of endocrine abnormalities in this group of patients. The most pronounced endocrine abnormalities in patients with chronic kidney disease are the deficiencies of: calcitriol, testosterone, insulin-like growth factor and, erythropoietin (EPO). Additionally accumulation of several hormones, such as: prolactin, growth hormone and insulin frequently also occur. The clinical consequences of the abovementioned endocrine abnormalities are among others: anemia, infertility and bone diseases.

Endocrine dysfunction among adult patients with tuberculosis: An African experience

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Davis Kibirige

2014-01-01

Full Text Available A broad spectrum of endocrine conditions has been reported among adult patients with tuberculosis in Africa. This review aims to describe the magnitude and pathogenesis of the following endocrinopathies among patients with tuberculosis in Africa: adrenal insufficiency, diabetes mellitus, disorders of calcium and vitamin D metabolism, thyroid dysfunction and hypogonadism. PubMed database and Google scholar were used to search for the relevant published English language studies and case reports relating to endocrine abnormalities and tuberculosis in Africa up to July 2013. The search terms used were endocrine dysfunction, endocrine abnormalities, adrenal insufficiency, diabetes mellitus, thyroid dysfunction, hypogonadism, disorders of calcium and vitamin D metabolism, tuberculosis, Africa. Reference lists of the identified articles were further used to identify other studies. Adrenal insufficiency, diabetes mellitus and calcium-vitamin D abnormalities were the most prevalent and frequently reported endocrine disorders among adult patients with tuberculosis in Africa. A meticulous endocrine evaluation among tuberculosis patients with suspected endocrine abnormalities should be encouraged in Africa and other high TB endemic regions. Treatment of these endocrine disorders has generally been shown to improve quality of life and reduce mortality.

Multiple endocrine diseases in dogs: 35 cases (1996-2009).

Science.gov (United States)

Blois, Shauna L; Dickie, Erica; Kruth, Stephen A; Allen, Dana G

2011-06-15

To characterize a population of dogs from a tertiary care center with 2 or more endocrine disorders, including the specific disorders and time intervals between diagnosis of each disorder. Retrospective case series. 35 dogs with 2 or more endocrine disorders. Medical records were reviewed, and the following was recorded: clinical signs, physical examination findings, and the results of CBC, serum biochemical analysis, urinalysis, aerobic bacterial culture of urine samples, endocrine testing, diagnostic imaging, and necropsy. 35 dogs with more than 1 endocrine disorder were identified. Seventy-seven percent (27/35) of the dogs were male, and the mean age at the time of diagnosis of the first endocrinopathy was 7.9 years. Miniature Schnauzer was the most common breed. Twenty-eight of 35 (80%) dogs had 2 disorders; 7 (20%) had 3 disorders. The most common combinations of disorders included diabetes mellitus and hyperadrenocorticism in 57.1 % (20/35) of dogs; hypoadrenocorticism and hypothyroidism in 22.9% (8/35) of dogs; and diabetes mellitus and hypothyroidism in 28.6% (10/35) of dogs. A mean of 14.5 months elapsed between diagnosis of the first and second endocrine disorders, whereas there was a mean of 31.1 months between diagnosis of the first and third endocrine disorders. Results suggested that the occurrence of multiple endocrine disorders was uncommon in dogs. The most common combinations of endocrine disorders in this population of dogs were diabetes mellitus and hyperadrenocorticism, followed by hypoadrenocorticism and hypothyroidism.

SEARCH FOR TARGET TISSUE IN THE EYE ORBIT FOR AUTOIMMUNE AGGRESSION OF THYROID ANTIBODIES IN ENDOCRINE OPHTHALMOPATHY

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V. G. Likhvantseva

2017-01-01

Full Text Available We searched for a possible target tissue in eye orbit for thyroid autoantibodies in endocrine ophthalmopathy (Graves’ disease, using correlation analysis method. We examined a group of 139 patients (278 eye orbits with thyroid-associated ophthalmopathy associated with diffuse toxic goiter. Serological parameters (antibodies to thyroid-stimulating hormone receptor; thyroglobulin, thyroid peroxidase were compared with instrumental diagnostic data (multi-layer CT, ultrasonography of eye orbit, and exophthalmometer, as well as clinical symptoms. Statistical correlation analysis enabled us to show different degrees of association between thyroid antibodies and clinical manifestations of Graves’ disease and eye orbit involvement. Especially, carriers of antibodies to TSH receptor and thyroglobulin (as compared to seronegative patients exhibited higher exophthalmos scores (19.16±0.26 mm, p < 0.001, and 19.41±0.40 mm, p < 0.05, respectively, and with total muscle index (2.42±0.05, p < 0.01, and 2.42±0.08, respectively. Meanwhile, eyelids in carriers of antibodies to TSH receptor and thyroid peroxidase proved to be more swollen (p < 0.001, p < 0.05, respectively. Carriage of antibodies to thyroglobulin was associated with synchronous involvement of two structures of the eye orbit: extraocular muscles and retrobulbar tissue, which is reflected by increase in the average ntegral exophthalmos index within the group.

The clandestine organs of the endocrine system.

Science.gov (United States)

Garcia-Reyero, Natàlia

2018-02-01

This review analyzes what could be regarded as the "clandestine organs" of the endocrine system: the gut microbiome, the immune system, and the stress system. The immune system is very closely related to the endocrine system, with many intertwined processes and signals. Many researchers now consider the microbiome as an 'organ' that affects the organism at many different levels. While stress is certainly not an organ, it affects so many processes, including endocrine-related processes, that the stress response system deserved a special section in this review. Understanding the connections, effects, and feedback mechanisms between the different "clandestine organs" and the endocrine system will provide us with a better understanding of how an organism functions, as well as reinforce the idea that there are no independent organs or systems, but a complex, interacting network of molecules, cells, tissues, signaling pathways, and mechanisms that constitute an individual. Published by Elsevier Inc.

Relationship between spermatogonial stem cell survival and testis function after cytotoxic therapy

International Nuclear Information System (INIS)

Meistrich, M.L.

1986-01-01

This review, with substantial bibliography, concludes that the acute effects of radiation and cytotoxic drugs are a result of toxicity to the most sensitive of the germ cells, which in most cases are the differentiating spermatogonia. Long-term sterility or reduction in sperm production depends directly on killing of spermatogonial stem cells. For a variety of cytotoxic agents, the same relationship holds between the stem cell survival index and the prompt recovery level of sperm production (at 56 days), the maximal recovered level of sperm production, and the time required for fertility to return. It also appears that the spermatogonial stem cell is the target for long-term sterility in man following cytotoxic therapy. It is not known whether the delay in recovery is a result of this direct damage to the stem cell or an effect on another target cell in the tissue. Data obtained in both experimental animals and man indicate very little direct changes in the secretory cells and other stromal cells of the testis, and there is no evidence as yet that any alterations in these cells adversely affect sperm production or reproductive performance. (UK)

Endocrine-disrupting chemicals-Mechanisms of action on male reproductive system.

Science.gov (United States)

Sidorkiewicz, Iwona; Zaręba, Kamil; Wołczyński, Sławomir; Czerniecki, Jan

2017-07-01

Endocrine-disrupting chemicals (EDCs) are exogenous compounds that can cause disturbances in the endocrine system and have multiple harmful effects on health by targeting different organs and systems in the human body. Mass industrial production and widespread use of EDCs have resulted in worldwide contamination. Accumulating evidence suggest that human exposure to EDCs is related to the impairment of male reproductive function and can interrupt other hormonally regulated metabolic processes, particularly if exposure occurs during early development. Investigation of studies absent in previous reviews and meta-analysis of adverse effects of EDCs on functioning of the male reproductive system is the core of this work. Four main modes of action of EDCs on male fertility have been summarized in this review. First, studies describing estrogen- pathway disturbing chemicals are investigated. Second, androgen-signaling pathway alterations and influence on androgen sensitive tissues are examined. Third, evaluation of steroidogenesis dysfunction is discussed by focusing on the steroid hormone biosynthesis pathway, which is targeted by EDCs. Last, the reportedly destructive role of reactive oxygen species (ROS) on sperm function is discussed. Spermatogenesis is a remarkably complex process, hence multiple studies point out various dysfunctions depending on the development state at which the exposure occurred. Collected data show the need to account for critical windows of exposure such as fetal, perinatal and pubertal periods as well as effects of mixtures of several compounds in future research.

SLEEP APNEA IN ENDOCRINE DISORDERS

Directory of Open Access Journals (Sweden)

I. V. Misnikova

2016-01-01

Full Text Available In the recent years, an association between sleep apnea and a  number of endocrine diseases has been established. The secretion of many hormones after falling asleep is considerably changed, compared to the period of wakefulness. In patients with endocrine disorders, abnormal hormonal secretion and its pathological consequences may contribute to sleep apnea. Sleep fragmentation and intermittent hypoxia arising in sleep apnea result in a decrease in insulin sensitivity, which contributes to the development of type 2 diabetes mellitus. The prevalence of sleep apnea increases in acromegaly, which may affect the risk of cardio-pulmonary complications. There is an association between sleep apnea and testosterone treatment in men, as well as in postmenopausal women. Sleep apnea in hypothyroidism is most frequently related to the development of hypothyroidism per se and can therefore be reversed with thyroid hormone replacement therapy. Timely detection and treatment of sleep apnea in patients with endocrine disorders can improve their survival prognosis and quality of life.

Endocrine manifestations in celiac disease.

Science.gov (United States)

Freeman, Hugh James

2016-10-14

Celiac disease (CD) is an autoimmune small intestinal mucosal disorder that often presents with diarrhea, malabsorption and weight loss. Often, one or more associated endocrine disorders may be associated with CD. For this review, methods involved an extensive review of published English-language materials. In children and adolescents, prospective studies have demonstrated a significant relationship to insulin-dependent or type 1 diabetes, whereas in adults, autoimmune forms of thyroid disease, particularly hypothyroidism, may commonly co-exist. In some with CD, multiple glandular endocrinopathies may also occur and complicate the initial presentation of the intestinal disease. In others presenting with an apparent isolated endocrine disorder, serological screening for underlying subclinical CD may prove to be positive, particularly if type 1 diabetes, autoimmune thyroid or other autoimmune endocrine diseases, such as Addison's disease are first detected. A number of reports have also recorded hypoparathyroidism or hypopituitarism or ovarian failure in CD and these may be improved with a strict gluten-free diet.

Study on the cytotoxicity of natural killer cells induced by endothelial cells in vitro in the model of xenotransplantation

International Nuclear Information System (INIS)

Huang Haoyue; Shen Zhenya; Liu Hongcheng; Meng Zili; Teng Xiaomei

2004-01-01

Objective: To explore the change of the cytotoxicity of natural killer cells induced by vascular endothelial cells in vitro and the relationship between this change and the variety of cytokine level. Methods: After fixed by paraformaldehyde, vascular endothelial cells from pigs were co-cultured in vitro with natural killer cells from Chinese monkeys at different ratios. The change of the cytotoxicity of natural killer cells occurring after this contact and the content of IFN-γ and TNF-α in the supernatants were detected. Results: The cytotoxicity of natural killer cells improved gradually in accordance with the co-culture ratio after co-cultured with fixed vascular endothelial cells. The secretion of INF-γ and TNF-α also improved gradually. Conclusion: After contact with xeno-target cells, the cytotoxicity of natural killer cells and the secretion of cytokines are related to the ratio of effective cells and target cells

Neurocutaneous spectrum of multiple endocrine neoplasia-1

Directory of Open Access Journals (Sweden)

Shireen Furtado

2012-01-01

Full Text Available Multiple endocrine neoplasia type I or Wermer syndrome is characterized by primary hyperparathyroidism, enteropancreatic endocrine tumor, and a pituitary pathology. A 35-year-old male presented with visual field defects, hyperprolactinemia, and hypogonadism. He also had multiple infraumbilical skin-colored nodules. A syndromal association of Wermer syndrome was derived using the dermal, pituitary, parathyroid, and gastrointestinal hormonal manifestations of the tumor. The radiological and histological findings of lesion which underwent biopsy are discussed. The presence of collagenomas, lipomas, and hypopigmented macules in a patient with neuroendocrine symptoms should raise the suspicion of an underlying multiple endocrine neoplasia.

Endocrine and Metabolic Aspects of OSA

Directory of Open Access Journals (Sweden)

Ravinder Goswami

2014-03-01

Full Text Available Obstructive sleep apnea (OSA is characterized by repeated spells of apnea.Collapsibility of hypopharynx due to multiple factors involving pharyngeal dilatormuscles and deposition of fat or fluid in the surrounding soft tissues are importantcontributing factors in its pathogenesis. OSA commonly affects obese individuals.Males are more commonly affected than the females probably due to the disturbingeffect of testosterone on sleep.The impact of OSA on human health include disturbances in endocrine and metabolicsystem affecting hypothalamic-pituitary-gonadal axis, adrenocorticotrophic-cortisolaxis, growth hormone, antidiuretic hormones and insulin resistance. There is atendency for predisposition of the metabolic syndrome or its components includingglycemic dysregulation, hypertension, hyperlipidemia and physical parameters relatedto adiposity. On the other hand, several endocrine disorders such as hypothyroidism,growth hormone excess, polycystic ovarian disease and testosterone replacement areassociated with increased prevalence of OSA.There is limited information on the effect of treatment of OSA by continuous positiveairway pressure (CPAP on the endocrine and metabolic disturbances. There is a needto conduct randomized controlled trials using CPAP therapy in patients with OSA andto study its cause and effect relationship with endocrine and metabolic disturbances.

The cytotoxicity evaluation of magnetic iron oxide nanoparticles on human aortic endothelial cells

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Ge, Gaoyuan; Wu, Hengfang; Xiong, Fei; Zhang, Yu; Guo, Zhirui; Bian, Zhiping; Xu, Jindan; Gu, Chunrong; Gu, Ning; Chen, Xiangjian; Yang, Di

2013-05-01

One major obstacle for successful application of nanoparticles in medicine is its potential nanotoxicity on the environment and human health. In this study, we evaluated the cytotoxicity effect of dimercaptosuccinic acid-coated iron oxide (DMSA-Fe2O3) using cultured human aortic endothelial cells (HAECs). Our results showed that DMSA-Fe2O3 in the culture medium could be absorbed into HAECs, and dispersed in the cytoplasm. The cytotoxicity effect of DMSA-Fe2O3 on HAECs was dose-dependent, and the concentrations no more than 0.02 mg/ml had little toxic effect which were revealed by tetrazolium dye assay. Meanwhile, the cell injury biomarker, lactate dehydrogenase, was not significantly higher than that from control cells (without DMSA-Fe2O3). However, the endocrine function for endothelin-1 and prostacyclin I-2, as well as the urea transporter function, was altered even without obvious evidence of cell injury in this context. We also showed by real-time PCR analysis that DMSA-Fe2O3 exposure resulted in differential effects on the expressions of pro- and anti-apoptosis genes of HAECs. Meanwhile, it was noted that DMSA-Fe2O3 exposure could activate the expression of genes related to oxidative stress and adhesion molecules, which suggested that inflammatory response might be evoked. Moreover, we demonstrated by in vitro endothelial tube formation that even a small amount of DMSA-Fe2O3 (0.01 and 0.02 mg/ml) could inhibit angiogenesis by the HAECs. Altogether, these results indicate that DMSA-Fe2O3 have some cytotoxicity that may cause side effects on normal endothelial cells.

Tailoring endocrine treatment for early breast cancer

NARCIS (Netherlands)

Fontein, Duveken Berthe Yvonne

2014-01-01

This thesis describes several important aspects of adjuvant endocrine therapy for postmenopausal women with endocrine-sensitive, early-stage breast cancer. In our ongoing efforts to tailor treatment so as to provide the best possible care to each of our patients, we studied the influence of various

Schedule for Rating Disabilities; the Endocrine System. Final rule.

Science.gov (United States)

2017-11-02

This document amends the Department of Veterans Affairs (VA) Schedule for Rating Disabilities (VASRD) by revising the portion of the Schedule that addresses endocrine conditions and disorders of the endocrine system. The effect of this action is to ensure that the VASRD uses current medical terminology and to provide detailed and updated criteria for evaluation of endocrine disorders.

Endocrine causes of nonalcoholic fatty liver disease.

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Marino, Laura; Jornayvaz, François R

2015-10-21

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the industrialized world. The prevalence of NAFLD is increasing, becoming a substantial public health burden. NAFLD includes a broad spectrum of disorders, from simple conditions such as steatosis to severe manifestations such as fibrosis and cirrhosis. The relationship of NAFLD with metabolic alterations such as type 2 diabetes is well described and related to insulin resistance, with NAFLD being recognized as the hepatic manifestation of metabolic syndrome. However, NAFLD may also coincide with endocrine diseases such as polycystic ovary syndrome, hypothyroidism, growth hormone deficiency or hypercortisolism. It is therefore essential to remember, when discovering altered liver enzymes or hepatic steatosis on radiological exams, that endocrine diseases can cause NAFLD. Indeed, the overall prognosis of NAFLD may be modified by treatment of the underlying endocrine pathology. In this review, we will discuss endocrine diseases that can cause NALFD. Underlying pathophysiological mechanisms will be presented and specific treatments will be reviewed.

Syndromes that Link the Endocrine System and Genitourinary Tract.

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Özlük, Yasemin; Kılıçaslan, Işın

2015-01-01

The endocrine system and genitourinary tract unite in various syndromes. Genitourinary malignancies may cause paraneoplastic endocrine syndromes by secreting hormonal substances. These entities include Cushing`s syndrome, hypercalcemia, hyperglycemia, polycythemia, hypertension, and inappropriate ADH or HCG production. The most important syndromic scenarios that links these two systems are hereditary renal cancer syndromes with specific genotype/phenotype correlation. There are also some very rare entities in which endocrine and genitourinary systems are involved such as Carney complex, congenital adrenal hyperplasia and Beckwith-Wiedemann syndrome. We will review all the syndromes regarding manifestations present in endocrine and genitourinary organs.

Radionuclide therapy of endocrine-related cancer

International Nuclear Information System (INIS)

Kratochwil, C.; Giesel, F.L.

2014-01-01

This article gives an overview of the established radionuclide therapies for endocrine-related cancer that already have market authorization or are currently under evaluation in clinical trials. Radioiodine therapy is still the gold standard for differentiated iodine-avid thyroid cancer. In patients with bone and lung metastases (near) total remission is seen in approximately 50 % and the 15-year survival rate for these patients is approximately 90 %. In contrast to the USA, meta-iodobenzylguanidine (MIBG) therapy has market approval in Europe. According to the current literature, in the setting of advanced stage neuroblastoma and malignant pheochromocytoma or paraganglioma, radiological remission can be achieved in > 30 % and symptom control in almost 80 % of the treated patients. Somatostatin receptor targeted radionuclide therapies (e.g. with DOTATATE or DOTATOC) demonstrated promising results in phase 2 trials, reporting progression-free survival in the range of 24-36 months. A first phase 3 pivotal trial for intestinal carcinoids is currently recruiting and another trial for pancreatic neuroendocrine tumors is planned. Radiopharmaceuticals based on glucagon-like peptide 1 (GLP1) or minigastrins are in the early evaluation stage for application in the treatment of insulinomas and medullary thyroid cancer. In general, radiopharmaceutical therapy belongs to the group of so-called theranostics which means that therapy is tailored for individual patients based on molecular imaging diagnostics to stratify target positive or target negative tumor phenotypes. (orig.) [de

Effect of radiotherapy on lymphocyte cytotoxicity against allogeneic lung cancer cells in patients with bronchogenic carcinoma

International Nuclear Information System (INIS)

Toyohira, Ken; Yasumoto, Kosei; Manabe, Hideo; Ohta, Mitsuo; Terashima, Hiromi

1979-01-01

Cytotoxicity of peripheral blood lymphocytes against allogeneic target cells of bronchogenic carcinoma was examined by a microcytotoxicity test before, during, and after radiotherapy in primary lung cancer patients. Before the treatment, cytotoxicity was depressed only slightly in patients in stage III and strikingly in those in stage IV, as compared to the values in patients at earlier stages of lung cancer such as stages I and II. Local irradiation scarcely affected cytotoxicity at stages II and III, but augmented remarkably at stage IV. The number of peripheral blood lymphocytes decreased profoundly during and after radiotherapy in all cases of stages II, III, and IV. Although radiotherapy exhibited various effects on the cytotoxic activity of lymphocytes and the number of peripheral blood lymphocytes, only the cytotoxic activity at the end of radiotherapy correlated well with the reduction in tumor size. (author)

The application of PET in endocrine tumors

International Nuclear Information System (INIS)

Yuan Zhibin

2003-01-01

There are wide application of PET in endocrine tumors, including thyroid cancer, parathyroid adenoma, pheochromocytoma and neuroblastoma. Many papers concluded that in diagnosing endocrine tumors, PET does not show apparent advantages comparing with traditional radionuclide imaging methods. But as a useful complementary method, its clinical value has been recognized

Exocrine cell-derived microparticles in response to lipopolysaccharide promote endocrine dysfunction in cystic fibrosis.

Science.gov (United States)

Constantinescu, Andrei Alexandru; Gleizes, Céline; Alhosin, Mahmoud; Yala, Elhassan; Zobairi, Fatiha; Leclercq, Alexandre; Stoian, Gheorghe; Mitrea, Ioan Liviu; Prévost, Gilles; Toti, Florence; Kessler, Laurence

2014-03-01

Diabetes in cystic fibrosis (CF) is a result of exocrine pancreas alteration followed by endocrine dysfunction at a later stage. Microparticles (MPs) are plasma membrane fragments shed from stimulated or damaged cells that act as cellular effectors. Our aim was to identify a new form of interaction between exocrine and endocrine pancreatic cells mediated by exocrine MPs, in the context of recurrent infection in CF. MPs from either human exocrine CFTRΔF508-mutated (CFPAC-1) cells or exocrine normal pancreatic (PANC-1) cells were collected after treatment by LPS from Pseudomonas aeruginosa and applied to rat endocrine normal insulin-secreting RIN-m5F cells. MP membrane integration in target cells was established by confocal microscopy and flow cytometry using PKH26 lipid probe. Apoptosis, lysosomal activity, insulin secretion were measured after 18 h. MP-mediated NF-κB activation was measured in HEK-Blue reporter cells by SEAP reporter gene system and in RIN-m5F cells by Western blot. In endocrine normal cells, CFTR inhibition was achieved using Inhibitor-172. Compared to PANC-1, MPs from CFPAC-1 significantly reduced insulin secretion and lysosomal activity in RIN-m5F. MPs induced NF-κB activation by increasing the level of IκB phosphorylation. Moreover, the inhibition of NF-κB activation using specific inhibitors was associated with a restored insulin secretion. Interestingly, CFTR inhibition in normal RIN-m5F cells promoted apoptosis and decreased insulin secretion. During recurrent infections associated with CF, exocrine MPs may contribute to endocrine cell dysfunction via NF-κB pathways. Membrane CFTR dysfunction is associated with decreased insulin secretion. © 2013. Published by Elsevier B.V. on behalf of European Cystic Fibrosis Society. All rights reserved.

In vitro cytotoxicity of alpha conjugates for human pancreatic cancer cell lines

International Nuclear Information System (INIS)

Qu, C.; Li, Y.; Rizvi, M.A.; Allen, B.; Samra, J.; Smith, R.

2003-01-01

Targeted Alpha therapy (TAT) can inhibit the growth of micrometastases by selectively killing isolated and preangiogenic clusters of cancer cells. The aim of this study is to demonstrate the cytotoxicity of different alpha conjugates in vitro to human metastatic pancreatic cancer cell lines (CAPAN-1, CFPAN-1 and PANC-1). We are labeling the C595 and J591 (non-specific controls) monoclonal antibodies (Mabs) with 213 Bi were performed according to the standard methods in our laboratory. 213 Bi-C595 is specifically cytotoxic to CAPAN-1, CFPAN-1 and PANC-1cell lines in a concentration-dependent fashion. While non-specific alpha conjugates only killed very small fractions of pancreatic cancer cells. These alpha conjugates might be useful agents for the treatment of micro-metastases in pancreatic cancer patients with over-expression of the targeted receptors

Long-term neuro-endocrine sequelae after treatment for childhood medulloblastoma

NARCIS (Netherlands)

Heikens, J.; Michiels, E. M.; Behrendt, H.; Endert, E.; Bakker, P. J.; Fliers, E.

1998-01-01

The occurrence of neuro-endocrine deficiencies following craniospinal irradiation for medulloblastoma is well known, but data concerning the spectrum and prevalence of endocrine abnormalities in adulthood are scarce. We studied endocrine function in 20 (median age 25 years) adult subjects, 8-25

Tributyltin: Advancing the Science on Assessing Endocrine Disruption with an Unconventional Endocrine-Disrupting Compound.

Science.gov (United States)

Lagadic, Laurent; Katsiadaki, Ioanna; Biever, Ron; Guiney, Patrick D; Karouna-Renier, Natalie; Schwarz, Tamar; Meador, James P

Tributyltin (TBT) has been recognized as an endocrine disrupting chemical (EDC) for several decades. However, only in the last decade, was its primary endocrine mechanism of action (MeOA) elucidated-interactions with the nuclear retinoid-X receptor (RXR), peroxisome proliferator-activated receptor γ (PPARγ), and their heterodimers. This molecular initiating event (MIE) alters a range of reproductive, developmental, and metabolic pathways at the organism level. It is noteworthy that a variety of MeOAs have been proposed over the years for the observed endocrine-type effects of TBT; however, convincing data for the MIE was provided only recently and now several researchers have confirmed and refined the information on this MeOA. One of the most important lessons learned from years of research on TBT concerns apparent species sensitivity. Several aspects such as the rates of uptake and elimination, chemical potency, and metabolic capacity are all important for identifying the most sensitive species for a given chemical, including EDCs. For TBT, much of this was discovered by trial and error, hence important relationships and important sensitive taxa were not identified until several decades after its introduction to the environment. As recognized for many years, TBT-induced responses are known to occur at very low concentrations for molluscs, a fact that has more recently also been observed in fish species. This review explores the MeOA and effects of TBT in different species (aquatic molluscs and other invertebrates, fish, amphibians, birds, and mammals) according to the OECD Conceptual Framework for Endocrine Disruptor Testing and Assessment (CFEDTA). The information gathered on biological effects that are relevant for populations of aquatic animals was used to construct Species Sensitivity Distributions (SSDs) based on No Observed Effect Concentrations (NOECs) and Lowest Observed Effect Concentrations (LOECs). Fish appear at the lower end of these distributions

Tributyltin: Advancing the science on assessing endocrine disruption with an unconventional endocrine-disrupting compound

Science.gov (United States)

Lagadic, Laurent; Katsiadaki, Ioanna; Biever, Ronald C.; Guiney, Patrick; Karouna-Renier, Natalie; Schwarz, Tamar; Meador, James P.

2018-01-01

Tributyltin (TBT) has been recognized as an endocrine disrupting chemical (EDC) for several decades. However, only in the last decade, was its primary endocrine mechanism of action (MeOA) elucidated—interactions with the nuclear retinoid-X receptor (RXR), peroxisome proliferator-activated receptor γ (PPARγ), and their heterodimers. This molecular initiating event (MIE) alters a range of reproductive, developmental, and metabolic pathways at the organism level. It is noteworthy that a variety of MeOAs have been proposed over the years for the observed endocrine-type effects of TBT; however, convincing data for the MIE was provided only recently and now several researchers have confirmed and refined the information on this MeOA. One of the most important lessons learned from years of research on TBT concerns apparent species sensitivity. Several aspects such as the rates of uptake and elimination, chemical potency, and metabolic capacity are all important for identifying the most sensitive species for a given chemical, including EDCs. For TBT, much of this was discovered by trial and error, hence important relationships and important sensitive taxa were not identified until several decades after its introduction to the environment. As recognized for many years, TBT-induced responses are known to occur at very low concentrations for molluscs, a fact that has more recently also been observed in fish species. This review explores the MeOA and effects of TBT in different species (aquatic molluscs and other invertebrates, fish, amphibians, birds, and mammals) according to the OECD Conceptual Framework for Endocrine Disruptor Testing and Assessment (CFEDTA). The information gathered on biological effects that are relevant for populations of aquatic animals was used to construct Species Sensitivity Distributions (SSDs) based on No Observed Effect Concentrations (NOECs) and Lowest Observed Effect Concentrations (LOECs). Fish appear at the lower end of these distributions

Endocrine disrupting chemicals: harmful substances and how to test them

Directory of Open Access Journals (Sweden)

Olea-Serrano Nicolás

2002-01-01

Full Text Available This paper presents an analysis of the opinions of different groups from: scientists, international regulatory bodies, non-governmental organizations and industry; with an interest in the problem of identifying chemical substances with endocrine disrupting activity. There is also discussion of the consequences that exposure to endocrine disruptors may have for human health, considering concrete issues related to: the estimation of risk; the tests that must be used to detect endocrine disruption; the difficulties to establish an association between dose, time of exposure, individual susceptibility, and effect; and the attempts to create a census of endocrine disruptors. Finally, it is proposed that not all hormonal mimics should be included under the single generic denomination of endocrine disruptors.

Endocrine neoplasms in familial syndromes of hyperparathyroidism.

Science.gov (United States)

Li, Yulong; Simonds, William F

2016-06-01

Familial syndromes of hyperparathyroidism, including multiple endocrine neoplasia type 1 (MEN1), multiple endocrine neoplasia type 2A (MEN2A), and the hyperparathyroidism-jaw tumor (HPT-JT), comprise 2-5% of primary hyperparathyroidism cases. Familial syndromes of hyperparathyroidism are also associated with a range of endocrine and nonendocrine tumors, including potential malignancies. Complications of the associated neoplasms are the major causes of morbidities and mortalities in these familial syndromes, e.g., parathyroid carcinoma in HPT-JT syndrome; thymic, bronchial, and enteropancreatic neuroendocrine tumors in MEN1; and medullary thyroid cancer and pheochromocytoma in MEN2A. Because of the different underlying mechanisms of neoplasia, these familial tumors may have different characteristics compared with their sporadic counterparts. Large-scale clinical trials are frequently lacking due to the rarity of these diseases. With technological advances and the development of new medications, the natural history, diagnosis, and management of these syndromes are also evolving. In this article, we summarize the recent knowledge on endocrine neoplasms in three familial hyperparathyroidism syndromes, with an emphasis on disease characteristics, molecular pathogenesis, recent developments in biochemical and radiological evaluation, and expert opinions on surgical and medical therapies. Because these familial hyperparathyroidism syndromes are associated with a wide variety of tumors in different organs, this review is focused on those endocrine neoplasms with malignant potential. © 2016 Society for Endocrinology.

Highlighting Indication of extracorporeal membrane oxygenation in endocrine emergencies.

Science.gov (United States)

Chao, Anne; Wang, Chih-Hsien; You, Hao-Chun; Chou, Nai-Kwoun; Yu, Hsi-Yu; Chi, Nai-Hsin; Huang, Shu-Chien; Wu, I-Hui; Tseng, Li-Jung; Lin, Ming-Hsien; Chen, Yih-Sharng

2015-08-24

Extracorporeal membrane oxygenation (ECMO) has been repeatedly used to rescue patients with cardiopulmonary arrest. However, its clinical utility in endocrine emergencies remains unclear. Herein, we describe a case series of 12 patients presenting with refractory shock secondary to endocrine emergencies who were rescued by ECMO support. Patients were identified between 2005 and 2012 from our ECMO registry. The diagnostic distribution was as follows: pheochromocytoma crisis (n = 4), thyroid storm (n = 5), and diabetic ketoacidosis (n = 3). The initial presentation of pheochromocytoma crisis was indistinguishable from acute myocardial infarction (AMI) and frequently accompanied by paroxysmal hypertension and limb ischemia. Thyroid storm was characterized by hyperbilirubinemia and severe gastrointestinal bleeding, whereas neurological symptoms were common in diabetic ketoacidosis. The clinical outcomes of patients with endocrine emergencies were compared with those of 80 cases with AMI who received ECMO because of cardiogenic shock. The cardiac function and the general conditions showed a significantly faster recovery in patients with endocrine emergencies than in those with AMI. We conclude that ECMO support can be clinically useful in endocrine emergencies. The screening of endocrine diseases should be considered during the resuscitation of patients with refractory circulatory shock.

The survival analysis on localized prostate cancer treated with neoadjuvant endocrine therapy followed by intensity modulated radiation therapy

International Nuclear Information System (INIS)

Gao Hong; Li Gaofeng; Wu Qinhong; Li Xuenan; Zhong Qiuzi; Xu Yonggang

2010-01-01

Objective: To retrospectively investigate clinical outcomes and prognostic factors in localized prostate cancer treated with neoadjuvant endocrine therapy followed by intensity modulated radiotherapy (IMRT). Methods: Between March 2003 and October 2008, 54 localized prostate cancer treated by IMRT were recruited. All patients had received endocrine therapy before IMRT. The endocrine therapy included surgical castration or medical castration in combination with antiandrogens. The target of IMRT was the prostate and seminal vesicles with or without pelvis. The biochemical failure was defined according to the phoenix definition. By using the risk grouping standard proposed by D'Amico, patients were divided into three groups: low-risk group (n = 5), intermediate-risk group (n = 12), and high-risk group (n = 37). Kaplan-Meier method was used to calculate the overall survival rate. Prognostic factors were analyzed by univariate and multiple Cox regression analysis. Results: The follow-up rate was 98%. The number of patients under follow-up was 39 at 3 years and 25 at 5 years. Potential prognostic factors, including risk groups, mode of endocrine therapy, time of endocrine therapy, phoenix grouping before IMRT, the prostate specific antigen doubling time (PSADT) before radiotherapy, PSA value before IMRT, interval of endocrine therapy and IMRT, irradiation region, and irradiation dose were analyzed by survival analysis. In univariate analysis, time of endocrine therapy (75 % vs 95 %, χ 2 = 6. 45, P = 0. 011), phoenix grouping before IMRT (87% vs 96%, χ 2 = 4. 36, P = 0. 037), interval of endocrine therapy and IMRT (80% vs 95%, χ 2 = 11.60, P= 0. 001), irradiation dose (75% vs 91%, χ 2 =5.92, P= 0. 015) were statistically significant prognostic factors for 3 - year overall survival , and risk groups (85 vs 53 vs 29, χ 2 = 6. 40, P =0. 041) and PSADT before IMRT (62 vs 120, U =24. 50, P =0. 003) were significant factors for the median survival time. In the multiple Cox

Appetite-Controlling Endocrine Systems in Teleosts

Science.gov (United States)

Rønnestad, Ivar; Gomes, Ana S.; Murashita, Koji; Angotzi, Rita; Jönsson, Elisabeth; Volkoff, Hélène

2017-01-01

Mammalian studies have shaped our understanding of the endocrine control of appetite and body weight in vertebrates and provided the basic vertebrate model that involves central (brain) and peripheral signaling pathways as well as environmental cues. The hypothalamus has a crucial function in the control of food intake, but other parts of the brain are also involved. The description of a range of key neuropeptides and hormones as well as more details of their specific roles in appetite control continues to be in progress. Endocrine signals are based on hormones that can be divided into two groups: those that induce (orexigenic), and those that inhibit (anorexigenic) appetite and food consumption. Peripheral signals originate in the gastrointestinal tract, liver, adipose tissue, and other tissues and reach the hypothalamus through both endocrine and neuroendocrine actions. While many mammalian-like endocrine appetite-controlling networks and mechanisms have been described for some key model teleosts, mainly zebrafish and goldfish, very little knowledge exists on these systems in fishes as a group. Fishes represent over 30,000 species, and there is a large variability in their ecological niches and habitats as well as life history adaptations, transitions between life stages and feeding behaviors. In the context of food intake and appetite control, common adaptations to extended periods of starvation or periods of abundant food availability are of particular interest. This review summarizes the recent findings on endocrine appetite-controlling systems in fish, highlights their impact on growth and survival, and discusses the perspectives in this research field to shed light on the intriguing adaptations that exist in fish and their underlying mechanisms. PMID:28458653

Interconnection between thyroid hormone signalling pathways and parvovirus cytotoxic functions.

Science.gov (United States)

Vanacker, J M; Laudet, V; Adelmant, G; Stéhelin, D; Rommelaere, J

1993-01-01

Nonstructural (NS) proteins of autonomous parvoviruses can repress expression driven by heterologous promoters, an activity which thus far has not been separated from their cytotoxic effects. It is shown here that, in transient transfection assays, the NS-1 protein of the parvovirus minute virus of mice (MVMp) activates the promoter of the human c-erbA1 gene, encoding the thyroid hormone (T3) receptor alpha. The endogenous c-erbA1 promoter is also a target for induction upon MVMp infection. Moreover, T3 was found to up-modulate the level of cell sensitivity to parvovirus attack. These data suggest an interconnection between T3 signalling and NS cytotoxic pathways. Images PMID:8230488

The Endocrine Machinery.

Science.gov (United States)

Fillman, David

1987-01-01

Promotes a reductionist approach to teaching about the endocrine system in high school biology and anatomy courses. Encourages the study of how hormones travel to the cells and affect them. Provides suggestions for activities and discussion questions, along with sample diagrams and flow charts. (TW)

Endocrine-disrupting Chemicals: Review of Toxicological Mechanisms Using Molecular Pathway Analysis

Science.gov (United States)

Yang, Oneyeol; Kim, Hye Lim; Weon, Jong-Il; Seo, Young Rok

2015-01-01

Endocrine disruptors are known to cause harmful effects to human through various exposure routes. These chemicals mainly appear to interfere with the endocrine or hormone systems. As importantly, numerous studies have demonstrated that the accumulation of endocrine disruptors can induce fatal disorders including obesity and cancer. Using diverse biological tools, the potential molecular mechanisms related with these diseases by exposure of endocrine disruptors. Recently, pathway analysis, a bioinformatics tool, is being widely used to predict the potential mechanism or biological network of certain chemicals. In this review, we initially summarize the major molecular mechanisms involved in the induction of the above mentioned diseases by endocrine disruptors. Additionally, we provide the potential markers and signaling mechanisms discovered via pathway analysis under exposure to representative endocrine disruptors, bisphenol, diethylhexylphthalate, and nonylphenol. The review emphasizes the importance of pathway analysis using bioinformatics to finding the specific mechanisms of toxic chemicals, including endocrine disruptors. PMID:25853100

Cytotoxicity and cell death mechanisms induced by the polyamine-vectorized anti-cancer drug F14512 targeting topoisomerase II.

Science.gov (United States)

Brel, Viviane; Annereau, Jean-Philippe; Vispé, Stéphane; Kruczynski, Anna; Bailly, Christian; Guilbaud, Nicolas

2011-12-15

The polyamines transport system (PTS) is usually enhanced in cancer cells and can be exploited to deliver anticancer drugs. The spermine-conjugated epipodophyllotoxin derivative F14512 is a topoisomerase II poison that exploits the PTS to target preferentially tumor cells. F14512 has been characterized as a potent anticancer drug candidate and is currently in phase 1 clinical trials. Here we have analyzed the mechanisms of cell death induced by F14512, compared to the parent drug etoposide lacking the polyamine tail. F14512 proved to be >30-fold more cytotoxic than etoposide against A549 non-small cell lung cancer cells and triggers less but unrecoverable DNA damages. The cytotoxic action of F14512 is extremely rapid (within 3 h) and does not lead to a marked accumulation in the S-phase of the cell cycle, unlike etoposide. Interestingly, A549 cells treated with F14512 were less prone to undergo apoptosis (neither caspases-dependent nor caspases-independent pathways) or autophagy but preferentially entered into senescence. Drug-induced senescence was characterized qualitatively and quantitatively by an increased β-galactosidase activity, both by cytochemical staining and by flow cytometry. A morphological analysis by electron microscopy revealed the presence of numerous multi-lamellar and vesicular bodies and large electron-lucent (methuosis-like) vacuoles in F14512-treated cell samples. The mechanism of drug-induced cell death is thus distinct for F14512 compared to etoposide, and this difference may account for their distinct pharmacological profiles and the markedly superior activity of F14512 in vivo. This study suggests that senescence markers should be considered as potential pharmacodynamic biomarkers of F14512 antitumor activity. Copyright © 2011 Elsevier Inc. All rights reserved.

Human exposure to endocrine disrupting compounds: Their role in reproductive systems, metabolic syndrome and breast cancer. A review.

Science.gov (United States)

Giulivo, Monica; Lopez de Alda, Miren; Capri, Ettore; Barceló, Damià

2016-11-01

Endocrine disrupting chemicals (EDCs) are released into the environment from different sources. They are mainly used in packaging industries, pesticides and food constituents. Clinical evidence, experimental models, and epidemiological studies suggest that EDCs have major risks for humans by targeting different organs and systems in the body (e.g. reproductive system, breast tissue, adipose tissue, pancreas, etc.). Due to the ubiquity of human exposure to these compounds the aim of this review is to describe the most recent data on the effects induced by phthalates, bisphenol A and parabens in a critical window of exposure: in utero, during pregnancy, infants, and children. The interactions and mechanisms of toxicity of EDCs in relation to human general health problems, especially those broadening the term of endocrine disruption to 'metabolic disruption', should be deeply investigated. These include endocrine disturbances, with particular reference to reproductive problems and breast, testicular and ovarian cancers, and metabolic diseases such as obesity or diabetes. Copyright © 2016 Elsevier Inc. All rights reserved.

Short-term cytotoxic effects and long-term instability of RNAi delivered using lentiviral vectors

Directory of Open Access Journals (Sweden)

Kruithof Egbert KO

2004-08-01

Full Text Available Abstract Background RNA interference (RNAi can potently reduce target gene expression in mammalian cells and is in wide use for loss-of-function studies. Several recent reports have demonstrated that short double-stranded RNAs (dsRNAs, used to mediate RNAi, can also induce an interferon-based response resulting in changes in the expression of many interferon-responsive genes. Off-target gene silencing has also been described, bringing into question the validity of certain RNAi-based approaches for studying gene function. We have targeted the plasminogen activator inhibitor-2 (PAI-2 or SERPINB2 mRNA using lentiviral vectors for delivery of U6 promoter-driven PAI-2-targeted short hairpin RNA (shRNA expression. PAI-2 is reported to have anti-apoptotic activity, thus reduction of endogenous expression may be expected to make cells more sensitive to programmed cell death. Results As expected, we encountered a cytotoxic phenotype when targeting the PAI-2 mRNA with vector-derived shRNA. However, this predicted phenotype was a potent non-specific effect of shRNA expression, as functional overexpression of the target protein failed to rescue the phenotype. By decreasing the shRNA length or modifying its sequence we maintained PAI-2 silencing and reduced, but did not eliminate, cytotoxicity. ShRNA of 21 complementary nucleotides (21 mers or more increased expression of the oligoadenylate synthase-1 (OAS1 interferon-responsive gene. 19 mer shRNA had no effect on OAS1 expression but long-term selective pressure on cell growth was observed. By lowering lentiviral vector titre we were able to reduce both expression of shRNA and induction of OAS1, without a major impact on the efficacy of gene silencing. Conclusions Our data demonstrate a rapid cytotoxic effect of shRNAs expressed in human tumor cell lines. There appears to be a cut-off of 21 complementary nucleotides below which there is no interferon response while target gene silencing is maintained

Endocrine manifestations of celiac disease

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R Philip

2012-01-01

Full Text Available Background: Celiac disease can have extra gastrointestinal tract (GIT presentations, most of which are endocrine. The aim of this study was to present patients diagnosed to have celiac disease from an endocrine department and to study the prevalence of endocrinopathies in celiac disease. Materials and Methods: A total of 36 patients from the endocrinology department (LLRM Medical College, Meerut between January 2011 and July 2012 and who were diagnosed to have celiac disease were included in the study. Results: Short stature was the commonest presentation (25%, other presentations included short stature and delayed puberty (20%, delayed puberty (11%, screening for celiac disease in type-1 DM patients (17%, rickets (6%, anemia not responding to oral therapy (6%, type-1 DM with recurrent hypoglycaemia (6%, and osteomalacia (3%. The endocrine manifestations include (after complete evaluation short stature (58%, delayed puberty (31%, elevated alkaline phospahatase (67%, low calcium (22%, X-rays suggestive of osteomalacia or rickets (8%, capopedal spasm (6%, and night blindness (6%. Anti-TPO antibody positivity was found in 53%, hypothyroidism in 28%, subclinical hypothyroidism in 17%, and type-1 DM in 25% of the patients. A total of 14% patients had no GI symptoms. Conclusion: Celiac disease is an endocrine disrupter as well as the great masquerader having varied presentations including short stature, delayed puberty, and rickets. Some patients who have celiac disease may not have any GI symptoms, making the diagnosis all the more difficult. Also, there is significant incidence of celiac disease with hypothyroidism and type-1 DM, making screening for it important in these diseases.

Idarubicin induces mTOR-dependent cytotoxic autophagy in leukemic cells

International Nuclear Information System (INIS)

Ristic, Biljana; Bosnjak, Mihajlo; Arsikin, Katarina; Mircic, Aleksandar; Suzin-Zivkovic, Violeta; Bogdanovic, Andrija; Perovic, Vladimir; Martinovic, Tamara; Kravic-Stevovic, Tamara; Bumbasirevic, Vladimir; Trajkovic, Vladimir; Harhaji-Trajkovic, Ljubica

2014-01-01

We investigated if the antileukemic drug idarubicin induces autophagy, a process of programmed cellular self-digestion, in leukemic cell lines and primary leukemic cells. Transmission electron microscopy and acridine orange staining demonstrated the presence of autophagic vesicles and intracellular acidification, respectively, in idarubicin-treated REH leukemic cell line. Idarubicin increased punctuation/aggregation of microtubule-associated light chain 3B (LC3B), enhanced the conversion of LC3B-I to autophagosome-associated LC3B-II in the presence of proteolysis inhibitors, and promoted the degradation of the selective autophagic target p62, thus indicating the increase in autophagic flux. Idarubicin inhibited the phosphorylation of the main autophagy repressor mammalian target of rapamycin (mTOR) and its downstream target p70S6 kinase. The treatment with the mTOR activator leucine prevented idarubicin-mediated autophagy induction. Idarubicin-induced mTOR repression was associated with the activation of the mTOR inhibitor AMP-activated protein kinase and down-regulation of the mTOR activator Akt. The suppression of autophagy by pharmacological inhibitors or LC3B and beclin-1 genetic knockdown rescued REH cells from idarubicin-mediated oxidative stress, mitochondrial depolarization, caspase activation and apoptotic DNA fragmentation. Idarubicin also caused mTOR inhibition and cytotoxic autophagy in K562 leukemic cell line and leukocytes from chronic myeloid leukemia patients, but not healthy controls. By demonstrating mTOR-dependent cytotoxic autophagy in idarubicin-treated leukemic cells, our results warrant caution when considering combining idarubicin with autophagy inhibitors in leukemia therapy. - Highlights: • Idarubicin induces autophagy in leukemic cell lines and primary leukemic cells. • Idarubicin induces autophagy by inhibiting mTOR in leukemic cells. • mTOR suppression by idarubicin is associated with AMPK activation and Akt blockade. �

Idarubicin induces mTOR-dependent cytotoxic autophagy in leukemic cells

Energy Technology Data Exchange (ETDEWEB)

Ristic, Biljana [Institute of Microbiology and Immunology, School of Medicine, University of Belgrade, Dr. Subotica 1, 11000 Belgrade (Serbia); Bosnjak, Mihajlo [Institute of Histology and Embryology, School of Medicine, University of Belgrade, Belgrade (Serbia); Arsikin, Katarina [Institute of Microbiology and Immunology, School of Medicine, University of Belgrade, Dr. Subotica 1, 11000 Belgrade (Serbia); Mircic, Aleksandar; Suzin-Zivkovic, Violeta [Institute of Histology and Embryology, School of Medicine, University of Belgrade, Belgrade (Serbia); Bogdanovic, Andrija [Clinic for Hematology, Clinical Centre of Serbia, School of Medicine, University of Belgrade, Belgrade (Serbia); Perovic, Vladimir [Institute of Microbiology and Immunology, School of Medicine, University of Belgrade, Dr. Subotica 1, 11000 Belgrade (Serbia); Martinovic, Tamara; Kravic-Stevovic, Tamara; Bumbasirevic, Vladimir [Institute of Histology and Embryology, School of Medicine, University of Belgrade, Belgrade (Serbia); Trajkovic, Vladimir, E-mail: vtrajkovic@med.bg.ac.rs [Institute of Microbiology and Immunology, School of Medicine, University of Belgrade, Dr. Subotica 1, 11000 Belgrade (Serbia); Harhaji-Trajkovic, Ljubica, E-mail: buajk@yahoo.com [Institute for Biological Research, University of Belgrade, Belgrade, Despot Stefan Blvd. 142, 11000 Belgrade (Serbia)

2014-08-01

We investigated if the antileukemic drug idarubicin induces autophagy, a process of programmed cellular self-digestion, in leukemic cell lines and primary leukemic cells. Transmission electron microscopy and acridine orange staining demonstrated the presence of autophagic vesicles and intracellular acidification, respectively, in idarubicin-treated REH leukemic cell line. Idarubicin increased punctuation/aggregation of microtubule-associated light chain 3B (LC3B), enhanced the conversion of LC3B-I to autophagosome-associated LC3B-II in the presence of proteolysis inhibitors, and promoted the degradation of the selective autophagic target p62, thus indicating the increase in autophagic flux. Idarubicin inhibited the phosphorylation of the main autophagy repressor mammalian target of rapamycin (mTOR) and its downstream target p70S6 kinase. The treatment with the mTOR activator leucine prevented idarubicin-mediated autophagy induction. Idarubicin-induced mTOR repression was associated with the activation of the mTOR inhibitor AMP-activated protein kinase and down-regulation of the mTOR activator Akt. The suppression of autophagy by pharmacological inhibitors or LC3B and beclin-1 genetic knockdown rescued REH cells from idarubicin-mediated oxidative stress, mitochondrial depolarization, caspase activation and apoptotic DNA fragmentation. Idarubicin also caused mTOR inhibition and cytotoxic autophagy in K562 leukemic cell line and leukocytes from chronic myeloid leukemia patients, but not healthy controls. By demonstrating mTOR-dependent cytotoxic autophagy in idarubicin-treated leukemic cells, our results warrant caution when considering combining idarubicin with autophagy inhibitors in leukemia therapy. - Highlights: • Idarubicin induces autophagy in leukemic cell lines and primary leukemic cells. • Idarubicin induces autophagy by inhibiting mTOR in leukemic cells. • mTOR suppression by idarubicin is associated with AMPK activation and Akt blockade. �

Myopathies of endocrine disorders: A prospective clinical and biochemical study

Directory of Open Access Journals (Sweden)

Vikas Sharma

2014-01-01

Full Text Available Introduction: Major categories of endocrine myopathy include those associated with: Adrenal dysfunction (as in Cushing′s disease or steroid myopathy; thyroid dysfunction (as in myxedema coma or thyrotoxic myopathy; vitamin D deficiency; parathyroid dysfunction; and pituitary dysfunction. Steroid myopathy is the most common endocrine myopathy. Objective: To study the etiology, varied presentations, and outcome after therapy of patients with endocrine myopathies. Materials and Methods: Myopathy was evaluated by the standard clinical procedures: Detailed clinical history, manual muscle strength testing, and creatine phosphokinase (CPK. Endocrine disorders were diagnosed as per clinical features and biochemical parameters. The treatment was given to patients as per underlying endocrine disease. Myopathy was assessed before and after treatment. Results: Out of the 37 patients who were diagnosed with endocrine myopathies, thyroid dysfunction was the most common cause (17 cases, followed by vitamin D deficiency in nine, adrenal dysfunction in six, parathyroid dysfunction in three, and pituitary dysfunction in two. Some patients had atypical presentation (repeated falls in one, tongue fasciculations in one, neck weakness in five, one with ptosis and facial weakness, asymmetrical onset in one, and calf hypertrophy in one. The serum creatine kinase (CK concentration did not correlate with muscle weakness. Following the treatment regimen which was specific for a given myopathy, 26 patients recovered fully. Conclusion: We found varied clinical presentations of endocrine myopathies. All the patients with neuromuscular complaints should be investigated for endocrine causes because significant number of them recovers fully with specific treatment.

Clinical review: kinase inhibitors: adverse effects related to the endocrine system.

Science.gov (United States)

Lodish, Maya B

2013-04-01

The use of kinase inhibitors (KIs) in the treatment of cancer has become increasingly common, and practitioners must be familiar with endocrine-related side effects associated with these agents. This review provides an update to the clinician regarding the management of potential endocrinological effects of KIs. PubMed was employed to identify relevant manuscripts. A review of the literature was conducted, and data were summarized and incorporated. KIs, including small molecule KIs and monoclonal antibodies directed against kinases, have emerged over the past decade as an important class of anticancer agents. KIs specifically interfere with signaling pathways that are dysregulated in certain types of cancers and also target common mechanisms of growth, invasion, metastasis, and angiogenesis. Currently, at least 20 KIs are approved as cancer therapeutics. However, KIs may affect a broad spectrum of targets and may have additional, unidentified mechanisms of action at the cellular level due to overlap between signaling pathways in the tumor cell and endocrine system. Recent reports in the literature have identified side effects associated with KIs, including alterations in thyroid function, bone metabolism, linear growth, gonadal function, fetal development, adrenal function, and glucose metabolism. Clinicians need to monitor the thyroid functions of patients on KIs. In addition, bone density and vitamin D status should be assessed. Special care should be taken to follow linear growth and development in children taking these agents. Clinicians should counsel patients appropriately on the potential adverse effects of KIs on fetal development.

Nigerian Endocrine Practice

African Journals Online (AJOL)

The journal accepts original contributions related to the practice and science of clinical endocrinology, articles updating the clinical endocrinologist on current areas of interest in the diagnosis and treatment of endocrine disorders, articles discussing dilemma facing endocrinologists in the clinical, social, and ethical arena of ...

REST represses a subset of the pancreatic endocrine differentiation program

DEFF Research Database (Denmark)

Martin, David; Kim, Yung-Hae; Sever, Dror

2015-01-01

in neurons and in endocrine cells, which is necessary for their normal function. During development, REST represses a subset of genes in the neuronal differentiation program and Rest is down-regulated as neurons differentiate. Here, we investigate the role of REST in the differentiation of pancreatic...... endocrine cells, which are molecularly close to neurons. We show that Rest is widely expressed in pancreas progenitors and that it is down-regulated in differentiated endocrine cells. Sustained expression of REST in Pdx1(+) progenitors impairs the differentiation of endocrine-committed Neurog3...

Synthesis and cytotoxic evaluation of novel C-10 nitrate derivatives of colchicine

International Nuclear Information System (INIS)

Shen, L.H.; Wang, B.; Liu, S.M.

2016-01-01

In our continuing search for more potent anticancer agent, eight novel nitrates couple with C-10 colchicine nitric oxide-releasing derivatives (5a-f and 7a-b) were prepared. These target compounds were assayed for their anti-tumor activity in vitro against four cancer cell lines, including human hepatocellular carcinoma cells (BEL7402), human ovary carcinoma cells (A2780), human lung adenocarcinoma cells (A549) and human breast carcinoma cells (MCF7). Preliminary results indicated that most of them exhibited significant cytotoxic effect toward cancer cells. Compound 7a was investigated further for its more potent cytotoxicity than colchicine. (author)

New-tools to assess the toxicological hazard of endocrine disruptor organoclorine contaminants in Mediterranean cetaceans

Energy Technology Data Exchange (ETDEWEB)

M. Cristina Fossi; Marsili, L.; Casini, S. [Dept. of Environmental Sciences, Univ. of Siena (Italy)

2004-09-15

The Mediterranean top predators, and particularly cetacean odontocetes, accumulate high concentrations of organochlorine contaminants (OCs), incurring high toxicological risk. Some organochlorine compounds, now with worldwide distribution, are known as endocrine disrupting chemicals (EDCs). Four types of organochlorine endocrine disruptors are commonly found in Mediterranean cetaceans: (1) environmental estrogens, (2) environmental androgens, (3) anti-estrogens and (4) anti-androgens. Endocrine disruptors act by mimicking sex steroid hormones, both estrogens and androgens, by binding to hormone receptors or influencing cell pathways (environmental estrogens and androgens), or by blocking and altering hormone receptor binding (anti-estrogens, antiandrogens). Environmental estrogens are the most common and most widely studied EDCs. The relative estrogenic power of these chemicals, identified by in vitro and in vivo screening methods is rather weak (10{sup -3} or less) compared with the reference power of 17-estradiol or DES. However, the high levels of organochlorine compounds detected in marine mammals, particularly in pinnipeds and odontocetes, and consequently, the high levels of organochlorines with ED capacity, cannot be ignored. Here the hypothesis that some Mediterranean cetaceans (Stenella coeruleoalba, Delphinus delphis, Tursiops truncatus and Balaenoptera physalus) are ''potentially at risk'' due to organochlorines with endocrine disrupting capacity is investigated using new non-lethal tools. As ''diagnostic'' tool we use benzo(a)pyrene monooxygenase (CYP1A1) activity in skin biopsies (non-lethal biomarker) as a potential indicator of exposure to organochlorines, with special reference to the compounds with endocrine disrupting capacity. As ''prognostic'' tool we propose the immunofluorescence technique in fibroblast cell cultures, for a qualitative and quantitative evaluation of the target

Endocrine function over time in patients with myotonic dystrophy type 1

DEFF Research Database (Denmark)

Dahlqvist, Julia Rebecka; Ørngreen, M C; Witting, N

2015-01-01

BACKGROUND AND PURPOSE: Patients with myotonic dystrophy type 1 (DM1) have an increased incidence of endocrine dysfunction. In this study, the temporal evolution of endocrine dysfunction in patients with DM1 was investigated. METHODS: Endocrine function was assessed in 68 patients with DM1, in whom...... endocrine function had been followed, on average, for 8 years. The endocrine function was assessed by measuring the concentration of hormones and metabolites in blood and by validating libido with questionnaires. RESULTS: At baseline, 30 of the 68 patients presented with at least one hormonal dysfunction....... When re-evaluated after 8 years, 57 of 68 patients had endocrine dysfunction. Diabetic patients had increased from one to four. At follow-up, hyperparathyroidism occurred in 25% and abnormal thyroid-stimulating hormone in 21%, compared with 14% and 9% at baseline. Sixteen of 33 men had increased...

Paediatric Endocrine Disorders at the University College Hospital ...

African Journals Online (AJOL)

Background: Until recently, most published research focus more on infectious diseases and malnutrition giving the impression that endocrine disorders are uncommon. Reports on endocrine disorders in children in developing countries are few compared to developed countries reflecting the different level of prevalence in ...

Ductuloinsular tumors of the pancreas - Endocrine tumors with entrapped nonneoplastic ductules

NARCIS (Netherlands)

van Eeden, Susanne; de Leng, Wendy W. J.; Offerhaus, G. Johan A.; Morsink, Folkert H.; Weterman, Marian A. J.; de Krijger, Ronald R.; Klöppel, Günter; Klimstra, David S.

2004-01-01

Rare pancreatic neoplasms have been reported that show both endocrine and exocrine differentiation in the neoplastic components. In addition, pancreatic endocrine tumors may contain small, cytologically bland ductules intimately admixed with the endocrine component. It was recently suggested that

Tumors of the endocrine/neuroendocrine system: an overview.

Science.gov (United States)

Erlandson, R A; Nesland, J M

1994-01-01

For the sake of discussion, the markedly diversified tumors of the endocrine/neuroendocrine system are classified as those originating in classic epithelial endocrine organs (eg, adrenal cortical adenomas), from the diffuse endocrine cells (eg, jejunal carcinoid tumors), or from clusters of these cells (eg, islet cell tumors); and those arising from neurosecretory neurons (eg, neuroblastoma) or paraganglia (eg, carotid body tumor). Although traditional transmission electron microscopy is useful for identifying neurosecretory or endosecretory granules as such, with few exceptions (eg, insulin-containing granules with a complex paracrystalline core) it is not possible to ascribe a granule type (size, shape, or ultrastructure) to a distinct nosologic entity or secretory product because of their overlapping fine structures in different cell types. Immunoelectron microscopy methods utilizing colloidal gold-labeled secondary antibodies can be used to localize virtually any antigen (peptide or neuroamine) to a specific neurosecretory or endosecretory granule or other cell structure. General endocrine/neuroendocrine cell markers such as neuron-specific enolase, the chromogranins, and synaptophysin are useful in identifying neuroendocrine differentiation in a neoplasm using routine immunohistochemical procedures. The current relevance of the APUD concept of Pearse as well as the biologic importance of endocrine/neuroendocrine secretory products such as bombesin and insulinlike growth factors also are discussed.

Endocrine autoimmune disease: genetics become complex.

Science.gov (United States)

Wiebolt, Janneke; Koeleman, Bobby P C; van Haeften, Timon W

2010-12-01

The endocrine system is a frequent target in pathogenic autoimmune responses. Type 1 diabetes and autoimmune thyroid disease are the prevailing examples. When several diseases cluster together in one individual, the phenomenon is called autoimmune polyglandular syndrome. Progress has been made in understanding the genetic factors involved in endocrine autoimmune diseases. Studies on monogenic autoimmune diseases such as autoimmune polyglandular syndrome type 1, immunodysregulation, polyendocrinopathy, enteropathy, X-linked and primary immune deficiencies helped uncover the role of key regulators in the preservation of immune tolerance. Alleles of the major histocompatibility complex have been known to contribute to the susceptibility to most forms of autoimmunity for more than 3 decades. Furthermore, sequencing studies revealed three non-major histocompatibility complex loci and some disease specific loci, which control T lymphocyte activation or signalling. Recent genome-wide association studies (GWAS) have enabled acceleration in the identification of novel (non-HLA) loci and hence other relevant immune response pathways. Interestingly, several loci are shared between autoimmune diseases, and surprisingly some work in opposite direction. This means that the same allele which predisposes to a certain autoimmune disease can be protective in another. Well powered GWAS in type 1 diabetes has led to the uncovering of a significant number of risk variants with modest effect. These studies showed that the innate immune system may also play a role in addition to the adaptive immune system. It is anticipated that next generation sequencing techniques will uncover other (rare) variants. For other autoimmune disease (such as autoimmune thyroid disease) GWAS are clearly needed. © 2010 The Authors. European Journal of Clinical Investigation © 2010 Stichting European Society for Clinical Investigation Journal Foundation.

KHYG-1, a model for the study of enhanced natural killer cell cytotoxicity.

Science.gov (United States)

Suck, Garnet; Branch, Donald R; Smyth, Mark J; Miller, Richard G; Vergidis, Joanna; Fahim, Soad; Keating, Armand

2005-10-01

To compare the cytotoxicity of KHYG-1 with other natural killer (NK)/NK T-cell lines and identify molecules that may be associated with enhanced cytotoxicity, thereby eventually leading to improved NK cell-mediated cancer immunotherapy. NK/NK T-cell lines KHYG-1, NK-92, YT, and SNT-8 were compared with a novel flow cytometric cytotoxicity assay under different culture conditions. Transcription, expression, and phosphorylation studies were performed using polymerase chain reaction sequence-specific primers, reverse transcription polymerase chain reaction, immunoblotting, and flow cytometry. KHYG-1 is a highly cytotoxic cell line, exceeding the cytolytic capacity of the other cell lines against K562. KHYG-1 is also highly cytotoxic against the leukemia cell lines EM2, EM3, and HL60. The novel activation receptor NKp44 and its adaptor, DAP12, NKG2D, and constitutively phosphorylated ERK2 may be associated with the enhanced cytotoxicity of KHYG-1. This cell line most likely mediates cytolysis by granzyme M (but not granzymes A and B) together with perforin, which is constitutively fully cleaved to the 60-kD form, in contrast to the other cell lines. KHYG-1 is a valuable model for the study of enhanced cytotoxicity by NK cells. In addition to the activation of NKp44, KHYG-1 may induce apoptosis of tumor cells by the newly described granzyme M/perforin pathway. Targeted modifications of effector molecules demonstrated in this model could generate NK cells with even greater killing ability that may be particularly attractive for clinical application. Moreover, our demonstration of greater cytotoxicity of KHYG-1 versus NK-92 cells, already in clinical trials, suggests a direct therapeutic role for KHYG-1.

Bridging the gap: metabolic and endocrine care of patients during transition

Directory of Open Access Journals (Sweden)

Anita Hokken-Koelega

2016-11-01

Full Text Available Objective: Seamless transition of endocrine patients from the paediatric to adult setting is still suboptimal, especially in patients with complex disorders, i.e., small for gestational age, Turner or Prader–Willi syndromes; Childhood Cancer Survivors, and those with childhood-onset growth hormone deficiency. Methods: An expert panel meeting comprised of European paediatric and adult endocrinologists was convened to explore the current gaps in managing the healthcare of patients with endocrine diseases during transition from paediatric to adult care settings. Results: While a consensus was reached that a team approach is best, discussions revealed that a ‘one size fits all’ model for transition is largely unsuccessful in these patients. They need more tailored care during adolescence to prevent complications like failure to achieve target adult height, reduced bone mineral density, morbid obesity, metabolic perturbations (obesity and body composition, inappropriate/inadequate puberty, compromised fertility, diminished quality of life and failure to adapt to the demands of adult life. Sometimes it is difficult for young people to detach emotionally from their paediatric endocrinologist and/or the abrupt change from an environment of parental responsibility to one of autonomy. Discussions about impending transition and healthcare autonomy should begin in early adolescence and continue throughout young adulthood to ensure seamless continuum of care and optimal treatment outcomes. Conclusions: Even amongst a group of healthcare professionals with a great interest in improving transition services for patients with endocrine diseases, there is still much work to be done to improve the quality of healthcare for transition patients.

Parabens and their effects on the endocrine system.

Science.gov (United States)

Nowak, Karolina; Ratajczak-Wrona, Wioletta; Górska, Maria; Jabłońska, Ewa

2018-03-27

Preservatives (ingredients which inhibit growth of microorganisms) are used to prolong shelf life of various foods, cosmetics, and pharmaceutical products. Parabens are one of the most popular preservatives used in the aforementioned products and is currently being used worldwide. Parabens are easily absorbed by the human body. Thus, it is important to discuss about their safety with respect to human physiology. In view of the current literature, which classifies parabens as a group of endocrine disrupting chemicals (EDCs), it seems that the precise assessment of their influence on the human endocrine system is particularly important. Disruption of the endocrine homoeostasis might lead to multidirectional implications causing disruption of fitness and functions of the body. Therefore, in this review article, we aimed to summarize the current literature on properties, occurrence, and metabolism of parabens as well as to present recent progress in knowledge about their influence on the human endocrine system. Copyright © 2018 Elsevier B.V. All rights reserved.

Endocrine Disorders in Cystic Fibrosis.

Science.gov (United States)

Blackman, Scott M; Tangpricha, Vin

2016-08-01

Cystic fibrosis is frequently complicated by endocrine disorders. Diabetes can be expected to affect most with CF and pancreatic insufficiency and varies widely in age of onset, but early identification and treatment improve morbidity and mortality. Short stature can be exacerbated by relative delay of puberty and by use of inhaled corticosteroids. Bone disease in CF causes fragility fractures and should be assessed by monitoring bone mineral density and optimizing vitamin D status. Detecting and managing endocrine complications in CF can reduce morbidity and mortality in CF. These complications can be expected to become more common as the CF population ages. Copyright © 2016 Elsevier Inc. All rights reserved.

Endocrine therapy and urogenital outcomes among women with a breast cancer diagnosis

Science.gov (United States)

Doll, Kemi M.; Bensen, Jeannette T.; Hendrix, Laura; Anders, Carey K.; Wu, Jennifer M.; Nichols, Hazel B.

2018-01-01

Purpose Endocrine therapy for breast cancer can exacerbate menopausal symptoms. The association between endocrine therapy and common pelvic floor disorders including urinary incontinence has rarely been evaluated. We examined urogenital and sexual side effects among women with a breast cancer diagnosis, comparing endocrine therapy users to nonusers. Methods Urogenital and sexual symptoms were self-reported during the enrollment interview within the University of North Carolina Cancer Survivorship Cohort. Tumor characteristics and endocrine therapy use were collected from medical and prescription records. We calculated multivariable prevalence ratios (PR) and 95 % confidence intervals (CI) for the association of endocrine therapy (versus no endocrine therapy) and urinary incontinence, overall and by therapy type (tamoxifen or aromatase inhibitors). PROMIS Sexual Function and Satisfaction domain scores were compared across endocrine therapy groups. Results Among the 548 women with a breast cancer diagnosis, 49 % received endocrine therapy. Overall, 18 % of women reported urinary incontinence symptoms. We observed no association between urinary incontinence and endocrine therapy use overall (PR = 0.97; 95 % CI 0.67, 1.43), tamoxifen (PR = 1.20; 95 % CI 0.74, 1.96), or aromatase inhibitors (PR = 0.89; 95 % CI 0.55, 1.42), compared to no use. Approximately 55 % of women were sexually active. Sexual function scores did not vary according to endocrine therapy use, although urinary incontinence was associated with lower satisfaction scores (p = 0.05). Conclusions Our findings demonstrate a high prevalence of urinary incontinence after breast cancer diagnosis similar to the overall prevalence in older U.S. women, and this did not vary strongly according to use of endocrine therapy. PMID:27680018

EDC-2: The Endocrine Society's Second Scientific Statement on Endocrine-Disrupting Chemicals

Science.gov (United States)

Chappell, V. A.; Fenton, S. E.; Flaws, J. A.; Nadal, A.; Prins, G. S.; Toppari, J.; Zoeller, R. T.

2015-01-01

The Endocrine Society's first Scientific Statement in 2009 provided a wake-up call to the scientific community about how environmental endocrine-disrupting chemicals (EDCs) affect health and disease. Five years later, a substantially larger body of literature has solidified our understanding of plausible mechanisms underlying EDC actions and how exposures in animals and humans—especially during development—may lay the foundations for disease later in life. At this point in history, we have much stronger knowledge about how EDCs alter gene-environment interactions via physiological, cellular, molecular, and epigenetic changes, thereby producing effects in exposed individuals as well as their descendants. Causal links between exposure and manifestation of disease are substantiated by experimental animal models and are consistent with correlative epidemiological data in humans. There are several caveats because differences in how experimental animal work is conducted can lead to difficulties in drawing broad conclusions, and we must continue to be cautious about inferring causality in humans. In this second Scientific Statement, we reviewed the literature on a subset of topics for which the translational evidence is strongest: 1) obesity and diabetes; 2) female reproduction; 3) male reproduction; 4) hormone-sensitive cancers in females; 5) prostate; 6) thyroid; and 7) neurodevelopment and neuroendocrine systems. Our inclusion criteria for studies were those conducted predominantly in the past 5 years deemed to be of high quality based on appropriate negative and positive control groups or populations, adequate sample size and experimental design, and mammalian animal studies with exposure levels in a range that was relevant to humans. We also focused on studies using the developmental origins of health and disease model. No report was excluded based on a positive or negative effect of the EDC exposure. The bulk of the results across the board strengthen the

Putative effects of endocrine disrupters on pubertal development in the human

DEFF Research Database (Denmark)

Teilmann, Grete; Juul, Anders; Skakkebaek, Niels E

2002-01-01

-called endocrine disrupters. Precocious puberty has been described in several case reports of accidental exposure to oestrogenic compounds in cosmetic products, food and pharmaceuticals. Local epidemics of premature thelarche have also been suggested to be linked to endocrine disrupters. Children adopted from...... developing countries to industrialized countries often develop precocious puberty. Not only precocious puberty, but also delayed puberty can, theoretically, be associated with exposure to endocrine disrupters. While it is very plausible that endocrine disrupters may disturb pubertal development...

Treatment challenges for community oncologists treating postmenopausal women with endocrine-resistant, hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer

International Nuclear Information System (INIS)

Gradishar, William J

2016-01-01

Community-based oncologists are faced with challenges and opportunities when delivering quality patient care, including high patient volumes and diminished resources; however, there may be the potential to deliver increased patient education and subsequently improve outcomes. This review discusses the treatment of postmenopausal women with endocrine-resistant, hormone receptor-positive, human epidermal growth factor receptor 2- negative advanced breast cancer in order to illustrate considerations in the provision of pertinent quality education in the treatment of these patients and the management of therapy-related adverse events. An overview of endocrine-resistant breast cancer and subsequent treatment challenges is also provided. Approved treatment options for endocrine-resistant breast cancer include hormonal therapies and mammalian target of rapamycin inhibitors. Compounds under clinical investigation are also discussed

Cytotoxicity and oxidative stress induced by different metallic nanoparticles on human kidney cells

Directory of Open Access Journals (Sweden)

Ohayon-Courtès Céline

2011-03-01

Full Text Available Abstract Background Some manufactured nanoparticles are metal-based and have a wide variety of applications in electronic, engineering and medicine. Until now, many studies have described the potential toxicity of NPs on pulmonary target, while little attention has been paid to kidney which is considered to be a secondary target organ. The objective of this study, on human renal culture cells, was to assess the toxicity profile of metallic nanoparticles (TiO2, ZnO and CdS usable in industrial production. Comparative studies were conducted, to identify whether particle properties impact cytotoxicity by altering the intracellular oxidative status. Results Nanoparticles were first characterized by size, surface charge, dispersion and solubility. Cytotoxicity of NPs was then evaluated in IP15 (glomerular mesangial and HK-2 (epithelial proximal cell lines. ZnO and CdS NPs significantly increased the cell mortality, in a dose-dependent manner. Cytotoxic effects were correlated with the physicochemical properties of NPs tested and the cell type used. Analysis of reactive oxygen species and intracellular levels of reduced and oxidized glutathione revealed that particles induced stress according to their composition, size and solubility. Protein involved in oxidative stress such as NF-κb was activated with ZnO and CdS nanoparticles. Such effects were not observed with TiO2 nanoparticles. Conclusion On glomerular and tubular human renal cells, ZnO and CdS nanoparticles exerted cytotoxic effects that were correlated with metal composition, particle scale and metal solubility. ROS production and oxidative stress induction clearly indicated their nephrotoxic potential.

Metastatic melanoma: results of 'classical' second-line treatment with cytotoxic chemotherapies.

Science.gov (United States)

Perrin, Christophe; Pracht, Marc; Talour, Karen; Adamski, Henri; Cumin, Isabelle; Porneuf, Marc; Talarmin, Marie; Mesbah, Habiba; Audrain, Odile; Moignet, Aline; Lefeuvre-Plesse, Claudia; Lesimple, Thierry

2014-10-01

Metastatic melanoma is one of the most aggressive tumours, with a median survival that does not exceed 12 months. None of the cytotoxic first-line therapies have shown survival benefit in randomised clinical trials. To describe clinical benefit of second-line cytotoxic chemotherapy in the second line of treatment for metastatic melanoma. In a retrospective study, we analyse the outcome of patients with metastatic melanoma who had received two lines or more of cytotoxic treatments in four French dermato-oncology departments between 1999 and 2009. We describe the outcomes for 109 patients. Most of these patients received dacarbazine for the first line of chemotherapy and fotemustine for the second line of chemotherapy (67.0 and 64.2%, respectively). A clinical benefit was observed in 24.1% of the patients and overall survival was 4.1 months after the second-line treatment. At least 23.8% of patients suffered from grade 3 or 4 toxicities. The presence of more than two sites of metastasis and an M1c staging according to the AJCC classification represented negative predictive factors of clinical benefit. This study shows the modest benefit of a second line of cytotoxic chemotherapy in a nonselected population. If eligible, these patients should be proposed for ongoing clinical trials or for targeted therapies.

[Endocrine function in obesity].

Science.gov (United States)

Álvarez-Castro, Paula; Sangiao-Alvarellos, Susana; Brandón-Sandá, Iria; Cordido, Fernando

2011-10-01

Obesity is associated to significant disturbances in endocrine function. Hyper insulinemia and insulin resistance are the best known changes in obesity, but their mechanisms and clinical significance are not clearly established. Adipose tissue is considered to be a hormone-secreting endocrine organ; and increased leptin secretion from the adipocyte, a satiety signal, is a well-established endocrine change in obesity. In obesity there is a decreased GH secretion. Impairment of somatotropic function in obesity is functional and may be reversed in certain circumstances. The pathophysiological mechanism responsible for low GH secretion in obesity is probably multifactorial. There are many data suggesting that a chronic state of somatostatin hypersecretion results in inhibition of GH release. Increased FFA levels, as well as a deficient ghrelin secretion, probably contribute to the impaired GH secretion. In women, abdominal obesity is associated to hyperandrogenism and low sex hormone-binding globulin levels. Obese men, particularly those with morbid obesity, have decreased testosterone and gonadotropin levels. Obesity is associated to an increased cortisol production rate, which is compensated for by a higher cortisol clearance, resulting in plasma free cortisol levels that do not change when body weight increases. Ghrelin is the only known circulating orexigenic factor, and has been found to be decreased in obese people. In obesity there is also a trend to increased TSH and free T3 levels. Copyright © 2011 SEEN. Published by Elsevier Espana. All rights reserved.

Structure-cytotoxicity relationships for dietary flavonoids

DEFF Research Database (Denmark)

Breinholt, V.; Dragsted, L.O.

1998-01-01

The cytotoxicity of a large series of dietary flavonoids was tested in a non-tumorigenic mouse and two human cancer cell lines, using the neutral red dye exclusion assay. All compounds tested exhibited a concentration-dependent cytotoxic action in the employed cell lines. The relative cytotoxicity...... of the flavonoids, however, Tvas found to vary greatly among the different cell Lines. With a few exceptions, the investigated flavonoids were more cytotoxic to the human cancer cell lines, than the mouse cell line. The differences in cytotoxicity were accounted for in part by differences in cellular uptake...... and metabolic capacity among the different cell types. In 3T3 cells fairly consistent structure-cytotoxicity relationships were found. The most cytotoxic structures tested in 3T3 cells were flavonoids with adjacent 3',4' hydroxy groups on the B-ring, such as luteolin, quercetin, myricetin, fisetin, eriodictyol...

Radiologic techniques in evaluation endocrine disorders

International Nuclear Information System (INIS)

Martino, C.R.; Schultz, C.L.; Butler, H.E.; Haaga, J.R.

1988-01-01

This paper discusses evaluation of normal and diseased endocrine organs that has been facilitated by the development of new radiologic-imaging techniques including nuclear medicine, ultrasound, computed tomography, and magnetic resonance imaging. With improvement in resolution and tissue contrast, abnormalities as small as 5 mm can now be imaged with these modalities. Endocrinologists and clinicians involved in the evaluation and diagnosis of patients with endocrine diseases can be substantially aided by a proper radiologic workup. The authors describe and illustrate various radiologic techniques that are useful for evaluating thyroid and parathyroid derangements

Manufacturing doubt about endocrine disrupter science

DEFF Research Database (Denmark)

Bergman, Åke; Becher, Georg; Blumberg, Bruce

2015-01-01

We present a detailed response to the critique of "State of the Science of Endocrine Disrupting Chemicals 2012" (UNEP/WHO, 2013) by financial stakeholders, authored by Lamb et al. (2014). Lamb et al.'s claim that UNEP/WHO (2013) does not provide a balanced perspective on endocrine disruption......) report is not particularly erudite and that their critique is not intended to be convincing to the scientific community, but to confuse the scientific data. Consequently, it promotes misinterpretation of the UNEP/WHO (2013) report by non-specialists, bureaucrats, politicians and other decision makers...

Irradiated KHYG-1 retains cytotoxicity: potential for adoptive immunotherapy with a natural killer cell line.

Science.gov (United States)

Suck, G; Branch, D R; Keating, A

2006-05-01

To evaluate gamma-irradiation on KHYG-1, a highly cytotoxic natural killer (NK) cell line and potential candidate for cancer immunotherapy. The NK cell line KHYG-1 was irradiated at 1 gray (Gy) to 50 Gy with gamma-irradiation, and evaluated for cell proliferation, cell survival, and cytotoxicity against tumor targets. We showed that a dose of at least 10 Gy was sufficient to inhibit proliferation of KHYG-1 within the first day but not its cytolytic activity. While 50 Gy had an apoptotic effect in the first hours after irradiation, the killing of K562 and HL60 targets was not different from non-irradiated cells but was reduced for the Ph + myeloid leukemia lines, EM-2 and EM-3. gamma-irradiation (at least 10 Gy) of KHYG-1 inhibits cell proliferation but does not diminish its enhanced cytolytic activity against several tumor targets. This study suggests that KHYG-1 may be a feasible immunotherapeutic agent in the treatment of cancers.

Immunohistochemical study on gastrointestinal endocrine cells of four reptiles

Science.gov (United States)

Huang, Xu-Gen; Wu, Xiao-Bing

2005-01-01

AIM: To clarify the types, regional distributions and distribution densities as well as morphological features of gastrointestinal (GI) endocrine cells in various parts of the gastrointestinal track (GIT) of four reptiles, Gekko japonicus, Eumeces chinensis, Sphenomorphus indicus and Eumeces elegans. METHODS: Paraffin-embedded sections (5 μm) of seven parts (cardia, fundus, pylorus, duodenum, jejunum, ileum, rectum) of GIT dissected from the four reptiles were prepared. GI endocrine cells were revealed by using immunohistochemical techniques of streptavidin-peroxidase (S-P) method. Seven types of antisera against 5-hydroxy-tryptamine (5-HT), somatostatin (SS), gastrin (GAS), glucagon (GLU), substance P (SP), insulin and pancreatic polypeptide were identified and then GI endocrine cells were photomicrographed and counted. RESULTS: The GI endocrine system of four reptiles was a complex structure containing many endocrine cell types similar in morphology to those found in higher vertebrates. Five types of GI endocrine cells, namely 5-HT, SS, GAS, SP and GLU immunoreactive (IR) cells were identified in the GIT of G. japonicus, E. chinensis and S. indicus; while in the GIT of E. elegans only the former three types of endocrine cells were observed. No PP- and INS- IR cells were found in all four reptiles. 5-HT-IR cells, which were most commonly found in the pylorus or duodenum, distributed throughout the whole GIT of four reptiles. However, their distribution patterns varied from each other. SS-IR cells, which were mainly found in the stomach especially in the pylorus and/or fundus, were demonstrated in the whole GIT of E. chinensis, only showed restricted distribution in the other three species. GAS-IR cells, with a much restricted distribution, were mainly demonstrated in the pylorus and/or the proximal small intestine of four reptiles. GLU-IR cells exhibited a limited and species-dependent variant distribution in the GIT of four reptiles. SP-IR cells were found

Endocrine-disrupting chemicals and male reproductive health: a review

Directory of Open Access Journals (Sweden)

Damjan Balabanič

2018-03-01

Full Text Available Balanced functioning of the endocrine system is essential for preservation of human species by providing normal growth and development, reproduction, and normal functioning of all other organ systems. In the last decades, emerging area of interest is the impact of environmental exposures to human health. Important environmental pollutants are endocrine-disrupting che- micals (EDCs, which can have adverse e ects on the living organism due to their interference with the endocrine system. The group of known EDCs embraces ubiquitous synthetic substan- ces used as industrial lubricants and solvents, with their by-products, incomplete combustion remains, pharmaceuticals and personal care products, pesticides and plasticizers. Natural com- pounds such as genistein, a phytoestrogen, and heavy metals can also have endocrine e ects. Endocrine disruption is a serious public health problem. EDCs among other health problems ge- nerate reproductive disorders in males, such as decreases in sperm count and quality, increases in testicular germ cell numbers, prostate and breast cancers, cryptorchidism and hypospadias, impaired fertility, and infertility. This paper critically reviews the current knowledge of the impa- ct of EDCs on reproductive disorders in human males.

Long non-coding RNAs as regulators of the endocrine system.

Science.gov (United States)

Knoll, Marko; Lodish, Harvey F; Sun, Lei

2015-03-01

Long non-coding RNAs (lncRNAs) are a large and diverse group of RNAs that are often lineage-specific and that regulate multiple biological functions. Many are nuclear and are essential parts of ribonucleoprotein complexes that modify chromatin segments and establish active or repressive chromatin states; others are cytosolic and regulate the stability of mRNA or act as microRNA sponges. This Review summarizes the current knowledge of lncRNAs as regulators of the endocrine system, with a focus on the identification and mode of action of several endocrine-important lncRNAs. We highlight lncRNAs that have a role in the development and function of pancreatic β cells, white and brown adipose tissue, and other endocrine organs, and discuss the involvement of these molecules in endocrine dysfunction (for example, diabetes mellitus). We also address the associations of lncRNAs with nuclear receptors involved in major hormonal signalling pathways, such as estrogen and androgen receptors, and the relevance of these associations in certain endocrine cancers.

Study of Cytotoxic Effects of Benzonitrile Pesticides

Science.gov (United States)

Lovecka, Petra; Thimova, Marketa; Grznarova, Petra; Lipov, Jan; Knejzlik, Zdenek; Stiborova, Hana; Nindhia, Tjokorda Gde Tirta; Demnerova, Katerina; Ruml, Tomas

2015-01-01

The benzonitrile herbicides bromoxynil, chloroxynil, dichlobenil, and ioxynil have been used actively worldwide to control weeds in agriculture since 1970s. Even though dichlobenil is prohibited in EU since 2008, studies addressing the fate of benzonitrile herbicides in the environment show that some metabolites of these herbicides are very persistent. We tested the cytotoxic effects of benzonitrile herbicides and their microbial metabolites using two human cell lines, Hep G2 and HEK293T, representing liver and kidneys as potential target organs in humans. The cell viability and proliferation were determined by MTT test and RTCA DP Analyzer system, respectively. The latter allows real-time monitoring of the effect of added substances. As the cytotoxic compounds could compromise cell membrane integrity, the lactate dehydrogenase test was performed as well. We observed high toxic effects of bromoxynil, chloroxynil, and ioxynil on both tested cell lines. In contrast, we determined only low inhibition of cell growth in presence of dichlobenil and microbial metabolites originating from the tested herbicides. PMID:26339609

Radiological imaging of endocrine diseases

International Nuclear Information System (INIS)

Bruneton, J.N.

1999-01-01

Imaging studies are playing an increasingly role in the evaluation of endocrine diseases; accordingly, familiarity with the specific indications for the various modalities, and with the characteristic findings, is essential. This multi-author work, which is intended for both radiologists and endocrinologists, considers the role of all the recent imaging techniques, including ultrasound (particular color Doppler), computed tomography, MRI, and scintigraphy. Following an extensive introduction on the pituitary, subsequent chapters discuss in detail the normal anatomy and pathology of the female and male reproductive systems. Remaining chapters provide state-of-the-art data on the thyroid, parathyroids, pancreatic endocrine tumors, adrenal glands, hormonal tumors (carcinoids and MEN), and imaging of the complications of hormone therapy. (orig.)

Endocrine ophthalmopathy and radioiodine therapy

International Nuclear Information System (INIS)

Karlsson, F. Anders

2006-01-01

Endocrine ophthalmopathy is to some degree present in most patients with Graves' disease. In few cases, a severe form of the condition develops and in the majority of these cases, the course of the eye problems has been influenced by the treatment for thyrotoxicosis. In this regard, radioiodine therapy has been increasingly recognized as carrying a special risk. Here, the current understanding of endocrine ophthalmopathy and the risks associated with the development of severe eye disease are discussed. The results of a retrospective investigation of patients with severe eye disease in our hospital, and the experience with corticosteroid administration following radioiodine in order to reduce the risk of ophthalmopathy, are also presented

Theory and applications of artificial endocrine system-an overview

Institute of Scientific and Technical Information of China (English)

CUI Wei; QIANG Sheng; GAO X Z

2006-01-01

Inspired by the biological endocrine system, the Artificial Endocrine System (AES) has been proposed and investigated during the past decade. As a novel branch of computational intelligence methods, it has its unique and distinguishing features. This paper intends to give an overview of the current research work in the AES. The preliminary theory of the AES, which is based on the simplified mathematic models of natural endocrine system, is first introduced here. Some typical AES algorithms and their applications are also briefly discussed. Finally, a few remarks and conclusions are made.

Endocrine System (For Parents)

Science.gov (United States)

... Problems With the Endocrine System Print en español Sistema endócrino Although we rarely think about them, the ... of Use Notice of Nondiscrimination Visit the Nemours Web site. Note: All information on KidsHealth® is for ...

Effective collaboration between marginal metallophilic macrophages and CD8+ dendritic cells in the generation of cytotoxic T cells

Science.gov (United States)

Backer, Ronald; Schwandt, Timo; Greuter, Mascha; Oosting, Marije; Jüngerkes, Frank; Tüting, Thomas; Boon, Louis; O’Toole, Tom; Kraal, Georg; Limmer, Andreas; den Haan, Joke M. M.

2009-01-01

The spleen is the lymphoid organ that induces immune responses toward blood-borne pathogens. Specialized macrophages in the splenic marginal zone are strategically positioned to phagocytose pathogens and cell debris, but are not known to play a role in the activation of T-cell responses. Here we demonstrate that splenic marginal metallophilic macrophages (MMM) are essential for cross-presentation of blood-borne antigens by splenic dendritic cells (DCs). Our data demonstrate that antigens targeted to MMM as well as blood-borne adenoviruses are efficiently captured by MMM and exclusively transferred to splenic CD8+ DCs for cross-presentation and for the activation of cytotoxic T lymphocytes. Depletion of macrophages in the marginal zone prevents cytotoxic T-lymphocyte activation by CD8+ DCs after antibody targeting or adenovirus infection. Moreover, we show that tumor antigen targeting to MMM is very effective as antitumor immunotherapy. Our studies point to an important role for splenic MMM in the initial steps of CD8+ T-cell immunity by capturing and concentrating blood-borne antigens and the transfer to cross-presenting DCs which can be used to design vaccination strategies to induce antitumor cytotoxic T-cell immunity. PMID:20018690

Design, Synthesis and Cytotoxic Evaluation of o-Carboxamido Stilbene Analogues

Directory of Open Access Journals (Sweden)

Mohamad Nurul Azmi

2013-11-01

Full Text Available Resveratrol, a natural stilbene found in grapes and wines exhibits a wide range of pharmacological properties. Resveratrol is also known as a good chemopreventive agent for inhibiting carcinogenesis processes that target kinases, cyclooxygenases, ribonucleotide reductase and DNA polymerases. A total of 19 analogues with an amide moiety were synthesized and the cytotoxic effects of the analogues on a series of human cancer cell lines are reported. Three compounds 6d, 6i and 6n showed potent cytotoxicity against prostate cancer DU-145 (IC50 = 16.68 µM, colon cancer HT-29 (IC50 = 7.51 µM and breast cancer MCF-7 (IC50 = 21.24 µM, respectively, which are comparable with vinblastine. The resveratrol analogues were synthesized using the Heck method.

Targeted drugs in radiation therapy

International Nuclear Information System (INIS)

Favaudon, V.; Hennequin, C.; Hennequin, C.

2004-01-01

New drugs aiming at the development of targeted therapies have been assayed in combination with ionizing radiation over the past few years. The rationale of this concept comes from the fact that the cytotoxic potential of targeted drugs is limited, thus requiring concomitant association with a cytotoxic agent for the eradication of tumor cells. Conversely a low level of cumulative toxicity is expected from targeted drugs. Most targeted drugs act through inhibition of post-translational modifications of proteins, such as dimerization of growth factor receptors, prenylation reactions, or phosphorylation of tyrosine or serine-threonine residues. Many systems involving the proteasome, neo-angiogenesis promoters, TGF-β, cyclooxygenase or the transcription factor NF-κB, are currently under investigation in hopes they will allow a control of cell proliferation, apoptosis, cell cycle progression, tumor angiogenesis and inflammation. A few drugs have demonstrated an antitumor potential in particular phenotypes. In most instances, however, radiation-drug interactions proved to be strictly additive in terms of cell growth inhibition or induced cell death. Strong potentiation of the response to radiotherapy is expected to require interaction with DNA repair mechanisms. (authors)

Addressing the Immunogenicity of the Cargo and of the Targeting Antibodies with a Focus on Deimmunized Bacterial Toxins and on Antibody-Targeted Human Effector Proteins

Science.gov (United States)

Grinberg, Yehudit; Benhar, Itai

2017-01-01

Third-generation immunotoxins are composed of a human, or humanized, targeting moiety, usually a monoclonal antibody or an antibody fragment, and a non-human effector molecule. Due to the non-human origin of the cytotoxic domain, these molecules stimulate potent anti-drug immune responses, which limit treatment options. Efforts are made to deimmunize such immunotoxins or to combine treatment with immunosuppression. An alternative approach is using the so-called “human cytotoxic fusion proteins”, in which antibodies are used to target human effector proteins. Here, we present three relevant approaches for reducing the immunogenicity of antibody-targeted protein therapeutics: (1) reducing the immunogenicity of the bacterial toxin, (2) fusing human cytokines to antibodies to generate immunocytokines and (3) addressing the immunogenicity of the targeting antibodies. PMID:28574434

Endocrine disorders in pregnancy

DEFF Research Database (Denmark)

Feldt-Rasmussen, Ulla; Mathiesen, Elisabeth R

2011-01-01

The endocrinology of pregnancy involves endocrine and metabolic changes as a consequence of physiological alterations at the foetoplacental boundary between mother and foetus. The vast changes in maternal hormones and their binding proteins complicate assessment of the normal level of most hormones...

The coagulation system in endocrine disorders: a narrative review

NARCIS (Netherlands)

Squizzato, A.; Gerdes, V. E. A.; Ageno, W.; Büller, H. R.

2007-01-01

Endocrine disorders can influence the haemostatic balance. Abnormal coagulation test results have been observed in patients with abnormal hormone levels. Also unprovoked bleeding or thrombotic events have been associated with endocrine disease. The aim of the present review is to summarise the

38 CFR 4.119 - Schedule of ratings-endocrine system.

Science.gov (United States)

2010-07-01

... minute), eye involvement, muscular weakness, loss of weight, and sympathetic nervous system...-endocrine system. 4.119 Section 4.119 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS SCHEDULE FOR RATING DISABILITIES Disability Ratings The Endocrine System § 4.119 Schedule of ratings...

Enhanced cytotoxicity of anticancer drug delivered by novel nanoscale polymeric carrier

Science.gov (United States)

Stoika, R.; Boiko, N.; Senkiv, Y.; Shlyakhtina, Y.; Panchuk, R.; Finiuk, N.; Filyak, Y.; Bilyy, R.; Kit, Y.; Skorohyd, N.; Klyuchivska, O.; Zaichenko, A.; Mitina, N.; Ryabceva, A.

2013-04-01

We compared in vitro action of highly toxic anticancer drug doxorubicin under its delivery to the mammalian tumor cells in free form and after encapsulation in novel bio-functionalized nanoscale polymeric carrier. Such encapsulation was found to enhance significantly drug uptake by the targeted cells, as well as its cytotoxic action. 10 times higher cytotoxicity of the carrier-immobilized doxorubicin comparing to its free form was demonstrated by direct cell counting, and 5 times higher cytotoxicity of encapsulated doxorubicin was shown by FACS analysis. The polymeric carrier itself did not possess significant toxicity in vitro or in vivo (laboratory mice). The carrier protected against negative side effects of doxorubicin in mice with experimental NK/Ly lymphoma. The life duration of tumor-bearing animals treated with doxorubicin-carrier complex was significantly longer than life duration in animals treated with free doxorubicin. Besides, the effective treatment dose of the carrier-delivered doxorubicin in tumor-bearing mice was 10 times lower than such dose of free doxorubicin. Thus, novel nanoscale polymers possess high potential as drug carrier.

Enhanced cytotoxicity of anticancer drug delivered by novel nanoscale polymeric carrier

International Nuclear Information System (INIS)

Stoika, R; Boiko, N; Panchuk, R; Filyak, Y; Senkiv, Y; Finiuk, N; Shlyakhtina, Y; Bilyy, R; Kit, Y; Skorohyd, N; Klyuchivska, O; Zaichenko, A; Mitina, N; Ryabceva, A

2013-01-01

We compared in vitro action of highly toxic anticancer drug doxorubicin under its delivery to the mammalian tumor cells in free form and after encapsulation in novel bio-functionalized nanoscale polymeric carrier. Such encapsulation was found to enhance significantly drug uptake by the targeted cells, as well as its cytotoxic action. 10 times higher cytotoxicity of the carrier-immobilized doxorubicin comparing to its free form was demonstrated by direct cell counting, and 5 times higher cytotoxicity of encapsulated doxorubicin was shown by FACS analysis. The polymeric carrier itself did not possess significant toxicity in vitro or in vivo (laboratory mice). The carrier protected against negative side effects of doxorubicin in mice with experimental NK/Ly lymphoma. The life duration of tumor-bearing animals treated with doxorubicin-carrier complex was significantly longer than life duration in animals treated with free doxorubicin. Besides, the effective treatment dose of the carrier-delivered doxorubicin in tumor-bearing mice was 10 times lower than such dose of free doxorubicin. Thus, novel nanoscale polymers possess high potential as drug carrier.

Multiple endocrine diseases in cats: 15 cases (1997-2008).

Science.gov (United States)

Blois, Shauna L; Dickie, Erica L; Kruth, Stephen A; Allen, Dana G

2010-08-01

The objective of this retrospective study was to characterize a population of cats from a tertiary care center diagnosed with multiple endocrine disorders, including the specific disorders and time intervals between diagnosis of each disorder. Medical records of 15 cats diagnosed with more than one endocrine disorder were reviewed. The majority of cats were domestic shorthairs, and the mean age at the time of diagnosis of the first disorder was 10.3 years. The most common combination of disorders was diabetes mellitus and hyperthyroidism. Two cats had concurrent diabetes mellitus and hyperadrenocorticism, one cat had concurrent central diabetes insipidus and diabetes mellitus. A mean of 25.7 months elapsed between diagnoses of the first and second endocrine disorder, but this was variable. This study suggests the occurrence of multiple endocrine disorders is uncommon in cats. Copyright 2010 ISFM and AAFP. Published by Elsevier Ltd. All rights reserved.

Affective disorders and endocrine disease. New insights from psychosomatic studies.

Science.gov (United States)

Fava, G A

1994-01-01

This is a review of psychosomatic interactions between affective disorders (depressive and anxiety disturbances, irritable mood) and endocrine disease. Particular reference is made to stressful life events in the pathogenesis of endocrine disease, psychopathology of hormonal disturbances, and pathophysiology of hypothalamic-pituitary-adrenal axis function in depression and Cushing's disease. These psychosomatic interactions may lead to appraisal of common etiological mechanisms in endocrine and psychiatric disorders, of the value of retaining the category of organic affective syndromes in psychiatric classification, and of the need for research on quality-of-life measures in endocrine disease. The establishment of "psychoendocrine units," where both endocrinologists and psychiatrists should work, is advocated. Such psychoendocrine units may serve and benefit clinical populations who currently defy traditional medical subdivisions.

Designing Endocrine Disruption Out of the Next Generation of Chemicals.

Science.gov (United States)

Schug, T T; Abagyan, R; Blumberg, B; Collins, T J; Crews, D; DeFur, P L; Dickerson, S M; Edwards, T M; Gore, A C; Guillette, L J; Hayes, T; Heindel, J J; Moores, A; Patisaul, H B; Tal, T L; Thayer, K A; Vandenberg, L N; Warner, J; Watson, C S; Saal, F S Vom; Zoeller, R T; O'Brien, K P; Myers, J P

2013-01-01

A central goal of green chemistry is to avoid hazard in the design of new chemicals. This objective is best achieved when information about a chemical's potential hazardous effects is obtained as early in the design process as feasible. Endocrine disruption is a type of hazard that to date has been inadequately addressed by both industrial and regulatory science. To aid chemists in avoiding this hazard, we propose an endocrine disruption testing protocol for use by chemists in the design of new chemicals. The Tiered Protocol for Endocrine Disruption (TiPED) has been created under the oversight of a scientific advisory committee composed of leading representatives from both green chemistry and the environmental health sciences. TiPED is conceived as a tool for new chemical design, thus it starts with a chemist theoretically at "the drawing board." It consists of five testing tiers ranging from broad in silico evaluation up through specific cell- and whole organism-based assays. To be effective at detecting endocrine disruption, a testing protocol must be able to measure potential hormone-like or hormone-inhibiting effects of chemicals, as well as the many possible interactions and signaling sequellae such chemicals may have with cell-based receptors. Accordingly, we have designed this protocol to broadly interrogate the endocrine system. The proposed protocol will not detect all possible mechanisms of endocrine disruption, because scientific understanding of these phenomena is advancing rapidly. To ensure that the protocol remains current, we have established a plan for incorporating new assays into the protocol as the science advances. In this paper we present the principles that should guide the science of testing new chemicals for endocrine disruption, as well as principles by which to evaluate individual assays for applicability, and laboratories for reliability. In a 'proof-of-principle' test, we ran 6 endocrine disrupting chemicals (EDCs) that act via

The cytotoxicity and genotoxicity of soluble and particulate cobalt in human lung fibroblast cells

Energy Technology Data Exchange (ETDEWEB)

Smith, Leah J.; Holmes, Amie L. [Wise Laboratory of Environmental and Genetic Toxicology, University of Southern Maine, 96 Falmouth St., P.O. Box 9300, Portland, ME 04101-9300 (United States); Maine Center for Environmental Toxicology and Health, University of Southern Maine, 96 Falmouth St., P.O. Box 9300, Portland, ME 04101-9300 (United States); Department of Applied Medical Science, University of Southern Maine, 96 Falmouth St., P.O. Box 9300, Portland, ME 04101-9300 (United States); Kandpal, Sanjeev Kumar; Mason, Michael D. [Department of Chemical and Biological Engineering, University of Maine, Orono, ME (United States); Zheng, Tongzhang [Department of Environmental Health Sciences, Yale School of Public Health, New Haven, CT (United States); Wise, John Pierce, E-mail: John.Wise@usm.maine.edu [Wise Laboratory of Environmental and Genetic Toxicology, University of Southern Maine, 96 Falmouth St., P.O. Box 9300, Portland, ME 04101-9300 (United States); Maine Center for Environmental Toxicology and Health, University of Southern Maine, 96 Falmouth St., P.O. Box 9300, Portland, ME 04101-9300 (United States); Department of Applied Medical Science, University of Southern Maine, 96 Falmouth St., P.O. Box 9300, Portland, ME 04101-9300 (United States)

2014-08-01

Cobalt exposure is increasing as cobalt demand rises worldwide due to its use in enhancing rechargeable battery efficiency, super-alloys, and magnetic products. Cobalt is considered a possible human carcinogen with the lung being a primary target. However, few studies have considered cobalt-induced toxicity in human lung cells. Therefore, in this study, we sought to determine the cytotoxicity and genotoxicity of particulate and soluble cobalt in human lung cells. Cobalt oxide and cobalt chloride were used as representative particulate and soluble cobalt compounds, respectively. Exposure to both particulate and soluble cobalt induced a concentration-dependent increase in cytotoxicity, genotoxicity, and intracellular cobalt ion levels. Based on intracellular cobalt ion levels, we found that soluble cobalt was more cytotoxic than particulate cobalt while particulate and soluble cobalt induced similar levels of genotoxicity. However, soluble cobalt induced cell cycle arrest indicated by the lack of metaphases at much lower intracellular cobalt concentrations compared to cobalt oxide. Accordingly, we investigated the role of particle internalization in cobalt oxide-induced toxicity and found that particle-cell contact was necessary to induce cytotoxicity and genotoxicity after cobalt exposure. These data indicate that cobalt compounds are cytotoxic and genotoxic to human lung fibroblasts, and solubility plays a key role in cobalt-induced lung toxicity. - Highlights: • Particulate and soluble cobalt are cytotoxic and genotoxic to human lung cells. • Soluble cobalt induces more cytotoxicity compared to particulate cobalt. • Soluble and particulate cobalt induce similar levels of genotoxicity. • Particle-cell contact is required for particulate cobalt-induced toxicity.

[Novel concepts in biology of diffuse endocrine system: results and future investigations].

Science.gov (United States)

Iaglov, V V; Iaglova, N V

2012-01-01

Diffuse endocrine system is a largest part of endocrine system of vertebrates. Recend findings showed that DES-cells are not neuroectodermal but have ectodermal, mesodermal, and entodermal ontogeny. The article reviews novel concept of diffuse endocrine system anatomy and physiology, functional role of DES hormones and poorly investigated aspects like DES-cell morphology, hormones secretion in normal and pathologic conditions. Further research of diffuse endocrine system has a great significance for biochemistry, morphology, and clinical medicine.

ENDOCRINE PANCREATIC FUNCTION IN ACUTE PANCREATITIS

Directory of Open Access Journals (Sweden)

P. V. Novokhatny

2014-02-01

Full Text Available Introduction Among the organs of internal secretion pancreas has a special place thanks to active exocrine function and a wide range of physiological actions of produced hormones. Violations of endocrine pancreas arises in 6.5-38 % of patients with acute pancreatitis. However, there is still no clear understanding of the pathogenetic mechanisms of hormonal dysfunction of the pancreas in acute pancreatitis, there is no uniform algorithms for its correction. Aim of the research was to study the endocrine function of pancreas in acute pancreatitis. To define the role of endocrine pancreatic function in the etiology and pathogenesis of the acute pancreatitis. To assess the prospects of the use of pancreatic hormones in the treatment and predicting the outcomes of acute pancreatitis. Materials and methods of the research Survey of publications in specialized periodical medical journals, PubMed sources developed by the National Center for Biotechnology Information. Search in PubMed was carried out in the following databases: MEDLINE, Pre MEDLINE. Results of the research. In a significant proportion of patients who recovered from acute pancreatitis, exocrine and endocrine functional impairments were found. This finding was not detected only in patients after severe acute pancreatitis. Routine evaluation of pancreatic function after acute pancreatitis should be considered. The comparative analysis of the synthetic analogues (somatostatin, calcitonin, leu-enkefalin-dalargin influence on the glucose metabolism of rats in acute pancreatitis of was made. Physiological reaction of beta-cells is preserved in infusion of somatostatin. However, infusion of calcitonin results in the distortion of counterregulatory action of insulin and glucagon. It was detected that pancreatic renin-angiotensin system is markedly activated in the experimental rat models of chronic hypoxia and acute pancreatitis. The activation of the pancreatic renin-angiotensin system by

Functional Hypothalamic Amenorrhea: An Endocrine Society Clinical Practice Guideline.

Science.gov (United States)

Gordon, Catherine M; Ackerman, Kathryn E; Berga, Sarah L; Kaplan, Jay R; Mastorakos, George; Misra, Madhusmita; Murad, M Hassan; Santoro, Nanette F; Warren, Michelle P

2017-05-01

The American Society for Reproductive Medicine, the European Society of Endocrinology, and the Pediatric Endocrine Society. This guideline was funded by the Endocrine Society. To formulate clinical practice guidelines for the diagnosis and treatment of functional hypothalamic amenorrhea (FHA). The participants include an Endocrine Society-appointed task force of eight experts, a methodologist, and a medical writer. This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation approach to describe the strength of recommendations and the quality of evidence. The task force commissioned two systematic reviews and used the best available evidence from other published systematic reviews and individual studies. One group meeting, several conference calls, and e-mail communications enabled consensus. Endocrine Society committees and members and cosponsoring organizations reviewed and commented on preliminary drafts of this guideline. FHA is a form of chronic anovulation, not due to identifiable organic causes, but often associated with stress, weight loss, excessive exercise, or a combination thereof. Investigations should include assessment of systemic and endocrinologic etiologies, as FHA is a diagnosis of exclusion. A multidisciplinary treatment approach is necessary, including medical, dietary, and mental health support. Medical complications include, among others, bone loss and infertility, and appropriate therapies are under debate and investigation. Copyright © 2017 Endocrine Society

Cells of the J774 macrophage cell line are primed for antibody-dependent cell-mediated cytotoxicity following exposure to γ-irradiation

International Nuclear Information System (INIS)

Duerst, R.; Werberig, K.

1991-01-01

Activation of macrophages (M phi) for host defense against tumor cells follows a sequence of priming events followed by an initiating stimulus that results in production and release of cytotoxic molecules that mediate target cell killing. The authors have developed a model to study specific macrophage cytotoxicity in vitro utilizing a cultured murine M phi cell line, J774. Specific cytotoxicity of cultured human gastrointestinal tumor cells is achieved in the presence of murine IgG2a monoclonal antibody (mAb) 17-1-A. The ability of these cells to mediate antibody-dependent cell-mediated cytotoxicity (ADCC) is greatly enhanced following gamma-irradiation. ADCC can be demonstrated at mAb 17-1-A concentrations greater than or equal to 1 microgram/ml and effector/target cell ratios greater than or equal to 2. Exposure to doses greater than or equal to 10 Gy of gamma-irradiation increases ADCC threefold. Varying the duration from J774 M phi exposure to γ-irradiation until addition of antibody-coated target cells showed that the primed state for ADCC is stable for at least 8 days but approximately 24 hr is required for complete development of the primed state. mAb-dependent target cell death begins 8 hr after addition of mAb and labeled target cells to primed effector cells and is complete by 24 hr. Incubation of unirradiated J774 M phi effector cells with recombinant murine interferon-γ (rmIFN-γ) also results in enhanced ADCC, but the extent of target cell killing achieved is less than that following priming by γ-irradiation. Concomitant priming of γ-irradiated J774 M phi with rmIFN-γ increases the extent of ADCC. Further study of irradiated J774 cells may elucidate the molecular pathways utilized by M phi for achieving and maintaining the primed state for ADCC

Cisplatin Induces Cytotoxicity through the Mitogen-Activated Protein Kinase Pathways ana Activating Transcription Factor 3

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Carly St. Germain

2010-07-01

Full Text Available The mechanisms underlying the proapoptotic effect of the chemotherapeutic agent, cisplatin, are largely undefined. Understanding the mechanisms regulating cisplatin cytotoxicity may uncover strategies to enhance the efficacy of this important therapeutic agent. This study evaluates the role of activating transcription factor 3 (ATF3 as a mediator of cisplatin-induced cytotoxicity. Cytotoxic doses of cisplatin and carboplatin treatments consistently induced ATF3 expression in five tumor-derived cell lines. Characterization of this induction revealed a p53, BRCA1, and integrated stress response-independent mechanism, all previously implicated in stress-mediated ATF3 induction. Analysis of mitogenactivated protein kinase (MAPK pathway involvement in ATF3 induction by cisplatin revealed a MAPK-dependent mechanism. Cisplatin treatment combined with specific inhibitors to each MAPK pathway (c-Jun N-terminal kinase, extracellularsignal-regulated kinase, and p38 resulted in decreasedATF3 induction at the protein level. MAPK pathway inhibition led to decreased ATF3 messenger RNA expression and reduced cytotoxic effects of cisplatin as measured by the 3-(4,5-dimethylthiazol-2-ylF2,5-diphenyltetrazolium bromide cell viability assay. In A549 lung carcinoma cells, targeting ATF3 with specific small hairpin RNA also attenuated the cytotoxic effects of cisplatin. Similarly, ATF3-/murine embryonic fibroblasts (MEFs were shown to be less sensitive to cisplatin-induced cytotoxicity compared with ATF3+/+ MEFs. This study identifies cisplatin as a MAPK pathway-dependent inducer of ATF3, whose expression influences cisplatin’s cytotoxic effects.

Specifying pancreatic endocrine cell fates.

Science.gov (United States)

Collombat, Patrick; Hecksher-Sørensen, Jacob; Serup, Palle; Mansouri, Ahmed

2006-07-01

Cell replacement therapy could represent an attractive alternative to insulin injections for the treatment of diabetes. However, this approach requires a thorough understanding of the molecular switches controlling the specification of the different pancreatic cell-types in vivo. These are derived from an apparently identical pool of cells originating from the early gut endoderm, which are successively specified towards the pancreatic, endocrine, and hormone-expressing cell lineages. Numerous studies have outlined the crucial roles exerted by transcription factors in promoting the cell destiny, defining the cell identity and maintaining a particular cell fate. This review focuses on the mechanisms regulating the morphogenesis of the pancreas with particular emphasis on recent findings concerning the transcription factor hierarchy orchestrating endocrine cell fate allocation.

Bicaudal C1 promotes pancreatic NEUROG3+ endocrine progenitor differentiation and ductal morphogenesis

DEFF Research Database (Denmark)

Lemaire, Laurence A; Goulley, Joan; Kim, Yung Hae

2015-01-01

that line the ducts during development, and in the ducts after birth, but not in differentiated endocrine or acinar cells. Genetic inactivation of Bicc1 leads to ductal cell over-proliferation and cyst formation. Transcriptome comparison between WT and Bicc1 KO pancreata, before the phenotype onset, reveals......(+) endocrine progenitor production. Its deletion leads to a late but sustained endocrine progenitor decrease, resulting in a 50% reduction of endocrine cells. We show that BICC1 functions downstream of ONECUT1 in the pathway controlling both NEUROG3(+) endocrine cell production and ductal morphogenesis...

Cytotoxicity Effects of Amoora rohituka and chittagonga on Breast and Pancreatic Cancer Cells

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Leo L. Chan

2011-01-01

Full Text Available Chemotherapeutic agents for cancer are highly toxic to healthy tissues and hence alternative medicine avenues are widely researched. Majority of the recent studies on alternative medicine suggested that Amoora rohituka possesses considerable antitumor and antibacterial properties. In this work, rohituka and chittagonga, fractionated with petroleum ether, dichloromethane, and ethanol, were explored for their anticancer potential against two breast cancer (MCF-7 and HTB-126 and three pancreatic cancer (Panc-1, Mia-Paca2, and Capan1. The human foreskin fibroblast, Hs68, was also included. Cytotoxicity of each extract was analyzed using the MTT assay and label-free photonic crystal biosensor assay. A concentration series of each extract was performed on the six cell lines. For MCF-7 cancer cells, the chittagonga (Pet-Ether and CH2Cl2 and rohituka (Pet-Ether extracts induced cytotoxicity; the chittagonga (EtoAC and rohituka (MeOH extracts did not induce cytotoxicity. For HTB126, Panc-1, Mia-Paca2, and Capan-1 cancer cells, only the chittagonga CH2Cl2 extract showed a significant cytotoxic effect. The extracts were not cytotoxic to normal fibroblast Hs68 cells, which may be correlated to the specificity of Amoora extracts in targeting cancerous cells. Based on these results, further examination of the potential anticancer properties Amoora species and the identification of the active ingredients of these extracts is warranted.

Practice patterns and job satisfaction in fellowship-trained endocrine surgeons.

Science.gov (United States)

Tsinberg, Michael; Duh, Quan-Yang; Cisco, Robin M; Gosnell, Jessica E; Scholten, Anouk; Clark, Orlo H; Shen, Wen T

2012-12-01

Debates about the difficult job market for young endocrine surgeons are ongoing. This study aimed to analyze the practice patterns and work-related satisfaction levels of recently trained endocrine surgeons. An anonymous survey was utilized. Participants were divided into 3 groups: "Young" (5 years). Fifty-six of 78 surgeons (72%) responded to the survey. Time in practice ranged from 1 to 9 years (mean, 3.9 ± 0.28). Forty-five (80%) described their practice as academic. Participants performed 244.1 ± 17.8 operations within the last year; 75.4 ± 3.3% were endocrine cases. More surgeons in the "young" group have academic practices (92%) and joined established endocrine surgery groups (54%) versus older surgeons (67% and 42%; P = .05). Of surgeons in the "young" group, 4% started their own practice versus 33% in the "older" group (P = .04). Level of satisfaction with financial compensation (3.2 on a 4-point scale versus 2.9) and lifestyle (3.6 vs 3.1) was also higher in the younger group (P = .009). Despite widespread speculation about scarcity of academic jobs after fellowship, recently trained endocrine surgeons are more likely to practice in academic settings and join established endocrine surgery practices when compared with older surgeons. Overall satisfaction level is higher among recently trained surgeons. Copyright © 2012 Mosby, Inc. All rights reserved.

Poly (D,L-lactide-co-glycolide nanoparticles: Uptake by epithelial cells and cytotoxicity

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J. H. Hamman

2014-03-01

Full Text Available Nanoparticles as drug delivery systems offer benefits such as protection of the encapsulated drug against degradation, site-specific targeting and prolonged blood circulation times. The aim of this study was to investigate nanoparticle uptake into Caco-2 cell monolayers, their co-localization within the lysosomal compartment and their cytotoxicity in different cell lines. Rhodamine-6G labelled poly(D,L-lactide-co-glycolide (PLGA nanoparticles were prepared by a double emulsion solvent evaporation freeze-drying method. Uptake and co-localisation of PLGA nanoparticles in lysosomes were visualized by confocal laser scanning microscopy. The cytotoxicity of the nanoparticles was evaluated on different mammalian cells lines by means of Trypan blue exclusion and the MTS assay. The PLGA nanoparticles accumulated in the intercellular spaces of Caco-2 cell monolayers, but were also taken up transcellularly into the Caco-2 cells and partially co-localized within the lysosomal compartment indicating involvement of endocytosis during uptake. PLGA nanoparticles did not show cytotoxic effects in all three cell lines. Intact PLGA nanoparticles are therefore capable of moving across epithelial cell membranes partly by means of endocytosis without causing cytotoxic effects.

Echovirus 6 Infects Human Exocrine and Endocrine Pancreatic Cells and Induces Pro-Inflammatory Innate Immune Response

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Luis Sarmiento

2017-01-01

Full Text Available Human enteroviruses (HEV, especially coxsackievirus serotype B (CVB and echovirus (E, have been associated with diseases of both the exocrine and endocrine pancreas, but so far evidence on HEV infection in human pancreas has been reported only in islets and ductal cells. This study aimed to investigate the capability of echovirus strains to infect human exocrine and endocrine pancreatic cells. Infection of explanted human islets and exocrine cells with seven field strains of E6 caused cytopathic effect, virus titer increase and production of HEV protein VP1 in both cell types. Virus particles were found in islets and acinar cells infected with E6. No cytopathic effect or infectious progeny production was observed in exocrine cells exposed to the beta cell-tropic strains of E16 and E30. Endocrine cells responded to E6, E16 and E30 by upregulating the transcription of interferon-induced with helicase C domain 1 (IF1H1, 2'-5'-oligoadenylate synthetase 1 (OAS1, interferon-β (IFN-β, chemokine (C–X–C motif ligand 10 (CXCL10 and chemokine (C–C motif ligand 5 (CCL5. Echovirus 6, but not E16 or E30, led to increased transcription of these genes in exocrine cells. These data demonstrate for the first time that human exocrine cells represent a target for E6 infection and suggest that certain HEV serotypes can replicate in human pancreatic exocrine cells, while the pancreatic endocrine cells are permissive to a wider range of HEV.

Endocrine control of epigenetic mechanisms in male reproduction.

Science.gov (United States)

Ankolkar, Mandar; Balasinor, N H

2016-01-01

Endocrine control of reproduction is very well known and has been echoed by many research groups. However, recent developments point to the ability of toxic endocrine disrupting chemicals (EDC) to alter epigenetic information of the gametes which gets transferred to the developing embryo and affects the immediate reproductive outcome or even persists transgenerationally. These epigenetic aberrations contribute to the ensuing pathophysiology of reproductive disorders. Investigations of the female in cases of poor reproductive outcome have been the main strategy towards diagnosis. However, despite the male partner contributing half of his genome to the progeny, thorough investigations in the male have been ignored. Environmental pollutants are all pervading and are encountered in our day-to-day life. Many of these pollutants have potential to disrupt the endocrine system. Here, we discuss how the male gametes (spermatozoa) are susceptible to a myriad of epigenetic insults inflicted by exposure to endocrine disruptors and how important is the contribution of the epigenetic marks of the spermatozoa in healthy reproduction. We advocate that sperm epigenetics should be considered as a significant contributor to reproductive health and should be researched further and be subsequently included in routine diagnostic workup in cases of poor reproductive outcome.

Endocrine diseases in ferrets

NARCIS (Netherlands)

Schoemaker, N.J.; van Zeeland, Y.R.A.

2013-01-01

SUMMARY Endocrine diseases are among the most commonly seen conditions in ferrets. Tumours of the islet cells in the pancreas, referred to as insulinomas, and tumours of the adrenal glands, referred to as hyperadrenocorticism, are more commonly described in this species than in any other species.

Molecular diagnosis of multiple endocrine neoplasia type 2A ...

African Journals Online (AJOL)

Molecular diagnosis of multiple endocrine neoplasia type 2A. RJ Pegoraro, DJ Hacking, RH Buck, L Rom, PA Lanning, GMB Berger. Abstract. Objective. To identify by means of genetic analyses individuals who are at risk of developing medullary thyroid cancer that is a component of multiple endocrine neoplasia. Subjects.

Recent findings within the microbiota–gut–brain–endocrine metabolic interactome

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Obrenovich M

2017-02-01

Full Text Available Mark Obrenovich,1–4 Thriveen Sankar Chittoor Mana,5 Herleen Rai,2 Dorjee Shola,4,6 Christopher Sass,2,3 Benjamin McCloskey,4 Bruce S Levison7 1Pathology and Laboratory Medicine Service, 2Research Service, Cleveland Veterans Affairs Medical Center, 3Department of Chemistry, Cleveland State University, 4Gilgamesh Foundation, 5Division of Infectious Diseases and HIV Medicine, Case Western Reserve University, Cleveland, OH, 6Gene Targeting Resource Center, The Rockefeller University, New York, NY, 7Department of Pediatrics, University of Toledo, Toledo, OH, USA Purpose of review: We have established that many metabolic biomes exist within the complex mammalian gut. Substantial metabolism occurs within these biomes and is called co-metabolism of the host and resident microorganisms. This gut–brain–endocrine metabolic interaction emphasizes how bacteria can affect the brain and the hormonal axes in the process of co-metabolism. This review highlights new findings in this regard. Recent findings: In this review, we explore how the gut microbiota affect the development and regulation of the hypothalamic–pituitary–adrenal axis and neurochemistry from mental health and behavioral health to memory, depression, mood, anxiety, obesity, and the development of the blood–brain barrier. Summary: This review describes the implications of the findings for clinical practice or research. Interaction of small molecules within these biomes is now described collectively as a “metabolic interactome”. Metabolites of the gut–brain–endocrine axis and our overall gut health constantly shape the host phenotype in ways previously unimagined, and this niche represents potential targets for treatment and drug design, since the interaction or biochemical interplay results in net metabolite production and/or end products to exercise either positive or negative effects on human health. Keywords: neurotransmitters, gut brain axis, metabolomics, microbiota

Inhibitor of Differentiation-3 and Estrogenic Endocrine Disruptors: Implications for Susceptibility to Obesity and Metabolic Disorders

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Mayur Doke

2018-01-01

Full Text Available The rising global incidence of obesity cannot be fully explained within the context of traditional risk factors such as an unhealthy diet, physical inactivity, aging, or genetics. Adipose tissue is an endocrine as well as a metabolic organ that may be susceptible to disruption by environmental estrogenic chemicals. Since some of the endocrine disruptors are lipophilic chemicals with long half-lives, they tend to bioaccumulate in the adipose tissue of exposed populations. Elevated exposure to these chemicals may predispose susceptible individuals to weight gain by increasing the number and size of fat cells. Genetic studies have demonstrated that the transcriptional regulator inhibitor of differentiation-3 (ID3 promotes high fat diet-induced obesity in vivo. We have shown previously that PCB153 and natural estrogen 17β-estradiol increase ID3 expression. Based on our findings, we postulate that ID3 is a molecular target of estrogenic endocrine disruptors (EEDs in the adipose tissue and a better understanding of this relationship may help to explain how EEDs can lead to the transcriptional programming of deviant fat cells. This review will discuss the current understanding of ID3 in excess fat accumulation and the potential for EEDs to influence susceptibility to obesity or metabolic disorders via ID3 signaling.

Diagnosis and Treatment of Endocrine Co-Morbidities in Patients with Cystic Fibrosis

Science.gov (United States)

Siwamogsatham, Oranan; Alvarez, Jessica

2015-01-01

Purpose of review The aim of this review is to provide an update on various relevant endocrine aspects of care in adolescents and adults with cystic fibrosis (CF). Recent findings As life expectancy in CF has continuously improved, endocrine complications have become more apparent. The common endocrine complications include cystic fibrosis related diabetes (CFRD), cystic fibrosis related bone disease, vitamin D deficiency and poor growth and pubertal development. Thyroid and adrenal disorders have also been reported, although the prevalence appears to be less common. Summary Endocrine diseases are an increasingly recognized complication that has a significant impact on the overall health of individuals with CF. This review summarizes the updated screening and management of endocrine diseases in the CF population. PMID:25105995

Secretory products from thrombin-stimulated human platelets exert an inhibitory effect on NK-cytotoxic activity

DEFF Research Database (Denmark)

Skov Madsen, P; Hokland, P; Hokland, M

1987-01-01

We have investigated the interaction between human platelets and the NK-system, with special emphasis on the action of secretory products from platelets in an NK assay with 51Cr-labelled K562 as target cells. Supernatants from thrombin-stimulated platelets added to the NK assay consistently...... decreased the NK-cytotoxicity by 40% +/- 4.3%, indicating the existence of secreted products from platelets as a source of NK-inhibiting substances. In contrast, no direct cytotoxic effect of these secretory products on the target cells (K562) was seen. Thus, normal human platelets, when stimulated...... with thrombin, are capable of secreting different, yet undefined factors, which significantly inhibit NK activity in vitro. The results also suggest that the role of products from contaminating in vitro activated platelets should be borne in mind when performing conventional NK assays. Udgivelsesdato: 1986-Oct...

Endocrine dysfunction in patients of leprosy

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Rohit Kumar Singh

2015-01-01

Full Text Available Background: Leprosy is a chronic granulomatous disease and affects many internal organs in addition to the skin and peripheral nerves. Endocrine dysfunction is often silent and is often missed in patients of leprosy leading to significant morbidity. We studied the presence of occult endocrine disorders in leprosy patients and compared the same with disease parameters. Materials and Methods: We evaluated 40 patients of leprosy (aged 18-70 years, any duration in this cross-sectional, observational study. All subjects were assessed for pituitary, thyroid, adrenal, gonadal function, and dynamic testing was done when deemed necessary. The participants were divided into two groups: Group 1 (Leprosy, n = 40 and Group 2 (Controls, n = 20 and the data were analyzed with appropriate statistical tests. Results: The study participants (35 males, 5 females had a mean age of 36.4 ± 11.3 years, and duration of the disease was 2.5 ± 5.5 years. Eleven out of 40 patients showed results consistent with an endocrine disorder, including subclinical hypothyroidism (n = 4, sick euthyroid syndrome (n = 3, growth hormone (GH deficiency (n = 2, primary hypogonadism (n = 2 and secondary hypogonadism in one patient. One patient had partial hypopituitarism (GH deficiency and secondary hypogonadism and none of the controls showed any hormonal dysfunction. Testosterone levels showed inverse correlation with the number of skin patches (P = 0.0006. Conclusion: Occult endocrine dysfunction is seen in a quarter of patients with leprosy. Thyroid and gonadal axes abnormalities are common, and the severity is more in lepromatous forms of the disease. Further large studies are required to confirm the findings observed in our study.

Cytomegalovirus Infection Leads to Development of High Frequencies of Cytotoxic Virus-Specific CD4+ T Cells Targeted to Vascular Endothelium

Science.gov (United States)

Begum, Jusnara; Lal, Neeraj; Zuo, Jianmin; Beggs, Andrew; Moss, Paul

2016-01-01

Cytomegalovirus (CMV) infection elicits a very strong and sustained intravascular T cell immune response which may contribute towards development of accelerated immune senescence and vascular disease in older people. Virus-specific CD8+ T cell responses have been investigated extensively through the use of HLA-peptide tetramers but much less is known regarding CMV-specific CD4+ T cells. We used a range of HLA class II-peptide tetramers to investigate the phenotypic and transcriptional profile of CMV-specific CD4+ T cells within healthy donors. We show that such cells comprise an average of 0.45% of the CD4+ T cell pool and can reach up to 24% in some individuals (range 0.01–24%). CMV-specific CD4+ T cells display a highly differentiated effector memory phenotype and express a range of cytokines, dominated by dual TNF-α and IFN-γ expression, although substantial populations which express IL-4 were seen in some donors. Microarray analysis and phenotypic expression revealed a profile of unique features. These include the expression of CX3CR1, which would direct cells towards fractalkine on activated endothelium, and the β2-adrenergic receptor, which could permit rapid response to stress. CMV-specific CD4+ T cells display an intense cytotoxic profile with high level expression of granzyme B and perforin, a pattern which increases further during aging. In addition CMV-specific CD4+ T cells demonstrate strong cytotoxic activity against antigen-loaded target cells when isolated directly ex vivo. PD-1 expression is present on 47% of cells but both the intensity and distribution of the inhibitory receptor is reduced in older people. These findings reveal the marked accumulation and unique phenotype of CMV-specific CD4+ T cells and indicate how such T cells may contribute to the vascular complications associated with CMV in older people. PMID:27606804

Nigerian Endocrine Practice: Submissions

African Journals Online (AJOL)

Original Articles should be restricted to clinical or basic studies, particularly translational research, which add new information to the etiology, treatment, and outcomes of endocrine disorders that have not been published previously. These manuscripts should be restricted to 3,500 words, no more than 40 references, and no ...

What Is Women's Endocrine Health?

Science.gov (United States)

... harness the power to prevent endocrine disorders, the Power of Prevention. Childhood Childhood is a time of rapid growth and development to learn healthy living habits and priorities. It can, however, be a great ...

Adipose tissue as an endocrine organ.

Science.gov (United States)

McGown, Christine; Birerdinc, Aybike; Younossi, Zobair M

2014-02-01

Obesity is one of the most important health challenges faced by developed countries and is increasingly affecting adolescents and children. Obesity is also a considerable risk factor for the development of numerous other chronic diseases, such as insulin resistance, type 2 diabetes, heart disease and nonalcoholic fatty liver disease. The epidemic proportions of obesity and its numerous comorbidities are bringing into focus the highly complex and metabolically active adipose tissue. Adipose tissue is increasingly being considered as a functional endocrine organ. This article discusses the endocrine effects of adipose tissue during obesity and the systemic impact of this signaling. Copyright © 2014 Elsevier Inc. All rights reserved.

Metabolic, endocrine, and related bone diseases

International Nuclear Information System (INIS)

Rogers, L.F.

1987-01-01

Bone is living tissue, and old bone is constantly removed and replaced with new bone. Normally this exchange is in balance, and the mineral content remains relatively constant. This balance may be disturbed as a result of certain metabolic and endocrinologic disorders. The term dystrophy, referring to a disturbance of nutrition, is applied to metabolic and endocrine bone diseases and should be distinguished from the term dysplasia, referring to a disturbance of bone growth. The two terms are easily confused but are not interchangeable. Metabolic bone disease is caused by endocrine imbalance, vitamin deficiency or excess, and other disturbances in bone metabolism leading to osteoporosis and osteomalacia

Afferent Endocrine Control of Eating

DEFF Research Database (Denmark)

Langhans, Wolfgang; Holst, Jens Juul

2016-01-01

The afferent endocrine factors that control eating can be separated into different categories. One obvious categorization is by the time course of their effects, with long-term factors that signal adiposity and short-term factors that operate within the time frame of single meals. The second...... obvious categorization is by the origin of the endocrine signalling molecules. The level of knowledge concerning the physiological mechanisms and relevance of the hormones that are implicated in the control of eating is clearly different. With the accumulating knowledge about the hormones' actions......, various criteria have been developed for when the effect of a hormone can be considered 'physiologic'. This chapter treats the hormones separately and categorizes them by origin. It discusses ALL hormones that are implicated in eating control such as Gastrointestinal (GI) hormone and glucagon-like peptide...

Radiation pathomorphology of the gastrointestinal endocrine cells

International Nuclear Information System (INIS)

Yuzhakov, V.V.; Yakovleva, N.D.; Kvetnoj, I.M.; Ulitina, E.D.

1994-01-01

The paper presents the results of histochemical, electronmicroscopic and radioautographic analysis of the effects of a total single gamma irradiation on the functional morphology of cells of the diffuse endocrine system of the gastrointestinal tract of rats and mice. Irradiation in dosses from 5 to 20 Gy results in reduction of the detectability of argyrophilic and argentaffine cells. Changes in these cells counts are related to the irradiation dose. The reaction observed early after the irradiation is related to changes in the endocrine and endoplasmatic reticulum

Polish Society of Endocrinology Position statement on endocrine disrupting chemicals (EDCs).

Science.gov (United States)

Rutkowska, Aleksandra; Rachoń, Dominik; Milewicz, Andrzej; Ruchała, Marek; Bolanowski, Marek; Jędrzejuk, Diana; Bednarczuk, Tomasz; Górska, Maria; Hubalewska-Dydejczyk, Alicja; Kos-Kudła, Beata; Lewiński, Andrzej; Zgliczyński, Wojciech

2015-01-01

With the reference to the position statements of the Endocrine Society, the Paediatric Endocrine Society, and the European Society of Paediatric Endocrinology, the Polish Society of Endocrinology points out the adverse health effects caused by endocrine disrupting chemicals (EDCs) commonly used in daily life as components of plastics, food containers, pharmaceuticals, and cosmetics. The statement is based on the alarming data about the increase of the prevalence of many endocrine disorders such as: cryptorchidism, precocious puberty in girls and boys, and hormone-dependent cancers (endometrium, breast, prostate). In our opinion, it is of human benefit to conduct epidemiological studies that will enable the estimation of the risk factors of exposure to EDCs and the probability of endocrine disorders. Increasing consumerism and the industrial boom has led to severe pollution of the environment with a corresponding negative impact on human health; thus, there is great necessity for the biomonitoring of EDCs in Poland.

Endocrine Therapy of Breast Cancer

National Research Council Canada - National Science Library

Clarke, Robert S

2005-01-01

...) or TAM should be given as first line endocrine therapy. Unfortunately, response rates are lower, and response durations are shorter, on crossover than when these agents are given as first line therapies, e.g., -40...

Science and policy on endocrine disrupters must not be mixed

DEFF Research Database (Denmark)

Bergman, Åke; Andersson, Anna-Maria; Becher, Georg

2013-01-01

The "common sense" intervention by toxicology journal editors regarding proposed European Union endocrine disrupter regulations ignores scientific evidence and well-established principles of chemical risk assessment. In this commentary, endocrine disrupter experts express their concerns about a r...

Antibody-drug conjugates: Promising and efficient tools for targeted cancer therapy.

Science.gov (United States)

Nasiri, Hadi; Valedkarimi, Zahra; Aghebati-Maleki, Leili; Majidi, Jafar

2018-09-01

Over the recent decades, the use of antibody-drug conjugates (ADCs) has led to a paradigm shift in cancer chemotherapy. Antibody-based treatment of various human tumors has presented dramatic efficacy and is now one of the most promising strategies used for targeted therapy of patients with a variety of malignancies, including hematological cancers and solid tumors. Monoclonal antibodies (mAbs) are able to selectively deliver cytotoxic drugs to tumor cells, which express specific antigens on their surface, and has been suggested as a novel category of agents for use in the development of anticancer targeted therapies. In contrast to conventional treatments that cause damage to healthy tissues, ADCs use mAbs to specifically attach to antigens on the surface of target cells and deliver their cytotoxic payloads. The therapeutic success of future ADCs depends on closely choosing the target antigen, increasing the potency of the cytotoxic cargo, improving the properties of the linker, and reducing drug resistance. If appropriate solutions are presented to address these issues, ADCs will play a more important role in the development of targeted therapeutics against cancer in the next years. We review the design of ADCs, and focus on how ADCs can be exploited to overcome multiple drug resistance (MDR). © 2018 Wiley Periodicals, Inc.

Comparing guidelines for adjuvant endocrine therapy in postmenopausal women with breast cancer: a coming of age.

Science.gov (United States)

Verma, Sunil; Jackisch, Christian

2011-02-01

Following surgery for early breast cancer, the standard of care for postmenopausal women is adjuvant therapy with any combination of radiation therapy, endocrine therapy, chemotherapy and/or targeted therapy. Clinicians rely on many tools, including guidelines, to make these treatment decisions. Such guidelines include the St Gallen consensus statement, the American Society of Clinical Oncology guidelines and the National Comprehensive Cancer Network guidelines, as well as various regional and national guidelines. Recommendations may vary, because different methods and criteria were used to assess the strength of supporting data. This article provides an overview of global guidelines for the adjuvant treatment of breast cancer and points out the major differences. Ongoing changes are highlighted, particularly those regarding the adjuvant endocrine treatment of postmenopausal women with breast cancer. While previous guidelines recommended tamoxifen alone, all major guidelines now recommend using third-generation aromatase inhibitors either in sequence with tamoxifen or as upfront treatment.

Early endocrine disruptors exposure acts on 3T3-L1 differentiation and endocrine activity

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Sofiane Boudalia

2017-06-01

Conclusion: This study confirms that EDs singularly or in mixtures, introduced during early stages of life, could affect the differentiation and the endocrine activity of adipocytes, and can act as potential factors for obesity.

Endocrine Therapy of Breast Cancer

National Research Council Canada - National Science Library

Clarke, Robert

2008-01-01

...) or TAM should be given as first line endocrine therapy. Unfortunately, response rates are lower, and response durations are shorter, on crossover than when these agents are given as first line therapies, e.g., ̃40...

Endocrine Therapy of Breast Cancer

National Research Council Canada - National Science Library

Clarke, Robert

2007-01-01

...) or TAM should be given as first line endocrine therapy. Unfortunately, response rates are lower, and response durations are shorter, on crossover than when these agents are given as first line therapies, e.g., ̃40...

The immune system of geriatric mice is modulated by estrogenic endocrine disruptors (diethylstilbestrol, α-zearalanol, and genistein): Effects on interferon-γ

International Nuclear Information System (INIS)

Calemine, Jillian; Zalenka, Julie; Karpuzoglu-Sahin, Ebru; Ward, Daniel L.; Lengi, Andrea; Ahmed, S. Ansar

2003-01-01

The immune system is a potential target for estrogenic endocrine disrupters. To date, there is limited information on whether estrogenic endocrine disruptors modulate the immune system of aged individuals. To address this issue, groups of 74-week-old mice were given nine oral doses of selected estrogenic endocrine disrupters: diethylstilbestrol (DES, 3 μg/100 g bw), α-zearalanol (0.5 mg/100 g bw), or genistein (0.15 mg/100 g bw) in corn oil, or corn oil alone, over 2.5 weeks. Both developmental (thymus) and mature (spleen) lymphoid organs were affected, although specific effects varied with the chemical. DES significantly decreased thymocyte numbers. However, relative percentages of thymocyte subsets were not altered. While splenic cellularity and percentages of T and B cells were unchanged, splenocytes from DES-exposed mice had significantly decreased ability to proliferate in response to Concanavalin-A (Con-A). Con-A-activated splenocytes from mice treated with genistein or α-zearalanol had decreased levels of interferon-γ (IFNγ) protein in their culture supernatants compared to similar cultures from oil-treated mice. RT-PCR analysis of Con-A-activated splenocytes revealed that the expression of IFNγ gene is altered by DES or genistein treatment. Together, these results suggest that estrogenic endocrine disruptors modulate the immune system of aged mice

Rhythms in the endocrine system of fish: a review.

Science.gov (United States)

Cowan, Mairi; Azpeleta, Clara; López-Olmeda, Jose Fernando

2017-12-01

The environment which living organisms inhabit is not constant and many factors, such as light, temperature, and food availability, display cyclic and predictable variations. To adapt to these cyclic changes, animals present biological rhythms in many of their physiological variables, timing their functions to occur when the possibility of success is greatest. Among these variables, many endocrine factors have been described as displaying rhythms in vertebrates. The aim of the present review is to provide a thorough review of the existing knowledge on the rhythms of the endocrine system of fish by examining the hormones that show rhythmicity, how environmental factors control these rhythms and the variation in the responses of the endocrine system depending on the time of the day. We mainly focused on the hypothalamic-pituitary axis, which can be considered as the master axis of the endocrine system of vertebrates and regulates a great variety of functions, including reproduction, growth, metabolism, energy homeostasis, stress response, and osmoregulation. In addition, the rhythms of other hormones, such as melatonin and the factors, produced in the gastrointestinal system of fish are reviewed.

A predictive data-driven framework for endocrine prioritization: a triazole fungicide case study

Science.gov (United States)

Paul Friedman, Katie; Papineni, Sabitha; Marty, M. Sue; Yi, Kun Don; Goetz, Amber K.; Rasoulpour, Reza J.; Kwiatkowski, Pat; Wolf, Douglas C.; Blacker, Ann M.; Peffer, Richard C.

2016-01-01

Abstract The US Environmental Protection Agency Endocrine Disruptor Screening Program (EDSP) is a tiered screening approach to determine the potential for a chemical to interact with estrogen, androgen, or thyroid hormone systems and/or perturb steroidogenesis. Use of high-throughput screening (HTS) to predict hazard and exposure is shifting the EDSP approach to (1) prioritization of chemicals for further screening; and (2) targeted use of EDSP Tier 1 assays to inform specific data needs. In this work, toxicology data for three triazole fungicides (triadimefon, propiconazole, and myclobutanil) were evaluated, including HTS results, EDSP Tier 1 screening (and other scientifically relevant information), and EPA guideline mammalian toxicology study data. The endocrine-related bioactivity predictions from HTS and information that satisfied the EDSP Tier 1 requirements were qualitatively concordant. Current limitations in the available HTS battery for thyroid and steroidogenesis pathways were mitigated by inclusion of guideline toxicology studies in this analysis. Similar margins (3–5 orders of magnitude) were observed between HTS-predicted human bioactivity and exposure values and between in vivo mammalian bioactivity and EPA chronic human exposure estimates for these products’ registered uses. Combined HTS hazard and human exposure predictions suggest low priority for higher-tiered endocrine testing of these triazoles. Comparison with the mammalian toxicology database indicated that this HTS-based prioritization would have been protective for any potential in vivo effects that form the basis of current risk assessment for these chemicals. This example demonstrates an effective, human health protective roadmap for EDSP evaluation of pesticide active ingredients via prioritization using HTS and guideline toxicology information. PMID:27347635

ECETOC Florence workshop on risk assessment of endocrine substances, including the potency concept.

Science.gov (United States)

Fegert, Ivana

2013-12-16

The European regulation on plant protection products (1107/2009) and the Biocidal Products Regulation (EC Regulation 528/2012) only support the marketing and use of chemicals if they do not cause endocrine disruption in humans or wildlife species. Also, substances with endocrine properties are subject to authorization under the European regulation on the registration, evaluation, authorization and restriction of chemicals (REACH; 1907/2006). Therefore, the regulatory consequences of identifying a substance as an endocrine disrupting chemical are severe. In contrast to that, basic scientific criteria, necessary to define endocrine disrupting properties, are not described in any of these legislative documents. Thus, the European Center for Ecotoxicology and Toxicology of Chemicals (ECETOC) established a task force to provide scientific criteria for the identification and assessment of chemicals with endocrine disrupting properties that may be used within the context of these three legislative texts (ECETOC, 2009a). In 2009, ECETOC introduced a scientific framework as a possible concept for identifying endocrine disrupting properties within a regulatory context (ECETOC, 2009b; Bars et al., 2011a,b). The proposed scientific criteria integrated, in a weight of evidence approach, information from regulatory (eco)toxicity studies and mechanistic/screening studies by combining evidence for adverse effects detected in apical whole-organism studies with an understanding of the mode of action (MoA) of endocrine toxicity. However, since not all chemicals with endocrine disrupting properties are of equal hazard, an adequate concept should also be able to differentiate between chemicals with endocrine properties of low concern from those of higher concern (for regulatory purposes). For this purpose, the task force refined this part of their concept. Following an investigation of the key factors at a second workshop of invited regulatory, academic and industry scientists, the

Endocrine and gonadial tumors among A-bomb survivors

International Nuclear Information System (INIS)

Takeichi, Nobuo; Dohi, Kiyohiko; Fujikura, Toshio

1986-01-01

A review of 4,136 consecutive autopsies between 1961 and 1977 and surgical cases from A-bomb survivors seen in Hiroshima University School of Medicine was made in terms of pituitary tumors, parathyroid tumors, thyroid cancer, carcinoid, tumors of the adrenal cortex, ovarian tumors, testicular tumors, and multiple endocrine gonadial tumors (MEGT). The occurrence of thyroid cancer, parathyroid tumors, and MEGT may be correlated with atomic radiation. Mortality from endocrine and gonadial tumors tended to be higher with increasing T65 doses. As for MEGT, the combination of thyroid cancer and ovarian tumors occurred frequently among A-bomb survivors. The combination of medullary carcinoma of the thyroid gland and pheochromacytoma of the adrenal gland was unlikely to be related to atomic radiation. Further study may be needed in elucidating possible effects of atomic radiation on endocrine hormones. (Namekawa, K.)

Evaluation of the cytotoxic and genotoxic potential of lecithin/chitosan nanoparticles

Science.gov (United States)

Taner, Gökçe; Yeşilöz, Recep; Özkan Vardar, Deniz; Şenyiğit, Taner; Özer, Özgen; Degen, Gisela H.; Başaran, Nurşen

2014-02-01

Nanoparticles-based drug targeting delivery systems have been introduced in the treatment for various diseases because of their effective properties, although there have been conflicting results on the toxicity of nanoparticles. In the present study, the aim was to evaluate the cytotoxicity and the genotoxicity of different concentrations of lecithin/chitosan nanoparticles with and without clobetasol-17-propionate (CP) by neutral red uptake (NRU) cytotoxicity assay and single cell gel electrophoresis (Comet) and cytokinesis-blocked micronucleus assays. The IC50 values of lecithin/chitosan nanoparticles with/without CP were found as 1.9 and 1.8 %, respectively, in the NRU cytotoxicity test. High concentrations of lecithin/chitosan nanoparticles induced DNA damage in human lymphocytes as evaluated by comet assay. The micronucleus frequency was increased by the lecithin/chitosan treatment in a dose-dependent manner. Also at the two highest concentrations, a significant increase in micronucleus formation was observed. Lecithin/chitosan nanoparticles with CP did not increase the frequency of micronucleus and also did not induce additional DNA damage when compared with lecithin/chitosan nanoparticles without CP; therefore, CP itself has not found to be genotoxic at the studied concentration.

Green synthesis of zero valent colloidal nanosilver targeting A549 lung cancer cell: In vitro cytotoxicity

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Minakshi Jha

2018-06-01

Full Text Available An eco-friendly green approach was proposed to synthesise stable, cytotoxic colloidal silver nanoparticles (AgNPs using Momordica charantia (M. charantia fruit extract. Bioinspired green method adopted for fabrication of AgNPs because of easy, fast, low-cost and benign bioprocess. Phytocomponents played the crucial role in capping, stabilisation and inherent cytotoxic potential of colloidal nanosilver. The physiochemical, crystalline, optical and morphological properties of AgNPs were characterized using UV-vis, FT-IR, XRD, SEM, TEM, EDX and AFM. FT-IR reveals the presence of carbonyl, methyl, polyphenol (flavonoid, primary and secondary amine (protein, carboxyl group, ester as major functional groups over the surface of nanomaterials. Mechanistic pathway for formation and stabilisation of colloidal nanosilver has been discussed. Average crystalline size of AgNPs was found to be 12.55 nm from XRD. TEM shows AgNPs nanosphere with size range 1–13.85 nm. Consistency in spherical morphology was also confirmed through Atomic Force Microscopy (AFM. AFM measurement provided image Rq value 3.62, image Ra 2.47, roughness Rmax 36.4 nm, skewness 1.99 and kurtosis 9.87. The SRB assay revealed substantial in vitro noticeable anti-cancer activity of colloidal nanosilver on A549 and HOP-62 human lung cancer cells in a dose dependent manner with IC50 value of 51.93 µg/ml and 76.92 µg/ml. In addition, M. charantia capped AgNPs were found to be more biocompatible in comparison to M. charantia FE. Our study demonstrated the integration of green chemistry principle in nanomaterials fabrication and focused on the potential use of M. charantia fruit extract as an efficient precursor for biocompatible AgNPs anodrug formulation with improved cytotoxic applications. Keywords: M. charantia, Silver nanoparticles, TEM, Anticancer activity, A549, HOP-62

How can we estimate natural selection on endocrine traits? Lessons from evolutionary biology.

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Bonier, Frances; Martin, Paul R

2016-11-30

An evolutionary perspective can enrich almost any endeavour in biology, providing a deeper understanding of the variation we see in nature. To this end, evolutionary endocrinologists seek to describe the fitness consequences of variation in endocrine traits. Much of the recent work in our field, however, follows a flawed approach to the study of how selection shapes endocrine traits. Briefly, this approach relies on among-individual correlations between endocrine phenotypes (often circulating hormone levels) and fitness metrics to estimate selection on those endocrine traits. Adaptive plasticity in both endocrine and fitness-related traits can drive these correlations, generating patterns that do not accurately reflect natural selection. We illustrate why this approach to studying selection on endocrine traits is problematic, referring to work from evolutionary biologists who, decades ago, described this problem as it relates to a variety of other plastic traits. We extend these arguments to evolutionary endocrinology, where the likelihood that this flaw generates bias in estimates of selection is unusually high due to the exceptional responsiveness of hormones to environmental conditions, and their function to induce adaptive life-history responses to environmental variation. We end with a review of productive approaches for investigating the fitness consequences of variation in endocrine traits that we expect will generate exciting advances in our understanding of endocrine system evolution. © 2016 The Author(s).

Neuro-endocrine effects of aqueous extract of Amaranthus viridis (Linn. leaf in male Wistar rat model of cyclophosphamide-induced reproductive toxicity

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Oladele Abiodun Ayoka

Full Text Available Cyclophosphamide (CP is a widely used cytotoxic alkylating agent with antitumor and immunosuppressant properties that is associated with various forms of reproductive toxicity. The significance of natural antioxidants of plant origin should be explored, especially in a world with increasing incidence of patients in need of chemotherapy. The neuro-endocrine effects of aqueous extract of Amaranthus viridis (Linn. leaf (AEAVL in Wistar rats with CP-induced reproductive toxicity was determined. Forty rats were used for this study such that graded doses of the extract were administered following CP-induced reproductive toxicity and comparisons were made against control, toxic and standard (vitamin E groups at p < 0.05. The synthetic drugs (CP, 65 mg/kg i.p. for 5 days; Vitamin E, 100 mg/kg p.o. for 30 days as well as the extract (100, 200 and 400 mg/kg p.o. for 30 days were administered to the rats at 0.2 mL/100 g. CP induced reproductive toxicity as evidenced by significantly lowered levels of FSH, LH and testosterone, perturbation of sperm characterization, deleterious disruptions of the antioxidant system as evidenced by decreased levels of GSH as well as elevation of TBARS activity. Histopathological examination showed hemorrhagic lesions with scanty and hypertrophied parenchymal cells in the pituitary while the testis showed ballooned seminiferous tubules with loosed connective tissues and vacuolation of testicular interstitium. These conditions were significantly reversed (p < 0.05 following administration of the graded doses of the extract. It was, therefore, concluded that AEAVL could potentially be a therapeutic choice in patients with CP-induced neuro-endocrine dysfunction and reproductive toxicity. Keywords: Cyclophosphamide, Neuro-endocrine dysfunction, Reproductive toxicity, Rats, Amaranthus viridis

Ex-vivo expanded human NK cells express activating receptors that mediate cytotoxicity of allogeneic and autologous cancer cell lines by direct recognition and antibody directed cellular cytotoxicity

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Campana Dario

2010-10-01

Full Text Available Abstract Background The possibility that autologous NK cells could serve as an effective treatment modality for solid tumors has long been considered. However, implementation is hampered by (i the small number of NK cells in peripheral blood, (ii the difficulties associated with large-scale production of GMP compliant cytolytic NK cells, (iii the need to activate the NK cells in order to induce NK cell mediated killing and (iv the constraints imposed by autologous inhibitory receptor-ligand interactions. To address these issues, we determined (i if large numbers of NK cells could be expanded from PBMC and GMP compliant cell fractions derived by elutriation, (ii their ability to kill allogeneic and autologous tumor targets by direct cytotoxitiy and by antibody-mediated cellular cytotoxicity and (iii defined NK cell specific receptor-ligand interactions that mediate tumor target cell killing. Methods Human NK cells were expanded during 14 days. Expansion efficiency, NK receptor repertoire before and after expansion, expression of NK specific ligands, cytolytic activity against allogeneic and autologous tumor targets, with and without the addition of chimeric EGFR monoclonal antibody, were investigated. Results Cell expansion shifted the NK cell receptor repertoire towards activation and resulted in cytotoxicity against various allogeneic tumor cell lines and autologous gastric cancer cells, while sparing normal PBMC. Blocking studies confirmed that autologous cytotoxicity is established through multiple activating receptor-ligand interactions. Importantly, expanded NK cells also mediated ADCC in an autologous and allogeneic setting by antibodies that are currently being used to treat patients with select solid tumors. Conclusion These data demonstrate that large numbers of cytolytic NK cells can be generated from PBMC and lymphocyte-enriched fractions obtained by GMP compliant counter current elutriation from PBMC, establishing the preclinical

Reprogramming of the ERRα and ERα target gene landscape triggers tamoxifen resistance in breast cancer.

Science.gov (United States)

Thewes, Verena; Simon, Ronald; Schroeter, Petra; Schlotter, Magdalena; Anzeneder, Tobias; Büttner, Reinhard; Benes, Vladimir; Sauter, Guido; Burwinkel, Barbara; Nicholson, Robert I; Sinn, Hans-Peter; Schneeweiss, Andreas; Deuschle, Ulrich; Zapatka, Marc; Heck, Stefanie; Lichter, Peter

2015-02-15

Endocrine treatment regimens for breast cancer that target the estrogen receptor-α (ERα) are effective, but acquired resistance remains a limiting drawback. One mechanism of acquired resistance that has been hypothesized is functional substitution of the orphan receptor estrogen-related receptor-α (ERRα) for ERα. To examine this hypothesis, we analyzed ERRα and ERα in recurrent tamoxifen-resistant breast tumors and conducted a genome-wide target gene profiling analysis of MCF-7 breast cancer cell populations that were sensitive or resistant to tamoxifen treatment. This analysis uncovered a global redirection in the target genes controlled by ERα, ERRα, and their coactivator AIB1, defining a novel set of target genes in tamoxifen-resistant cells. Beyond differences in the ERα and ERRα target gene repertoires, both factors were engaged in similar pathobiologic processes relevant to acquired resistance. Functional analyses confirmed a requirement for ERRα in tamoxifen- and fulvestrant-resistant MCF-7 cells, with pharmacologic inhibition of ERRα sufficient to partly restore sensitivity to antiestrogens. In clinical specimens (n = 1041), increased expression of ERRα was associated with enhanced proliferation and aggressive disease parameters, including increased levels of p53 in ERα-positive cases. In addition, increased ERRα expression was linked to reduced overall survival in independent tamoxifen-treated patient cohorts. Taken together, our results suggest that ERα and ERRα cooperate to promote endocrine resistance, and they provide a rationale for the exploration of ERRα as a candidate drug target to treat endocrine-resistant breast cancer. ©2015 American Association for Cancer Research.

Pathophysiology of the Effects of Alcohol Abuse on the Endocrine System.

Science.gov (United States)

Rachdaoui, Nadia; Sarkar, Dipak K

2017-01-01

Alcohol can permeate virtually every organ and tissue in the body, resulting in tissue injury and organ dysfunction. Considerable evidence indicates that alcohol abuse results in clinical abnormalities of one of the body's most important systems, the endocrine system. This system ensures proper communication between various organs, also interfacing with the immune and nervous systems, and is essential for maintaining a constant internal environment. The endocrine system includes the hypothalamic-pituitary-adrenal axis, the hypothalamic-pituitary-gonadal axis, the hypothalamic-pituitary-thyroid axis, the hypothalamic-pituitary-growth hormone/insulin-like growth factor-1 axis, and the hypothalamic-posterior pituitary axis, as well as other sources of hormones, such as the endocrine pancreas and endocrine adipose tissue. Alcohol abuse disrupts all of these systems and causes hormonal disturbances that may result in various disorders, such as stress intolerance, reproductive dysfunction, thyroid problems, immune abnormalities, and psychological and behavioral disorders. Studies in both humans and animal models have helped shed light on alcohol's effects on various components of the endocrine system and their consequences.

Endocrine emergencies in critically ill patients: Challenges in diagnosis and management

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Sukhminder Jit Singh Bajwa

2012-01-01

Full Text Available Endocrine emergencies pose unique challenges for the attending intensivist while managing critically ill patients. Besides taking care of primary disease state, one has to divert an equal attention to the possible associated endocrinopathies also. One of the common reasons for inability to timely diagnose an endocrinal failure in critically ill patients being the dominance of other severe systemic diseases and their clinical presentation. The timely diagnosis and administration of therapeutic interventions for these endocrine disorders can improve the outcome in critically ill patients. The timely diagnosis and administration of timely therapeutics in common endocrine disorders like severe thyroid disease, acute adrenal insufficiency and diabetic ketoacidosis significantly influence the outcome and prognosis. Careful evaluation of clinical history and a high degree of suspicion are the corner stone to diagnose such problems. Aggressive management of the patient is equally important as the complications are devastating and can prove highly fatal. The present article is an attempt to review some of the common endocrine emergencies in intensive care unit and the challenges associated with their diagnosis and management.

A single-layer peptide nanofiber for enhancing the cytotoxicity of trastuzumab (anti-HER)

Energy Technology Data Exchange (ETDEWEB)

Malik, Ruchi; Wagh, Anil; Qian, Steven; Law, Benedict, E-mail: Shek.law@ndsu.edu [College of Pharmacy, Nursing, and Allied Sciences, North Dakota State University, Department of Pharmaceutical Sciences (United States)

2013-06-15

A multivalent system is often employed to enhance the effectiveness of a targeted therapy. In the present study, we report a single-layer peptide nanofiber (NFP) as a multivalent targeting platform to improve the cytotoxicity of trastuzumab (anti-HER), a monoclonal antibody targeting the human epidermal growth factor receptor 2 (HER-2) in approximately 20 % of breast cancer patients. The trastuzumab-conjugated nanofiber (anti-HER/NFP) was 100 Multiplication-Sign 4 nm in size and was assembled from multiple peptide units (mPEG-BK(FITC)SGASNRA-kldlkldlkldl-CONH{sub 2}). The optimized preparation was attached with approximately 10 antibodies at the surface. Because of an increase in the multivalency, anti-HER/NFP was able to truncate more cell surface HER-2 and, thus, showed an enhanced cytotoxicity toward HER-2 positive SKBr-3 human breast cancer as compared to the free anti-HER. Western blot analysis and fluorescence microscopic studies confirmed that there was a significant downregulation of the HER-2 level and also inhibition of the cell survival cell signaling pathways including the phosphatidylinositol 3-kinase (PI3K) and the mitogen activated protein kinase (MAPK) pathway. Our data suggested that NFP can be useful as a multivalent platform for immunotherapy, especially in combination with other chemotherapeutic agents in the future.

Mitochondria-targeted vitamin E analogs inhibit breast cancer cell energy metabolism and promote cell death

International Nuclear Information System (INIS)

Cheng, Gang; Zielonka, Jacek; McAllister, Donna M; Mackinnon, A Craig Jr; Joseph, Joy; Dwinell, Michael B; Kalyanaraman, Balaraman

2013-01-01

Recent research has revealed that targeting mitochondrial bioenergetic metabolism is a promising chemotherapeutic strategy. Key to successful implementation of this chemotherapeutic strategy is the use of new and improved mitochondria-targeted cationic agents that selectively inhibit energy metabolism in breast cancer cells, while exerting little or no long-term cytotoxic effect in normal cells. In this study, we investigated the cytotoxicity and alterations in bioenergetic metabolism induced by mitochondria-targeted vitamin E analog (Mito-chromanol, Mito-ChM) and its acetylated ester analog (Mito-ChMAc). Assays of cell death, colony formation, mitochondrial bioenergetic function, intracellular ATP levels, intracellular and tissue concentrations of tested compounds, and in vivo tumor growth were performed. Both Mito-ChM and Mito-ChMAc selectively depleted intracellular ATP and caused prolonged inhibition of ATP-linked oxygen consumption rate in breast cancer cells, but not in non-cancerous cells. These effects were significantly augmented by inhibition of glycolysis. Mito-ChM and Mito-ChMAc exhibited anti-proliferative effects and cytotoxicity in several breast cancer cells with different genetic background. Furthermore, Mito-ChM selectively accumulated in tumor tissue and inhibited tumor growth in a xenograft model of human breast cancer. We conclude that mitochondria-targeted small molecular weight chromanols exhibit selective anti-proliferative effects and cytotoxicity in multiple breast cancer cells, and that esterification of the hydroxyl group in mito-chromanols is not a critical requirement for its anti-proliferative and cytotoxic effect

Thirty-day outcomes underestimate endocrine and exocrine insufficiency after pancreatic resection.

Science.gov (United States)

Lim, Pei-Wen; Dinh, Kate H; Sullivan, Mary; Wassef, Wahid Y; Zivny, Jaroslav; Whalen, Giles F; LaFemina, Jennifer

2016-04-01

Long-term incidence of endocrine and exocrine insufficiency after pancreatectomy is poorly described. We analyze the long-term risks of pancreatic insufficiency after pancreatectomy. Subjects who underwent pancreatectomy from 2002 to 2012 were identified from a prospective database (n = 227). Subjects who underwent total pancreatectomy or pancreatitis surgery were excluded. New post-operative endocrine and exocrine insufficiency was defined as the need for new pharmacologic intervention within 1000 days from resection. 28 (16%) of 178 subjects without pre-existing endocrine insufficiency developed post-operative endocrine insufficiency: 7 (25%) did so within 30 days, 8 (29%) between 30 and 90 days, and 13 (46%) after 90 days. 94 (43%) of 214 subjects without pre-operative exocrine insufficiency developed exocrine insufficiency: 20 (21%) did so within 30 days, 29 (31%) between 30 and 90 days, and 45 (48%) after 90 days. Adjuvant radiation was associated with new endocrine insufficiency. On multivariate regression, pancreaticoduodenectomy and chemotherapy were associated with a greater risk of exocrine insufficiency. Reporting 30-day functional outcomes for pancreatic resection is insufficient, as nearly 45% of subjects who develop disease do so after 90 days. Reporting of at least 90-day outcomes may more reliably assess risk for post-operative endocrine and exocrine insufficiency. Copyright © 2016 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.

Endocrine therapy for recurrence after definitive radiotherapy in patients with prostate cancer

International Nuclear Information System (INIS)

Furuya, Yuzo; Akakura, Koichiro; Ichikawa, Tomohiko; Igarashi, Tatsuo; Ito, Haruo; Tanaka, Masashi; Murakami, Shino

2001-01-01

Long-term results were analyzed to evaluate the role of endocrine therapy in the management of local and distant recurrence of prostate cancer following external radiation therapy. Between 1976 and 1994, 92 patients with untreated prostate cancer underwent external beam radiation therapy alone. Endocrine therapy had been started when relapse was evident. Failure was seen in 35 of 92 patients: 10 local, 19 distant and six biochemical failures. Endocrine treatment was performed in 28 patients with nine local and 19 distant failures. The cancer-specific survival rate from the endocrine treatment was 54.5% at 5 years. Prostate-specific antigen level in 20 of 20 patients (100%) decreased to below the normal limit 3 months after the start of endocrine therapy. In univariate analysis, T classification was the most significant variable for cancer-specific survival from the initial treatment. A favorable outcome was achieved by endocrine therapy in patients who had relapsed after external beam radiation monotherapy. Even the recurrent tumor had a sensitivity to androgen. Patients with locally advanced disease (T2b and T3) had poorer prognosis than those with minimally extended disease (T1b and T2a). (author)

Alloreactive cytotoxic T lymphocytes from aged mice express increased lysis of autologous and third-party target cells

NARCIS (Netherlands)

Kruisbeek, A.M.; Steinmeier, F.A.

1980-01-01

Much data support the notion that with increasing age a decline in T cell effector function occurs. In the present study, qualitative rather than quantitative age-related changes in vitro alloreactive cytotoxic T lymphocyte (CTL) responses were observed. The level of specific alloreactive CTL

Nuclear Receptors and Multiple Endocrine Neoplasia type 1 (MEN1)

NARCIS (Netherlands)

Dreijerink, K.M.A.

2009-01-01

Multiple Endocrine Neoplasia type 1 (MEN1) is an inherited syndrome that is characterized by the occurrence of tumours of the parathyroid glands, gastroenteropancreatic tumours, pitui-tary gland adenomas, as well as adrenal adenomas and neuro-endocrine tumours, often at a young age. MEN1 tumours can

Adjuvant psychological therapy in long-term endocrine conditions.

Science.gov (United States)

Daniels, J; Turner-Cobb, J M

2017-06-01

Consideration of psychological distress in long-term endocrine conditions is of vital importance given the prevalence of anxiety and depression in such disorders. Poor mental health can lead to compromised self-care, higher utilization of health services, lower rates of adherence, reduced quality of life and ultimately poorer outcomes. Adjuvant psychological therapy offers an effective resource to reduce distress in endocrine conditions. While the vast majority of work in this area has focused on psychological screening and intervention in diabetes, identification and recognition of psychological distress are equally important in other endocrinological conditions, with supportive evidence in polycystic ovary syndrome and Addison's disease. Referral pathways and recommendations set out by UK guidelines and the Department of Health mandate requires greater attention across a wider range of long-term endocrine conditions to facilitate improved quality of life and health outcome. © 2017 John Wiley & Sons Ltd.

Circulating miRNAs as biomarkers for endocrine disorders.

Science.gov (United States)

Butz, H; Kinga, N; Racz, K; Patocs, A

2016-01-01

Specific, sensitive and non-invasive biomarkers are always needed in endocrine disorders. miRNAs are short, non-coding RNA molecules with well-known role in gene expression regulation. They are frequently dysregulated in metabolic and endocrine diseases. Recently it has been shown that they are secreted into biofluids by nearly all kind of cell types. As they can be taken up by other cells they may have a role in a new kind of paracrine, cell-to-cell communication. Circulating miRNAs are protected by RNA-binding proteins or microvesicles hence they can be attractive candidates as diagnostic or prognostic biomarkers. In this review, we summarize the characteristics of extracellular miRNA's and our knowledge about their origin and potential roles in endocrine and metabolic diseases. Discussions about the technical challenges occurring during identification and measurement of extracellular miRNAs and future perspectives about their roles are also highlighted.

Information/testing strategy for identification of substances with endocrine disrupting properties

DEFF Research Database (Denmark)

Hass, Ulla; Christiansen, Sofie; Bjerregaard, Poul

This report has been prepared by the Danish Centre on Endocrine Disrupters (CeHoS) as a project contracted by the Danish Environmental Protection Agency. The Danish Centre on Endocrine Disrupters is an interdisciplinary scientific network without walls. The main purpose of the Centre is to build ...... of substances with endocrine disrupting properties under various legislative frameworks, including REACH (EC No 1907/2006), the Plant Protection Products Regulation (PPPR) (EC No 1107/2009) and the Biocidal Products Regulation (BPR) (EC No 528/2012) ....

How does obesity affect the endocrine system? A narrative review.

Science.gov (United States)

Poddar, M; Chetty, Y; Chetty, V T

2017-06-01

Obesity is a chronic, relapsing medical condition that results from an imbalance of energy expenditure and consumption. It is a leading cause of preventable illness, disability and premature death. The causes of obesity are multifactorial and include behavioural, socioeconomic, genetic, environmental and psychosocial factors. Rarely are endocrine diseases, e.g., hypothyroidism or Cushing's syndrome, the cause of obesity. What is less understood is how obesity affects the endocrine system. In this review, we will discuss the impact of obesity on multiple endocrine systems, including the hypothalamic-pituitary axis, changes in vitamin D homeostasis, gender steroids and thyroid hormones. We will also examine the renin angiotensin aldosterone system and insulin pathophysiology associated with obesity. We will provide a general overview of the biochemical changes that can be seen in patients with obesity, review possible aetiologies of these changes and briefly consider current guidelines on their management. This review will not discuss endocrine causes of obesity. © 2017 World Obesity Federation.

Effects of alcohol on the endocrine system.

Science.gov (United States)

Rachdaoui, Nadia; Sarkar, Dipak K

2013-09-01

Chronic consumption of a large amount of alcohol disrupts the communication between nervous, endocrine, and immune system and causes hormonal disturbances that lead to profound and serious consequences at physiologic and behavioral levels. These alcohol-induced hormonal dysregulations affect the entire body and can result in various disorders such as stress abnormalities, reproductive deficits, body growth defect, thyroid problems, immune dysfunction, cancers, bone disease, and psychological and behavioral disorders. This review summarizes the findings from human and animal studies that provide consistent evidence on the various effects of alcohol abuse on the endocrine system. Copyright © 2013 Elsevier Inc. All rights reserved.

Genetic basis of endocrine pathology

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T.V. Sorokman

2017-05-01

Full Text Available The purpose of the review was analysis of literature data relating to the molecular genetic basis and diagnosis of endocrine pathology. We searched for published and unpublished researches using Pubmed as the search engine by the keywords: ‘genes’, ‘endocrine diseases’, ‘molecular diagnostics’, ‘prohormones’, ‘nuclear receptors and transcription factors’, taking into consideration studies conducted over the last 10 years, citation review of relevant primary and review articles, conference abstracts, personal files, and contact with expert informants. The criterion for the selection of articles for the study was based on their close relevance to the topic, thus out of 144 analyzed articles, the findings of the researchers covered in 32 articles were crucial. The described nosologies presented various heredi­tary forms of hypopituitarism, disturbances of steroid hormone biosynthesis, abnormal gender formation, monogenic forms of diabetes mellitus, endocrine tumors, etc. Pathology is identified that is associated with a mutation of genes encoding protein prohormones, receptors, steroid biosynthesis enzymes, intracellular signaling molecules, transport proteins, ion channels, and transcription factors. Among the endocrine diseases associated with defects in genes encoding protein prohormones, the defects of the GH1 gene are most common, the defects in the gene CYP21A2 (21-hydroxylase are among diseases associated with defects in genes encoding enzymes. More often mutations of genes encoding proteins belong to the class of G-protein coupled receptors. Most of the mutations associated with MEN-2A are concentrated in the rich cysteine region of the Ret receptor. More than 70 monogenic syndromes are known, in which there is a marked tolerance to glucose and some form of diabetes mellitus is diagnosed, diabetes mellitus caused by mutation of the mitochondrial gene (mutation tRNALeu, UUR is also detected. Of all the monogenic forms of

The Vitamin D Endocrine System.

Science.gov (United States)

Norman, Anthony W.

1985-01-01

Discusses the physiology and biochemistry of the vitamin D endocrine system, including role of biological calcium and phosphorus, vitamin D metabolism, and related diseases. A 10-item, multiple-choice test which can be used to obtain continuing medical education credit is included. (JN)

Bioinformatic analysis of xenobiotic reactive metabolite target proteins and their interacting partners

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Hanzlik Robert P

2009-06-01

Full Text Available Abstract Background Protein covalent binding by reactive metabolites of drugs, chemicals and natural products can lead to acute cytotoxicity. Recent rapid progress in reactive metabolite target protein identification has shown that adduction is surprisingly selective and inspired the hope that analysis of target proteins might reveal protein factors that differentiate target- vs. non-target proteins and illuminate mechanisms connecting covalent binding to cytotoxicity. Results Sorting 171 known reactive metabolite target proteins revealed a number of GO categories and KEGG pathways to be significantly enriched in targets, but in most cases the classes were too large, and the "percent coverage" too small, to allow meaningful conclusions about mechanisms of toxicity. However, a similar analysis of the directlyinteracting partners of 28 common targets of multiple reactive metabolites revealed highly significant enrichments in terms likely to be highly relevant to cytotoxicity (e.g., MAP kinase pathways, apoptosis, response to unfolded protein. Machine learning was used to rank the contribution of 211 computed protein features to determining protein susceptibility to adduction. Protein lysine (but not cysteine content and protein instability index (i.e., rate of turnover in vivo were among the features most important to determining susceptibility. Conclusion As yet there is no good explanation for why some low-abundance proteins become heavily adducted while some abundant proteins become only lightly adducted in vivo. Analyzing the directly interacting partners of target proteins appears to yield greater insight into mechanisms of toxicity than analyzing target proteins per se. The insights provided can readily be formulated as hypotheses to test in future experimental studies.

Cosmetics as endocrine disruptors: are they a health risk?

Science.gov (United States)

Nicolopoulou-Stamati, Polyxeni; Hens, Luc; Sasco, Annie J

2015-12-01

Exposure to chemicals from different sources in everyday life is widespread; one such source is the wide range of products listed under the title "cosmetics", including the different types of popular and widely-advertised sunscreens. Women are encouraged through advertising to buy into the myth of everlasting youth, and one of the most alarming consequences is in utero exposure to chemicals. The main route of exposure is the skin, but the main endpoint of exposure is endocrine disruption. This is due to many substances in cosmetics and sunscreens that have endocrine active properties which affect reproductive health but which also have other endpoints, such as cancer. Reducing the exposure to endocrine disruptors is framed not only in the context of the reduction of health risks, but is also significant against the background and rise of ethical consumerism, and the responsibility of the cosmetics industry in this respect. Although some plants show endocrine-disrupting activity, the use of well-selected natural products might reduce the use of synthetic chemicals. Instruments dealing with this problem include life-cycle analysis, eco-design, and green labels; in combination with the committed use of environmental management systems, they contribute to "corporate social responsibility".

Human cytotoxic T-lymphocyte membrane-camouflaged nanoparticles combined with low-dose irradiation: a new approach to enhance drug targeting in gastric cancer

Directory of Open Access Journals (Sweden)

Zhang L

2017-03-01

Full Text Available Lianru Zhang, Rutian Li, Hong Chen, Jia Wei, Hanqing Qian, Shu Su, Jie Shao, Lifeng Wang, Xiaoping Qian, Baorui Liu The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University and Clinical Cancer Institute of Nanjing University, Nanjing, People’s Republic of China Abstract: Cell membrane-derived nanoparticles are becoming more attractive because of their ability to mimic many features of their source cells. This study reports on a biomimetic delivery platform based on human cytotoxic T-lymphocyte membranes. In this system, the surface of poly-lactic-co-glycolic acid nanoparticles was camouflaged using T-lymphocyte membranes, and local low-dose irradiation (LDI was used as a chemoattractant for nanoparticle targeting. The T-lymphocyte membrane coating was verified using dynamic light scattering, transmission electron microscopy, and confocal laser scanning microscopy. This new platform reduced nanoparticle phagocytosis by macrophages to 23.99% (P=0.002. Systemic administration of paclitaxel-loaded T-lymphocyte membrane-coated nanoparticles inhibited the growth of human gastric cancer by 56.68% in Balb/c nude mice. Application of LDI at the tumor site significantly increased the tumor growth inhibition rate to 88.50%, and two mice achieved complete remission. Furthermore, LDI could upregulate the expression of adhesion molecules in tumor vessels, which is important in the process of leukocyte adhesion and might contribute to the localization of T-lymphocyte membrane-encapsulated nanoparticles in tumors. Therefore, this new drug-delivery platform retained both the long circulation time and tumor site accumulation ability of human cytotoxic T lymphocytes, while local LDI could significantly enhance tumor localization. Keywords: cell membrane, drug delivery system, gastric cancer, low-dose irradiation, nanoparticles

Purinergic receptors in the endocrine and exocrine pancreas.

Science.gov (United States)

Novak, I

2008-09-01

The pancreas is a complex gland performing both endocrine and exocrine functions. In recent years there has been increasing evidence that both endocrine and exocrine cells possess purinergic receptors, which influence processes such as insulin secretion and epithelial ion transport. Most commonly, these processes have been viewed separately. In beta cells, stimulation of P2Y(1) receptors amplifies secretion of insulin in the presence of glucose. Nucleotides released from secretory granules could also contribute to autocrine/paracrine regulation in pancreatic islets. In addition to P2Y(1) receptors, there is also evidence for other P2 and adenosine receptors in beta cells (P2Y(2), P2Y(4), P2Y(6), P2X subtypes and A(1) receptors) and in glucagon-secreting alpha cells (P2X(7), A(2) receptors). In the exocrine pancreas, acini release ATP and ATP-hydrolysing and ATP-generating enzymes. P2 receptors are prominent in pancreatic ducts, and several studies indicate that P2Y(2), P2Y(4), P2Y(11), P2X(4) and P2X(7) receptors could regulate secretion, primarily by affecting Cl(-) and K(+) channels and intracellular Ca(2+) signalling. In order to understand the physiology of the whole organ, it is necessary to consider the full complement of purinergic receptors on different cells as well as the structural and functional relation between various cells within the whole organ. In addition to the possible physiological function of purinergic receptors, this review analyses whether the receptors could be potential therapeutic targets for drug design aimed at treatment of pancreatic diseases.

Endocrine Disruption of Vasopressin Systems and Related Behaviors

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Heather B. Patisaul

2017-06-01

Full Text Available Endocrine disrupting chemicals (EDCs are chemicals that interfere with the organizational or activational effects of hormones. Although the vast majority of the EDC literature focuses on steroid hormone signaling related impacts, growing evidence from a myriad of species reveals that the nonapeptide hormones vasopressin (AVP and oxytocin (OT may also be EDC targets. EDCs shown to alter pathways and behaviors coordinated by AVP and/or OT include the plastics component bisphenol A (BPA, the soy phytoestrogen genistein (GEN, and various flame retardants. Many effects are sex specific and likely involve action at nuclear estrogen receptors. Effects include the elimination or reversal of well-characterized sexually dimorphic aspects of the AVP system, including innervation of the lateral septum and other brain regions critical for social and other non-reproductive behaviors. Disruption of magnocellular AVP function has also been reported in rats, suggesting possible effects on hemodynamics and cardiovascular function.

Novel MUC1 aptamer selectively delivers cytotoxic agent to cancer cells in vitro.

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Yan Hu

Full Text Available Chemotherapy is a primary treatment for cancer, but its efficacy is often limited by the adverse effects of cytotoxic agents. Targeted drug delivery may reduce the non-specific toxicity of chemotherapy by selectively directing anticancer drugs to tumor cells. MUC1 protein is an attractive target for tumor-specific drug delivery owning to its overexpression in most adenocarcinomas. In this study, a novel MUC1 aptamer is exploited as the targeting ligand for carrying doxorubicin (Dox to cancer cells. We developed an 86-base DNA aptamer (MA3 that bound to a peptide epitope of MUC1 with a K(d of 38.3 nM and minimal cross reactivity to albumin. Using A549 lung cancer and MCF-7 breast cancer cells as MUC1-expressing models, MA3 was found to preferentially bind to MUC1-positive but not MUC1-negative cells. An aptamer-doxorubicin complex (Apt-Dox was formulated by intercalating doxorubicin into the DNA structure of MA3. Apt-Dox was found capable of carrying doxorubicin into MUC1-positive tumor cells, while significantly reducing the drug intake by MUC1-negative cells. Moreover, Apt-Dox retained the efficacy of doxorubicin against MUC1-positive tumor cells, but lowered the toxicity to MUC1-negative cells (P<0.01. The results suggest that the MUC1 aptamer may have potential utility as a targeting ligand for selective delivery of cytotoxic agent to MUC1-expressing tumors.

Production of pancreatic hormone-expressing endocrine cells from human embryonic stem cells.

Science.gov (United States)

D'Amour, Kevin A; Bang, Anne G; Eliazer, Susan; Kelly, Olivia G; Agulnick, Alan D; Smart, Nora G; Moorman, Mark A; Kroon, Evert; Carpenter, Melissa K; Baetge, Emmanuel E

2006-11-01

Of paramount importance for the development of cell therapies to treat diabetes is the production of sufficient numbers of pancreatic endocrine cells that function similarly to primary islets. We have developed a differentiation process that converts human embryonic stem (hES) cells to endocrine cells capable of synthesizing the pancreatic hormones insulin, glucagon, somatostatin, pancreatic polypeptide and ghrelin. This process mimics in vivo pancreatic organogenesis by directing cells through stages resembling definitive endoderm, gut-tube endoderm, pancreatic endoderm and endocrine precursor--en route to cells that express endocrine hormones. The hES cell-derived insulin-expressing cells have an insulin content approaching that of adult islets. Similar to fetal beta-cells, they release C-peptide in response to multiple secretory stimuli, but only minimally to glucose. Production of these hES cell-derived endocrine cells may represent a critical step in the development of a renewable source of cells for diabetes cell therapy.

Examining the effects of hyperglycemia on pancreatic endocrine function in humans

DEFF Research Database (Denmark)

Solomon, Thomas P J; Knudsen, Sine H; Karstoft, Kristian

2012-01-01

Investigating the impact of hyperglycemia on pancreatic endocrine function promotes our understanding of the pathophysiology of hyperglycemia-related disease.......Investigating the impact of hyperglycemia on pancreatic endocrine function promotes our understanding of the pathophysiology of hyperglycemia-related disease....

Putative effects of endocrine disrupters on pubertal development in the human

DEFF Research Database (Denmark)

Teilmann, Grete; Juul, Anders; Skakkebaek, Niels E

2002-01-01

developing countries to industrialized countries often develop precocious puberty. Not only precocious puberty, but also delayed puberty can, theoretically, be associated with exposure to endocrine disrupters. While it is very plausible that endocrine disrupters may disturb pubertal development...

Endocrine sequelae after radiotherapy in childhood and adolescence

International Nuclear Information System (INIS)

Couto-Silva, Ana Claudia; Adan, Luis Fernando; Brauner, Raja

2005-01-01

Radiotherapy may result in endocrine abnormalities, osteoporosis, obesity and neurological sequelae in patients treated for cancer. In the hypothalamo-pituitary area, GH deficiency is the most frequent complication. The frequency, delay of appearance and severity of GH deficiency depend most on the dose delivered during cranial irradiation but variables as age at treatment and fractionation schedule may play an important role as well. Other hypothalamo-pituitary dysfunctions are also dose-dependent. Low dose cranial irradiation may induce precocious or early puberty, while high doses are related to gonadotropin deficiency. Endocrine complications due to extracranial irradiation such as gonadal or thyroid abnormalities are described. In spite of normal GH secretion, linear growth may be impaired by bone lesions secondary to craniospinal or total body irradiation. Results on final height have been optimized by better indicators of GH therapy associated with adequate treatment of early or precocious puberty. The purpose of this review is to explore the late endocrine sequelae of radiotherapy. (author)

Molecular cytotoxic mechanisms of anticancer hydroxychalcones.

Science.gov (United States)

Sabzevari, Omid; Galati, Giuseppe; Moridani, Majid Y; Siraki, Arno; O'Brien, Peter J

2004-06-30

Chalcones are being considered as anticancer agents as they are natural compounds that are particularly cytotoxic towards K562 leukemia or melanoma cells. In this study, we have investigated phloretin, isoliquiritigenin, and 10 other hydroxylated chalcones for their cytotoxic mechanisms towards isolated rat hepatocytes. All hydroxychalcones partly depleted hepatocyte GSH and oxidized GSH to GSSG. These chalcones also caused a collapse of mitochondrial membrane potential and increased oxygen uptake. Furthermore, glycolytic or citric acid cycle substrates prevented cytotoxicity and mitochondrial membrane potential collapse. The highest pKa chalcones were the most effective at collapsing the mitochondrial membrane potential which suggests that the cytotoxic activity of hydroxychalcones are likely because of their ability to uncouple mitochondria.

Hormones in the city: endocrine ecology of urban birds.

Science.gov (United States)

Bonier, Frances

2012-05-01

Urbanization dramatically changes the landscape, presenting organisms with novel challenges and often leading to reduced species diversity. Urban ecologists have documented numerous biotic and abiotic consequences of urbanization, such as altered climate, species interactions, and community composition, but we lack an understanding of the mechanisms underlying organisms' responses to urbanization. Here, I review findings from the nascent field of study of the endocrine ecology of urban birds. Thus far, no clear or consistent patterns have been revealed, but we do have evidence that urban habitat can shape endocrine traits, and that those traits might contribute to adaptation to the urban environment. I suggest strong approaches for future work addressing exciting questions about the role of endocrine traits in mediating responses to urbanization within species across the globe. Copyright © 2012 Elsevier Inc. All rights reserved.

Evaluation of yolk protein as biomarkers for endocrine disruption in molluscs

DEFF Research Database (Denmark)

Morthorst, Jane Ebsen; Holbech, Henrik; Kinnberg, Karin Lund

is also regulated by estrogens in molluscs even though it still remains unknown if and where vertebrate steroids are synthesized in molluscs and regulation of the endocrine system in molluscs is also unknown. By using our newly developed ELISA the present work investigates if yolk protein is a suitable......During recent years invertebrates and especially molluscs have received increasing attention in the field of endocrine disruption and development of OECD test guidelines to assess the effects of endocrine disrupting compounds (EDCs) in molluscs is under development. The development of standardized...... tests to detect effects of EDCs in molluscs has proved cumbersome due to lack of specific biomarkers and endpoints for endocrine effects. Intersex (presence of oocytes in the testis) and induction of vitellogenin (the yolk protein precursor in oviparous vertebrates) have been used as biomarkers for EDCs...

Endocrine actions of vitamin D in skin: Relevance for photocarcinogenesis of non-melanoma skin cancer, and beyond.

Science.gov (United States)

Reichrath, Jörg; Saternus, Roman; Vogt, Thomas

2017-09-15

The skin represents a pivotal organ for the human body's vitamin D endocrine system, being both the site of ultraviolet (UV)-B-induced vitamin D synthesis and a target tissue for the pluripotent effects of 1,25(OH) 2 D 3 and other biologically active vitamin D metabolites. As many other steroid hormones, 1,25(OH) 2 D 3 exerts its effects via two independent signal transduction pathways: the classical genomic and the non-genomic pathway. While non-genomic effects of 1,25(OH) 2 D 3 are in part exerted via effects on intracellular calcium, genomic effects are mediated by the vitamin D receptor (VDR). Recent findings convincingly support the concept of a new function of the VDR as a tumor suppressor in skin, with key components of the vitamin D endocrine system, including VDR, CYP24A1, CYP27A1, and CYP27B1 being strongly expressed in non-melanoma skin cancer (NMSC). It has now been shown that anti-tumor effects of VDR, that include some of its ligand-induced growth-regulatory effects, are at least in part mediated by interacting in a highly coordinated manner with the p53 family (p53/p63/p73) in response to a large number of alterations in cell homeostasis, including UV-induced DNA damage, a hallmark for skin photocarcinogenesis. Considering the relevance of the vitamin D endocrine system for carcinogenesis of skin cancer, it is not surprising that low 25(OH)D serum concentrations and genetic variants (SNPs) of the vitamin D endocrine system have been identified as potential risk factors for occurrence and prognosis of skin malignancies. In conclusion, an increasing body of evidence now convincingly supports the concept that the vitamin D endocrine system is of relevance for photocarcinogenesis and progression of NMSC and that its pharmacologic modulation by vitamin D, 1,25(OH) 2 D 3, and analogs represents a promising new strategy for prevention and/or treatment of these malignancies. Copyright © 2017 Elsevier B.V. All rights reserved.

Selective cytotoxicity of an oxygen-radical-generating enzyme conjugated to a monoclonal antibody.

Science.gov (United States)

Battelli, M G; Abbondanza, A; Tazzari, P L; Dinota, A; Rizzi, S; Grassi, G; Gobbi, M; Stirpe, F

1988-07-01

The monoclonal antibody 8A, which recognizes a human plasma cell-associated antigen, was covalently linked to xanthine oxidase in a conjugate maintaining both immunological and enzymatic properties. A significant degree of target cell lysis was obtained at an enzyme concentration that was ineffective on non-target cells and on myeloid staminal cells (CFU-GM). The cytotoxic activity was abolished by an excess of antibody, by allopurinol and by superoxide dismutase and catalase. A possible use of the conjugate for bone marrow purging in multiple myeloma patients is suggested.

Surface-modified gold nanorods for specific cell targeting

Science.gov (United States)

Wang, Chan-Ung; Arai, Yoshie; Kim, Insun; Jang, Wonhee; Lee, Seonghyun; Hafner, Jason H.; Jeoung, Eunhee; Jung, Deokho; Kwon, Youngeun

2012-05-01

Gold nanoparticles (GNPs) have unique properties that make them highly attractive materials for developing functional reagents for various biomedical applications including photothermal therapy, targeted drug delivery, and molecular imaging. For in vivo applications, GNPs need to be prepared with very little or negligible cytotoxicitiy. Most GNPs are, however, prepared using growth-directing surfactants such as cetyl trimethylammonium bromide (CTAB), which are known to have considerable cytotoxicity. In this paper, we describe an approach to remove CTAB to a non-toxic concentration. We optimized the conditions for surface modification with methoxypolyethylene glycol thiol (mPEG), which replaced CTAB and formed a protective layer on the surface of gold nanorods (GNRs). The cytotoxicities of pristine and surface-modified GNRs were measured in primary human umbilical vein endothelial cells and human cell lines derived from hepatic carcinoma cells, embryonic kidney cells, and thyroid papillary carcinoma cells. Cytotoxicity assays revealed that treating cells with GNRs did not significantly affect cell viability except for thyroid papillary carcinoma cells. Thyroid cancer cells were more susceptible to residual CTAB, so CTAB had to be further removed by dialysis in order to use GNRs for thyroid cell targeting. PEGylated GNRs are further modified to present monoclonal antibodies that recognize a specific surface marker, Na-I symporter, for thyroid cells. Antibody-conjugated GNRs specifically targeted human thyroid cells in vitro.

[Autoimmune thyroid disease and other non-endocrine autoimmune diseases].

Science.gov (United States)

Dilas, Ljiljana Todorović; Icin, Tijana; Paro, Jovanka Novaković; Bajkin, Ivana

2011-01-01

Autoimmune diseases are chronic conditions initiated by the loss of immunological tolerance to self-antigens. They constitute heterogeneous group of disorders, in which multiple alterations in the immune system result in a spectrum of syndromes that either target specific organs or affect the body systematically. Recent epidemiological studies have shown a possible shift of one autoimmune disease to another or the fact that more than one autoimmune disease may coexist in a single patient or in the same family. Numerous autoimmune diseases have been shown to coexist frequently with thyroid autoimmune diseases. AUTOIMMNUNE THYROID DISEASE AND OTHER ORGAN SPECIFIC NON-ENDOCRINE AUTOIMMUNE DISEASES: This part of the study reviews the prevalence of autoimmune thyroid disease coexisting with: pernicious anaemia, vitiligo, celiac disease, autoimmune liver disease, miastenia gravis, alopecia areata and sclerosis multiplex, and several recommendations for screening have been given. AUTOIMMUNE THYROID DISEASE AND OTHER ORGAN NON-SPECIFIC NON-ENDOCRINE AUTOIMMUNE DISEASES: Special attention is given to the correlation between autoimmune thyroid disease and rheumatoid arthritis, systemic lupus erythematosus, syndrome Sjögren, systemic sclerosis and mixed connective tissue disease. Screening for autoimmune thyroid diseases should be recommended in everyday clinical practice, in patients with primary organ-specific or organ non-specific autoimmune disease. Otherwise, in patients with primary thyroid autoimmune disease, there is no good reason of seeking for all other autoimmune diseases, although these patients have a greater risk of developing other autoimmune disease. Economic aspects of medicine require further analyzing of these data, from cost/benefit point of view to justified either mandatory screening or medical practitioner judgment.

Imaging of endocrine system

International Nuclear Information System (INIS)

Das, B.K.; Noreen Norfaraheen Lee Abdullah

2012-01-01

In recent years, the role of nuclear medicine in the study of morphology and pathophysiology of various endocrine organs has greatly expanded. Newly developed radiopharmaceuticals, new instrumentation, innovative study designs and dual isotope techniques have contributed significantly to the evaluation of parathyroid and adrenal diseases. In selected cases, patients with metabolic bone disorders and infertility have greatly been benefited. (author)

Genetics of Endocrine and Neuroendocrine Neoplasias (PDQ®)—Health Professional Version

Science.gov (United States)

Genetics of Endocrine and Neuroendocrine Neoplasias discusses inherited syndromes multiple endocrine neoplasia types 1, 2, and 4 (MEN1, MEN2, MEN4), familial pheochromocytoma and paraganglioma, Carney-Stratakis syndrome, and familial nonmedullary thyroid cancer. Learn more in this clinician summary.

Hedgehog signaling: endocrine gland development and function.

Science.gov (United States)

Cohen, M Michael

2010-01-01

The role of hedgehog signaling is analyzed in relation to the developing endocrine glands: pituitary, ovary, testis, adrenal cortex, pancreas, prostate, and epiphyseal growth. Experimental and pathological correlates of these organs are also discussed. The second section addresses a number of topics. First, the pituitary gland, no matter how hypoplastic, is present in most cases of human holoprosencephaly, unlike animals in which it is always said to be absent. The difference appears to be that animal mutations and teratogenic models involve both copies of the gene in question, whereas in humans the condition is most commonly heterozygous. Second, tests of endocrine function are not reported with great frequency, and an early demise in severe cases of holoprosencephaly accounts for this trend. Reported tests of endocrine function are reviewed. Third, diabetes insipidus has been recorded in a number of cases of holoprosencephaly. Its frequency is unknown because it could be masked by adrenal insufficiency in some cases and may not be recognized in others. Because of the abnormal hypothalamic-infundibular region in holoprosencephaly, diabetes insipidus could be caused by a defect in the supra-optic or paraventricular hypothalamic nuclei or in release of ADH via the infundibulum and posterior pituitary.

Negative role of the environmental endocrine disruptors in the human neurodevelopment

Directory of Open Access Journals (Sweden)

Luca Roncati

2016-08-01

Full Text Available The endocrine disruptors (EDs are able to influence the endocrine system, mimicking or antagonizing hormonal molecules. They are bio-persistent for their degradation resistance in the environment. Our research group has investigated by gas chromatography-mass spectrometry (GC-MS the EDs presence in 35 brain samples, coming from 27 cases of sudden intrauterine unexplained death syndrome (SIUDS and 8 cases of sudden infant death syndrome (SIDS, collected by centralization in the last year (2015. More in detail, a mixture of 25 EDs has been subjected to analytical procedure, following standard protocols. Among the target analytes, some organochlorine pesticides (OCPs, that is α-chlordane, γ-chlordane, heptachlor, p,p-DDE, p,p-DDT, and the two most commonly used organophosphorus pesticides (OPPs, chlorpyrifos and chlorfenvinfos, have been found in 7 and 3 samples, respectively. The analytical procedure used to detect the presence of environmental EDs in cortex samples has been successfully implemented on SIUDS and SIDS victims. The environmental EDs have been found to be able to overcome the placental barrier, reaching also the basal ganglia assigned to the control of the vital functions. This finding, related to the OPPs bio-persistence, implies a conceptual redefinition of the fetal-placental and fetal blood-brain barriers: not real safety barriers, but simply time-deferral mechanisms of absorption.

Endocannabinoids and the Endocrine System in Health and Disease.

Science.gov (United States)

Hillard, Cecilia J

2015-01-01

Some of the earliest reports of the effects of cannabis consumption on humans were related to endocrine system changes. In this review, the effects of cannabinoids and the role of the CB1 cannabinoid receptor in the regulation of the following endocrine systems are discussed: the hypothalamic-pituitary-gonadal axis, prolactin and oxytocin, thyroid hormone and growth hormone, and the hypothalamic-pituitary-adrenal axis. Preclinical and human study results are presented.

Endocrine Therapy of Estrogen Receptor-Positive Breast Cancer Cells: Early Differential Effects on Stem Cell Markers

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Euphemia Y. Leung

2017-09-01

Full Text Available IntroductionEndocrine therapy of breast cancer, which either deprives cancer tissue of estrogen or prevents estrogen pathway signaling, is the most common treatment after surgery and radiotherapy. We have previously shown for the estrogen-responsive MCF-7 cell line that exposure to tamoxifen, or deprivation of estrogen, leads initially to inhibition of cell proliferation, followed after several months by the emergence of resistant sub-lines that are phenotypically different from the parental line. We examined the early responses of MCF-7 cells following either exposure to 4-hydroxytamoxifen or deprivation of estrogen for periods of 2 days–4 weeks.MethodsEndocrine-sensitive or -resistant breast cancer cell lines were used to examine the expression of the stem cell gene SOX2, and the Wnt effector genes AXIN2 and DKK1 using quantitative PCR analysis. Breast cancer cell lines were used to assess the anti-proliferative effects (as determined by IC50 values of Wnt pathway inhibitors LGK974 and IWP-2.ResultsHormone therapy led to time-dependent increases of up to 10-fold in SOX2 expression, up to threefold in expression of the Wnt target genes AXIN2 and DKK1, and variable changes in NANOG and OCT4 expression. The cells also showed increased mammosphere formation and increased CD24 surface protein expression. Some but not all hormone-resistant MCF-7 sub-lines, emerging after long-term hormonal stress, showed up to 50-fold increases in SOX2 expression and smaller increases in AXIN2 and DKK1 expression. However, the increase in Wnt target gene expression was not accompanied by an increase in sensitivity to Wnt pathway inhibitors LGK974 and IWP-2. A general trend of lower IC50 values was observed in 3-dimensional spheroid culture conditions (which allowed enrichment of cells with cancer stem cell phenotype relative to monolayer cultures. The endocrine-resistant cell lines showed no significant increase in sensitivity to Wnt inhibitors

Toxicity of compounds with endocrine activity in the OECD 421 reproductive toxicity screening test

NARCIS (Netherlands)

Piersma AH; Verhoef A; Elvers LH; Wester PW; LEO; LPI

1998-01-01

The issue of endocrine disruption has, in view of human risk assessment, raised the question on whether more sensitive test methods are needed to detect the reproductive toxic properties of xenobiotic compounds with endocrine properties. We studied six known and alleged endocrine disruptors in an

Monoclonal antibodies for radioimmunodetection of tumours and for targeting

International Nuclear Information System (INIS)

Baldwin, R.W.; Embleton, M.J.; Pimm, M.V.

1983-01-01

A monoclonal antibody 791T/36 prepared against human osteogenic sarcoma has been used to detect primary and metastatic colorectal carcinomas by external imaging of patients following injection of 131 I-labelled antibody. In 10 of 11 patients radiolabelled 791T/36 antibody localized in tumours, the tumour/non tumour ratio of radioactivity ranging from 1.5:1 to 8.1. 791T/36 antibody was also evaluated for its potential for targeting anti-tumour agents including cytotoxic drugs (Vindesine) and immunomodulating agents (interferon). Vindesine-791T/36 conjugates were preferentially cytotoxic in vitro for target cells expressing the 791T/36 anti-body defined antigen. Also interferon conjugated to 791T/36 antibody, like free interferon activated peripheral blood natural killer cell activity. These in vitro tests together with related studies on antibody localization in vivo indicate the potential of monoclonal antibody targeting of anti-tumour agents

Cytotoxicity and inhibitory properties against topoisomerase II of doxorubicin and its formamidine derivatives.

Science.gov (United States)

Kik, Krzysztof; Studzian, Kazimierz; Wasowska-Łukawska, Małgorzata; Oszczapowicz, Irena; Szmigiero, Leszek

2009-01-01

This work was undertaken to compare cytotoxicity, DNA damaging properties and effect on DNA cleavage by topoisomerase II of the anthracycline drug doxorubicin (DOX) and its two derivatives with a formamidino group containing a cyclic amine moiety such as morpholine (DOXM) or hexamethyleneimine (DOXH). The tetrazolium dye colorimetric assay was used to determine the cytotoxic activity of anthracyclines toward L1210 leukemia cells. DNA damage was measured by alkaline elution technique. The effect of anthracyclines on DNA cleavage was studied in a cell-free system containing supercoiled pBR322 DNA and purified human topoisomerase II. The cytotoxicity data and the results of studies on the mechanism of DNA break formation by anthracyclines at the cellular level and in the cell-free system showed that the presence of the formamidino group in the doxorubicin molecule reduced its ability to stimulate DNA cleavage by DNA topoisomerase II. DNA topoisomerase II is not a primary cellular target for DOXM or DOXH. An advantageous feature of formamidinoanthracyclines is their mechanism of cytotoxic action which is not related to the inhibition of DNA topoisomerase II. Therefore this class of anthracyclines seems to be a good source for selection of an anticancer drug directed toward cancer cells with the developed multidrug resistance attributed to the presence of altered DNA topoisomerase II.

Interconnection between thyroid hormone signalling pathways and parvovirus cytotoxic functions.

OpenAIRE

Vanacker, J M; Laudet, V; Adelmant, G; Stéhelin, D; Rommelaere, J

1993-01-01

Nonstructural (NS) proteins of autonomous parvoviruses can repress expression driven by heterologous promoters, an activity which thus far has not been separated from their cytotoxic effects. It is shown here that, in transient transfection assays, the NS-1 protein of the parvovirus minute virus of mice (MVMp) activates the promoter of the human c-erbA1 gene, encoding the thyroid hormone (T3) receptor alpha. The endogenous c-erbA1 promoter is also a target for induction upon MVMp infection. M...

Meeting report: Measuring endocrine-sensitive endpoints within the first years of life

DEFF Research Database (Denmark)

Arbuckle, T.E.; Hauser, R.; Swan, S.H.

2008-01-01

An international workshop tided "Assessing Endocrine-Related Endpoints within the First Years of Life" was held 30 April-1 May 2007, in Ottawa, Ontario, Canada. Representatives from a number of pregnancy cohort studies in North America and Europe presented options for measuring various endocrine......-sensitive endpoints in early life and discussed issues related to performing and using those measures. The workshop focused on measuring reproductive tract developmental endpoints [e.g., anogenital distance (AGD)], endocrine status, and infant anthropometry. To the extent possible, workshop participants strove...... on the genital exam. Although a number of outcome measures recommended during the genital exam have been associated with exposure to endocrine-disrupting chemicals, little is known about how predictive these effects are of later reproductive health or other chronic health conditions....

Requirement for Pdx1 in specification of latent endocrine progenitors in zebrafish

Directory of Open Access Journals (Sweden)

Ellertsdottir Elin

2011-10-01

Full Text Available Abstract Background Insulin-producing beta cells emerge during pancreas development in two sequential waves. Recently described later-forming beta cells in zebrafish show high similarity to second wave mammalian beta cells in developmental capacity. Loss-of-function studies in mouse and zebrafish demonstrated that the homeobox transcription factors Pdx1 and Hb9 are both critical for pancreas and beta cell development and discrete stage-specific requirements for these genes have been uncovered. Previously, exocrine and endocrine cell recovery was shown to follow loss of pdx1 in zebrafish, but the progenitor cells and molecular mechanisms responsible have not been clearly defined. In addition, interactions of pdx1 and hb9 in beta cell formation have not been addressed. Results To learn more about endocrine progenitor specification, we examined beta cell formation following morpholino-mediated depletion of pdx1 and hb9. We find that after early beta cell reduction, recovery occurs following loss of either pdx1 or hb9 function. Unexpectedly, simultaneous knockdown of both hb9 and pdx1 leads to virtually complete and persistent beta cell deficiency. We used a NeuroD:EGFP transgenic line to examine endocrine cell behavior in vivo and developed a novel live-imaging technique to document emergence and migration of late-forming endocrine precursors in real time. Our data show that Notch-responsive progenitors for late-arising endocrine cells are predominantly post mitotic and depend on pdx1. By contrast, early-arising endocrine cells are specified and differentiate independent of pdx1. Conclusions The nearly complete beta cell deficiency after combined loss of hb9 and pdx1 suggests functional cooperation, which we clarify as distinct roles in early and late endocrine cell formation. A novel imaging approach permitted visualization of the emergence of late endocrine cells within developing embryos for the first time. We demonstrate a pdx1-dependent

The impact of opioids on the endocrine system.

Science.gov (United States)

Katz, Nathaniel; Mazer, Norman A

2009-02-01

Opioids have been used for medicinal and analgesic purposes for centuries. However, their negative effects on the endocrine system, which have been known for some times, are barely discussed in modern medicine. Therefore, we conducted a systematic review of the impact of opioids on the endocrine system. A review of the English language literature on preclinical and clinical studies of any type on the influence of opioids on the endocrine system was conducted. Preliminary recommendations for monitoring and managing these problems were provided. Long-term opioid therapy for either addiction or chronic pain often induces hypogonadism owing to central suppression of hypothalamic secretion of gonadotropin-releasing hormone. Symptoms of opioid-induced hypogonadism include loss of libido, infertility, fatigue, depression, anxiety, loss of muscle strength and mass, osteoporosis, and compression fractures in both men and women; impotence in men; and menstrual irregularities and galactorrhea in women. In view of the increased use of opioids for chronic pain, it has become increasingly important to monitor patients taking opioids and manage endocrine complications. Therefore, patients on opioid therapy should be routinely screened for such symptoms and for laboratory abnormalities in sex hormones. Opioid-induced hypogonadism seems to be a common complication of therapeutic or illicit opioid use. Patients on long-term opioid therapy should be prospectively monitored, and in cases of opioid-induced hypogonadism, we recommend nonopioid pain management, opioid rotation, or sex hormone supplementation after careful consideration of the risks and benefits.

CT and MR imaging findings of endocrine tumor of the pancreas according to WHO classification

International Nuclear Information System (INIS)

Rha, Sung Eun; Jung, Seung Eun; Lee, Kang Hoon; Ku, Young Mi; Byun, Jae Young; Lee, Jae Mun

2007-01-01

The pancreatic endocrine tumors are rare neuroendocrine tumors of the pancreas originating from totipotential stem cells or differentiated mature endocrine cells within the exocrine gland. Endocrine tumors are usually classified into functioning and non-functioning tumors and presents with a range of benignity or malignancy. In this article, we present the various CT and MR imaging findings of endocrine tumors of pancreas according to recent WHO classification

Muscular Dystrophies at Different Ages: Metabolic and Endocrine Alterations

Directory of Open Access Journals (Sweden)

Oriana del Rocío Cruz Guzmán

2012-01-01

Full Text Available Common metabolic and endocrine alterations exist across a wide range of muscular dystrophies. Skeletal muscle plays an important role in glucose metabolism and is a major participant in different signaling pathways. Therefore, its damage may lead to different metabolic disruptions. Two of the most important metabolic alterations in muscular dystrophies may be insulin resistance and obesity. However, only insulin resistance has been demonstrated in myotonic dystrophy. In addition, endocrine disturbances such as hypogonadism, low levels of testosterone, and growth hormone have been reported. This eventually will result in consequences such as growth failure and delayed puberty in the case of childhood dystrophies. Other consequences may be reduced male fertility, reduced spermatogenesis, and oligospermia, both in childhood as well as in adult muscular dystrophies. These facts all suggest that there is a need for better comprehension of metabolic and endocrine implications for muscular dystrophies with the purpose of developing improved clinical treatments and/or improvements in the quality of life of patients with dystrophy. Therefore, the aim of this paper is to describe the current knowledge about of metabolic and endocrine alterations in diverse types of dystrophinopathies, which will be divided into two groups: childhood and adult dystrophies which have different age of onset.

Synthesis and Cytotoxic Evaluation of a Series of 2-Amino-Naphthoquinones against Human Cancer Cells

Directory of Open Access Journals (Sweden)

Thiago A. P. de Moraes

2014-08-01

Full Text Available The cytotoxicity of a series of aminonaphthoquinones resulting from the reaction of suitable aminoacids with 1,4-naphthoquinone was assayed against SF-295 (glioblastoma, MDAMB-435 (breast, HCT-8 (colon, HCT-116 (colon, HL-60 (leukemia, OVCAR-8 (ovarian, NCI-H358M (bronchoalveolar lung carcinoma and PC3-M (prostate cancer cells and also against PBMC (peripheral blood mononuclear cells. The results demonstrated that all the synthetic aminonaphthoquinones had relevant cytotoxic activity against all human cancer lines used in this experiment. Five of the compounds showed high cytotoxicity and selectivity against all cancer cell lines tested (IC50 = 0.49 to 3.89 µg·mL−1. The title compounds were less toxic to PBMC, since IC50 was 1.5 to eighteen times higher (IC50 = 5.51 to 17.61 µg·mL−1 than values shown by tumour cell lines. The mechanism of cell growth inhibition and structure–activity relationships remains as a target for future investigations.

Recent Advances on Endocrine Disrupting Effects of UV Filters

Directory of Open Access Journals (Sweden)

Jiaying Wang

2016-08-01

Full Text Available Ultraviolet (UV filters are used widely in cosmetics, plastics, adhesives and other industrial products to protect human skin or products against direct exposure to deleterious UV radiation. With growing usage and mis-disposition of UV filters, they currently represent a new class of contaminants of emerging concern with increasingly reported adverse effects to humans and other organisms. Exposure to UV filters induce various endocrine disrupting effects, as revealed by increasing number of toxicological studies performed in recent years. It is necessary to compile a systematic review on the current research status on endocrine disrupting effects of UV filters toward different organisms. We therefore summarized the recent advances on the evaluation of the potential endocrine disruptors and the mechanism of toxicity for many kinds of UV filters such as benzophenones, camphor derivatives and cinnamate derivatives.

The endocrine system and sarcopenia: potential therapeutic benefits.

Science.gov (United States)

McIntire, Kevin L; Hoffman, Andrew R

2011-12-01

Age related muscle loss, known as sarcopenia, is a major factor in disability, loss of mobility and quality of life in the elderly. There are many proposed mechanisms of age-related muscle loss that include the endocrine system. A variety of hormones regulate growth, development and metabolism throughout the lifespan. Hormone activity may change with age as a result of reduced hormone secretion or decreased tissue responsiveness. This review will focus on the complex interplay between the endocrine system, aging and skeletal muscle and will present possible benefits of therapeutic interventions for sarcopenia.

Application of biotests for the characterization of exposure pathways for endocrine disrupters from plastics; Anwendung von Biotests zur Charakterisierung der Expositionspfade fuer Umwelthormone aus Kunststoffen

Energy Technology Data Exchange (ETDEWEB)

Wagner, Martin; Oehlmann, Joerg [Frankfurt Univ., Frankfurt am Main (Germany). Abteilung Aquatische Oekotoxikologie

2011-12-15

The present project aims to characterise the exposure pathways for endocrine disruptors from plastic materials. A bioassay-based approach was employed to investigate and characterise the endocrine activity. Migration studies with food packaging and plastic preforms document the leaching of estrogen-like compounds from several types of plastic in the Yeast Estrogen Screen and the E-Screen. Additionally, anti-estrogenic activity was predominant in many samples. The detection of complex migration profiles provides evidence for the leaching of several, diverse-acting endocrine disruptors. Moreover, extracts of plastic food packaging exhibited agonistic activity on the estrogen receptor, retinoid X receptor, and vitamin D receptor. A theoretical exposure assessment for marine molluscs implies that endocrine disruptors from plastic might induce relevant effect in the environment. Within the exemplary investigation of bottled mineral water, 60% of the products were characterised as significantly estrogenic using the YES and E-Screen. These in vitro data point to the plastic packaging being one source of estrogenic contamination. An in vivo study employing the estrogen-sensitive model organism Potamopyrgus antipodarum supports this hypothesis. By using several analytical techniques (GC-MS, LC-MS/MS) we identified several well-known endocrine disruptors in bottled water and the plastic material, e.g. numerous phthalates and phenols. Moreover, potent antagonists of the estrogen and androgen receptor were extracted from bottled water. In a non-target analysis (Orbitrap-MS) a compound with the exact mass of 363.1992 [M+H{sup +}] correlated highly significantly with the biological activity. On the basis of the methods optimised and applied within the project we elaborated a set of aspects that are crucial for the applicability of bioassays to characterise the endocrine activity of complex samples. Employing a bioassay-based approach we provide evidence for the presence and

Late effects of early exposures to endocrine disrupting chemicals in rats

DEFF Research Database (Denmark)

Boberg, Julie; Hass, Ulla

2017-01-01

Endocrine disrupting compounds may interfere with tissues at critical developmental stages and give rise to cancer later in life. This talk will focus on early-life exposure to endocrine disrupting chemicals which is associated with increased risk for carcinogenesis in mammary and prostate glands...

Nanotoxicity: a growing need for study in the endocrine system.

Science.gov (United States)

Lu, Xuefei; Liu, Ying; Kong, Xiangjun; Lobie, Peter E; Chen, Chunying; Zhu, Tao

2013-05-27

Nanomaterials (NMs) are engineered for commercial purposes such as semiconductors, building materials, cosmetics, and drug carriers, while natural nanoparticles (NPs) already exist in the environment. Due to their unique physicochemical properties, they may interact actively with biological systems. Some of these interactions might be detrimental to human health, and therefore studies on the potential 'nanotoxicity' of these materials in different organ systems are warranted. The purpose of developing the concept of nanotoxicity is to recognize and evaluate the hazards and risks of NMs and evaluate safety. This review will summarize and discuss recent reports derived from cell lines or animal models concerning the effects of NMs on, and their application in, the endocrine system of mammalian and other species. It will present an update on current studies of the effects of some typical NMs-such as metal-based NMs, carbon-based NMs, and dendrimers-on endocrine functions, in which some effects are adverse or unwanted and others are favorable or intended. Disruption of endocrine function is associated with adverse health outcomes including reproductive failure, metabolic syndrome, and some types of cancer. Further investigations are therefore required to obtain a thorough understanding of any potential risk of pathological endocrine disruption from products containing NMs. This review aims to provide impetus for further studies on the interactions of NMs with endocrine functions. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Screening for secondary endocrine hypertension in young patients.

Science.gov (United States)

Trifanescu, Raluca; Carsote, Mara; Caragheorgheopol, Andra; Hortopan, Dan; Dumitrascu, Anda; Dobrescu, Mariana; Poiana, Catalina

2013-06-01

Secondary endocrine hypertension accounts for 5-12% of hypertension's causes. In selected patients (type 2 diabetes mellitus, sleep apnea syndrome with resistant hypertension, sudden deterioration in hypertension control), prevalence could be higher. To present etiology of endocrine secondary hypertension in a series of patients younger than 40 years at hypertension's onset. Medical records of 80 patients (39M/41F), aged 30.1 ± 8.2 years (range: 12-40 years), with maximum systolic blood pressure=190.4 ± 29.2 mm Hg, range: 145-300 mm Hg, maximum diastolic blood pressure=107.7 ± 16.9 mm Hg, range: 80-170 mm Hg) referred by cardiologists for endocrine hypertension screening were retrospectively reviewed. Cardiac and renal causes of secondary hypertension were previously excluded. In all patients, plasma catecholamines were measured by ELISA and plasma cortisol by immunochemiluminescence. Orthostatic aldosterone (ELISA) and direct renin (chemiluminescence) were measured in 48 patients. Secondary endocrine hypertension was confirmed in 16 out of 80 patients (20%). Primary hyperaldosteronism was diagnosed in 7 (4M/3F) out of 48 screened patients (14.6%). i.e. 8.75% from whole group: 5 patients with adrenal tumors (3 left/2 right), 2 patients with bilateral adrenal hyperplasia; all patients were hypokalemic at diagnostic (average nadir K+ levels = 2.5 ± 0.5 mmol/L); four patients were hypokalaemic on diuretic therapy (indapamidum); other 3 patients were hypokalaemic in the absence of diuretic therapy. Cushing's syndrome was diagnosed in 6 patients (7.5%): subclinical Cushing due to 4 cm right adrenal tumour - n = 1, overt ACTH-independent Cushing's syndrome due to: macronodular adrenal hyperplasia associated with primary hyperparathyroidism - n = 1; due to adrenal carcinoma - n = 1; due to adrenal adenomas - n = 2; Cushing's disease - n = 1). Pheochromocytomas were diagnosed in 3 patients (3.75%). Primary hyperaldosteronism was the most frequent cause of secondary

Formulation and optimization of oxaliplatin immuno-nanoparticles using Box-Behnken design and cytotoxicity assessment for synergistic and receptor-mediated targeting in the treatment of colorectal cancer.

Science.gov (United States)

Tummala, Shashank; Gowthamarajan, K; Satish Kumar, M N; Praveen, T K; Yamjala, Karthik; Tripuraneni, Naga Srinivas; Prakash, Ashwati

2016-12-01

Conventional chemotherapy majorly lacks clinical application attributed to its inspecificity, adverse effects and inability to penetrate into tumor cells. Hence, the aim of the study was to prepare oxaliplatin solid lipid nanoparticles (OP-SLN) by microemulsion method optimizing it by Box-Behnken design and then covalently conjugated to TRAIL (CD-253) monoclonal antibody (TR-OP-SLN) for targeting colorectal cancer cells. The optimized OP-SLN3 has shown an appreciable particle size (121 ± 1.22 nm), entrapment efficiency (78 ± 0.09%) and drug loading (32 ± 1.01%). Fluorescence study and the Bradford assay further confirmed the binding of the protein. A 1.5-fold increase in cytotoxicity of immuno-nanoparticles (4.9 μM) was observed.

Comparative microstructures and cytotoxicity assays for ballistic aerosols composed of micrometals and nanometals: respiratory health implications

Science.gov (United States)

Machado, Brenda I; Suro, Raquel M; Garza, Kristine M; Murr, Lawrence E

2011-01-01

Aerosol particulates collected on filters from ballistic penetration and erosion events for W–Ni–Co and W–Ni–Fe kinetic energy rod projectiles penetrating steel target plates were observed to be highly cytotoxic to human epithelial A549 lung cells in culture after 48 hours of exposure. The aerosol consisted of micron-sized Fe particulates and nanoparticulate aggregates consisting of W, Ni or W, Co, and some Fe, characterized by scanning electron microscopy and transmission electron microscopy, and using energy-dispersive (X-ray) spectrometry for elemental analysis and mapping. Cytotoxic assays of manufactured micron-sized and nanosized metal particulates of W, Ni, Fe, and Co demonstrated that, consistent with many studies in the literature, only the nanoparticulate elements demonstrated measurable cytotoxicity. These results suggest the potential for very severe, short-term, human toxicity, in particular to the respiratory system on inhaling ballistic aerosols. PMID:21499416

A novel multiparametric flow cytometry-based cytotoxicity assay simultaneously immunophenotypes effector cells: comparisons to a 4 h 51Cr-release assay.

Science.gov (United States)

Kim, G G; Donnenberg, V S; Donnenberg, A D; Gooding, W; Whiteside, T L

2007-08-31

Natural killer (NK) cell-or T cell-mediated cytotoxicity traditionally is measured in 4-16 h (51)Cr-release assays (CRA). A new four-color flow cytometry-based cytotoxicity assay (FCC) was developed to simultaneously measure NK cell cytotoxicity and NK cell phenotype (CD3(-)CD16(+)CD56(+)). Target cells, K562 or Daudi, were labeled with Cell Tracker Orange (CTO) prior to the addition of effector cells. Following co-incubation, 7 amino-actinomycin D (7-AAD) was added to measure death of target cells. The phenotype of effectors, viability of targets, the formation of tumor-effector cell conjugates and absolute numbers of all cells were measured based on light scatter (FSC/SSC), double discrimination of the fluorescence peak integral and height, and fluorescence intensity. Kinetic studies (0.5 and 1 to 4 h) at different effector to target (E:T) cell ratios (50, 25, 12, and 6) confirmed that the 3 h incubation was optimal. The FCC assay is more sensitive than the CRA, has a coefficient of variation (CV) 8-13% and reliably measures NK cell-or lymphokine-activated killer (LAK) cell-mediated killing of target cells in normal controls and subjects with cancer. The FCC assay can be used to study a range of phenotypic attributes, in addition to lytic activity of various subsets of effector cells, without radioactive tracers and thus, it is relatively inexpensive. The FCC assay has a potential for providing information about molecular interactions underlying target cell lysis and thus becoming a major tool for studies of disease pathogenesis as well as development of novel immune therapies.

The Cdk4-E2f1 pathway regulates early pancreas development by targeting Pdx1+ progenitors and Ngn3+ endocrine precursors

Science.gov (United States)

Kim, So Yoon; Rane, Sushil G.

2011-01-01

Cell division and cell differentiation are intricately regulated processes vital to organ development. Cyclin-dependent kinases (Cdks) are master regulators of the cell cycle that orchestrate the cell division and differentiation programs. Cdk1 is essential to drive cell division and is required for the first embryonic divisions, whereas Cdks 2, 4 and 6 are dispensable for organogenesis but vital for tissue-specific cell development. Here, we illustrate an important role for Cdk4 in regulating early pancreas development. Pancreatic development involves extensive morphogenesis, proliferation and differentiation of the epithelium to give rise to the distinct cell lineages of the adult pancreas. The cell cycle molecules that specify lineage commitment within the early pancreas are unknown. We show that Cdk4 and its downstream transcription factor E2f1 regulate mouse pancreas development prior to and during the secondary transition. Cdk4 deficiency reduces embryonic pancreas size owing to impaired mesenchyme development and fewer Pdx1+ pancreatic progenitor cells. Expression of activated Cdk4R24C kinase leads to increased Nkx2.2+ and Nkx6.1+ cells and a rise in the number and proliferation of Ngn3+ endocrine precursors, resulting in expansion of the β cell lineage. We show that E2f1 binds and activates the Ngn3 promoter to modulate Ngn3 expression levels in the embryonic pancreas in a Cdk4-dependent manner. These results suggest that Cdk4 promotes β cell development by directing E2f1-mediated activation of Ngn3 and increasing the pool of endocrine precursors, and identify Cdk4 as an important regulator of early pancreas development that modulates the proliferation potential of pancreatic progenitors and endocrine precursors. PMID:21490060

Targeting Wnt Pathways in Disease

Science.gov (United States)

Zimmerman, Zachary F.; Moon, Randall T.

2012-01-01

Wnt-mediated signal transduction pathways have long been recognized for their roles in regulating embryonic development, and have more recently been linked to cancer, neurologic diseases, inflammatory diseases, and disorders of endocrine function and bone metabolism in adults. Although therapies targeting Wnt signaling are attractive in theory, in practice it has been difficult to obtain specific therapeutics because many components of Wnt signaling pathways are also involved in other cellular processes, thereby reducing the specificity of candidate therapeutics. New technologies, and advances in understanding the mechanisms of Wnt signaling, have improved our understanding of the nuances of Wnt signaling and are leading to promising new strategies to target Wnt signaling pathways. PMID:23001988

Multiple endocrine neoplasia type I

International Nuclear Information System (INIS)

Fischer, H.J.; Lois, J.F.; Gomes, A.S.

1985-01-01

A case of multiple endocrine neoplasia (Men) consisting of an unusual combination of an insulin-producing islet cell tumour and an adrenal adenoma is reported. CT clearly demonstrated the adrenal mass whereas the pancreatic lesion remained questionable. Conversely angiography located the pancreatic tumour but the adrenal findings were subtle. (orig.)

Cell-mediated immunity in herpes simplex virus-infected mice: functional analysis of lymph node cells during periods of acute and latent infection, with reference to cytotoxic and memory cells.

Science.gov (United States)

Nash, A A; Quartey-Papafio, R; Wildy, P

1980-08-01

The functional characteristics of lymphoid cells were investigated during acute and latent infection of mice with herpes simplex virus (HSV). Cytotoxic T cells were found in the draining lymph node (DLN) 4 days p.i. and had reached maximum activity between 6 and 9 days. After the 12th day and during the period of latent infection (> 20 days) no cytotoxic cell activity was observed. Cytotoxic activity could only be detected when the lymphoid cells had been cultured for a period of 3 days. In general, the cell killing was specific for syngeneic infected target cells, although some killing of uninfected targets was observed. In contrast to the cytotoxic response, DLN cells responding to HSV in a proliferation assay were detected towards the end of the acute phase and at lease up to 9 months thereafter. The significance of these observations for the pathogenesis of HSV is discussed.

Early and late endocrine effects in pediatric central nervous system diseases.

Science.gov (United States)

Aslan, Ivy R; Cheung, Clement C

2014-01-01

Endocrinopathies are frequently linked to central nervous system disease, both as early effects prior to the disease diagnosis and/or late effects after the disease has been treated. In particular, tumors and infiltrative diseases of the brain and pituitary, such as craniopharyngioma, optic pathway and hypothalamic gliomas, intracranial germ cell tumor, and Langerhans cell histiocytosis, can present with abnormal endocrine manifestations that precede the development of neurological symptoms. Early endocrine effects include diabetes insipidus, growth failure, obesity, and precocious or delayed puberty. With improving prognosis and treatment of childhood brain tumors, many survivors experience late endocrine effects related to medical and surgical interventions. Chemotherapeutic agents and radiation therapy can affect the hypothalamic-pituitary axes governing growth, thyroid, gonadal, and adrenal function. In addition, obesity and metabolic alterations are frequent late manifestations. Diagnosing and treating both early and late endocrine manifestations can dramatically improve the growth, well-being, and quality of life of patients with childhood central nervous system diseases.

Cytotoxic glucosphingolipid from Celtis Africana.

Science.gov (United States)

Perveen, Shagufta; Al-Taweel, Areej Mohammad; Fawzy, Ghada Ahmed; El-Shafae, Azza Muhammed; Khan, Afsar; Proksch, Peter

2015-05-01

Literature survey proved the use of the powdered sun-dried bark and roots of Celtis africana for the treatment of cancer in South Africa. The aim of this study was to do further isolation work on the ethyl acetate fraction and to investigate the cytotoxic activities of the various fractions and isolated compound. Cytotoxicity of petroleum ether, chloroform, ethyl acetate, n-butanol fractions and compound 1 were tested on mouse lymphoma cell line L5178Y using the microculture tetrazolium assay. One new glucosphingolipid 1 was isolated from the aerial parts of C. africana. The structure of the new compound was determined by extensive analysis by one-dimensional and two-dimensional nuclear magnetic resonance spectroscopy and mass spectrometry. The ethyl acetate fraction and compound 1 showed strong cytotoxic activity with an EC50 value of 8.3 μg/mL and 7.8 μg/mL, respectively, compared with Kahalalide F positive control (6.3 μg/mL). This is the first report of the occurrence of a cytotoxic glucosphingolipid in family Ulmaceae.

Barriers to and facilitative processes of endocrine therapy adherence among women with breast cancer.

Science.gov (United States)

Bright, Emma E; Petrie, Keith J; Partridge, Ann H; Stanton, Annette L

2016-07-01

The treatment of chronic illness, and the prevention of disease progression and recurrence, often involve long-term adherence to prescription medications in breast cancer. Despite the survival benefit of endocrine therapies, nonadherence remains high. In this study, we examined barriers to and facilitators of endocrine therapy adherence among women with breast cancer (n = 1371). Participants currently taking tamoxifen or aromatase inhibitors were recruited from Dr. Susan Love Research Foundation's Army of Women(®) Registry. Participants responded online to open-ended and close-ended questions about thoughts, feelings, and behaviors relevant to endocrine therapy. Two weeks later, women were invited to complete a second online questionnaire regarding current endocrine therapy adherence. Approximately one-third (36 %) of participants reported the presence of factors that make endocrine therapy difficult; reporting any barrier to medication adherence was significantly associated with nonadherence (P adhere and the use of cognitive self-talk (e.g., thoughts regarding endocrine therapy efficacy) was related to higher adherence. Hierarchical linear regressions revealed a significant behavioral barrier × behavioral facilitator interaction (P behavioral barrier in the absence of a behavioral facilitator reported the lowest adherence. Findings suggest that a sizeable minority of women face barriers to taking endocrine therapy, which are associated with nonadherence.

Phytochemicals for taming agitated immune-endocrine-neural axis.

Science.gov (United States)

Patel, Seema

2017-07-01

Homeostasis of immune-endocrine-neural axis is paramount for human health. If this axis gets agitated due to age, genetic variations, environmental exposures or lifestyle assaults, a cascade of adverse reactions occurs in human body. Cytokines, hormones and neurotransmitters, the effector molecules of this axis behave erratically, leading to a gamut of neural, endocrine, autoimmune, and metabolic diseases. Current panel of drugs can tackle some of them but not in a sustainable, benign way as a myriad of side effects, causal of them have been documented. In this context, phytochemicals, the secondary metabolites of plants seem beneficial. These bioactive constituents encompassing polyphenols, alkaloids, flavonoids, terpenoids, tannins, lignans, stilbenoids (resveratrol), saponins, polysaccharides, glycosides, and lectins etc. have been proven to exert antioxidant, anti-inflammatory, hypolipidemic, hypotensive, antidiabetic, anticancer, immunomodulatory, anti-allergic, analgesic, hepatoprotective, neuroprotective, dermatoprotective, and antimicrobial properties, among a litany of other biological effects. This review presents a holistic perspective of common afflictions resultant of immune-endocrine-neural axis disruption, and the phytochemicals capable of restoring their normalcy and mitigating the ailments. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Addressing the Immunogenicity of the Cargo and of the Targeting Antibodies with a Focus on Deimmunized Bacterial Toxins and on Antibody-Targeted Human Effector Proteins

OpenAIRE

Grinberg, Yehudit; Benhar, Itai

2017-01-01

Third-generation immunotoxins are composed of a human, or humanized, targeting moiety, usually a monoclonal antibody or an antibody fragment, and a non-human effector molecule. Due to the non-human origin of the cytotoxic domain, these molecules stimulate potent anti-drug immune responses, which limit treatment options. Efforts are made to deimmunize such immunotoxins or to combine treatment with immunosuppression. An alternative approach is using the so-called ?human cytotoxic fusion protein...

Augmented simvastatin cytotoxicity using optimized lipid nanocapsules: a potential for breast cancer treatment.

Science.gov (United States)

Safwat, Sally; Hathout, Rania M; Ishak, Rania A; Mortada, Nahed D

2017-03-01

We noticed paucity in exploiting solutol-based lipid nanocapsules in statins formulations though they carry all favorable properties that are needed for cancer passive targeting such as their small particle size, stealth properties, ability to highly accommodate lipophilic drugs, good internalization and P-gp pump inhibition. The aim of this study was to design and optimize new simvastatin drug delivery systems; lipid nanocapsules intended for administration through the intravenous route as potential treatment for breast cancer. Optimized nanocapsules were prepared by the phase-inversion method according to a D-optimal mixture design, characterized and assessed for their cytotoxicity. Three successful models for particle size, polydispersity index (PDI) and percentage of drug released after 48 h were generated. The prepared lipid nanocapsules acquired spherical and homogenous morphology, good stability and tolerance to sterilization. The obtained release profiles demonstrated desired sustained release pattern. Furthermore, testing selected formulations on human breast cancer adenocarcinoma cells showed augmented cytotoxicity of simvastatin reaching low IC50 values as 1.4 ± 0.02 μg/ml compared to the pure drug. The proposed lipid nanocapsules pose promising candidates as simvastatin carriers intended for the targeting of breast cancer.

Rapid analysis for 567 pesticides and endocrine disrupters by GC/MS using deconvolution reporting software

Energy Technology Data Exchange (ETDEWEB)

Wylie, P.; Szelewski, M.; Meng, Chin-Kai [Agilent Technologies, Wilmington, DE (United States)

2004-09-15

More than 700 pesticides are approved for use around the world, many of which are suspected endocrine disrupters. Other pesticides, though no longer used, persist in the environment where they bioaccumulate in the flora and fauna. Analytical methods target only a subset of the possible compounds. The analysis of food and environmental samples for pesticides is usually complicated by the presence of co-extracted natural products. Food or tissue extracts can be exceedingly complex matrices that require several stages of sample cleanup prior to analysis. Even then, it can be difficult to detect trace levels of contaminants in the presence of the remaining matrix. For efficiency, multi-residue methods (MRMs) must be used to analyze for most pesticides. Traditionally, these methods have relied upon gas chromatography (GC) with a constellation of element-selective detectors to locate pesticides in the midst of a variable matrix. GC with mass spectral detection (GC/MS) has been widely used for confirmation of hits. Liquid chromatography (LC) has been used for those compounds that are not amenable to GC. Today, more and more pesticide laboratories are relying upon LC with mass spectral detection (LC/MS) and GC/MS as their primary analytical tools. Still, most MRMs are target compound methods that look for a small subset of the possible pesticides. Any compound not on the target list is likely to be missed by these methods. Using the techniques of retention time locking (RTL) and RTL database searching together with spectral deconvolution, a method has been developed to screen for 567 pesticides and suspected endocrine disrupters in a single GC/MS analysis. Spectral deconvolution helps to identify pesticides even when they co-elute with matrix compounds while RTL helps to eliminate false positives and gives greater confidence in the results.

Endocrine system on chip for a diabetes treatment model.

Science.gov (United States)

Nguyen, Dao Thi Thuy; van Noort, Danny; Jeong, In-Kyung; Park, Sungsu

2017-02-21

The endocrine system is a collection of glands producing hormones which, among others, regulates metabolism, growth and development. One important group of endocrine diseases is diabetes, which is caused by a deficiency or diminished effectiveness of endogenous insulin. By using a microfluidic perfused 3D cell-culture chip, we developed an 'endocrine system on chip' to potentially be able to screen drugs for the treatment of diabetes by measuring insulin release over time. Insulin-secreting β-cells are located in the pancreas, while L-cells, located in the small intestines, stimulate insulin secretion. Thus, we constructed a co-culture of intestinal-pancreatic cells to measure the effect of glucose on the production of glucagon-like peptide-1 (GLP-1) from the L-cell line (GLUTag) and insulin from the pancreatic β-cell line (INS-1). After three days of culture, both cell lines formed aggregates, exhibited 3D cell morphology, and showed good viability (>95%). We separately measured the dynamic profile of GLP-1 and insulin release at glucose concentrations of 0.5 and 20 mM, as well as the combined effect of GLP-1 on insulin production at these glucose concentrations. In response to glucose stimuli, GLUTag and INS-1 cells produced higher amounts of GLP-1 and insulin, respectively, compared to a static 2D cell culture. INS-1 combined with GLUTag cells exhibited an even higher insulin production in response to glucose stimulation. At higher glucose concentrations, the diabetes model on chip showed faster saturation of the insulin level. Our results suggest that the endocrine system developed in this study is a useful tool for observing dynamical changes in endocrine hormones (GLP-1 and insulin) in a glucose-dependent environment. Moreover, it can potentially be used to screen GLP-1 analogues and natural insulin and GLP-1 stimulants for diabetes treatment.

Childhood obesity and endocrine disrupting chemicals

Directory of Open Access Journals (Sweden)

Jin Taek Kim

2017-12-01

Full Text Available The prevalence of obesity around the world has increased sharply. Strong evidence has emerged over the last decades that human exposure to numerous endocrine disrupting chemicals (EDCs is the cause of obesity and obesity-related metabolic diseases. Many EDCs are manmade chemicals that are released into the environment. EDCs are exogenous compounds that interfere with hormonal regulation and normal endocrine systems, thereby affecting the health of animals and humans. The number of chemicals belonging to EDCs is increasing and some of them are very stable; they persist in the environment (persistent organic pollutants. Although they are banned, their concentrations have been continuously increasing over time. This review gives a brief introduction to common EDCs, and evidence of harmful effects of EDCs on obesity-related diseases; we focus in particular on EDCs’ role in causing mitochondrial dysfunction.

Neurobehavioral endocrine regulation of small mammal populations

International Nuclear Information System (INIS)

Christian, J.J.

1978-01-01

A brief review is given of the hypothesis that density-dependent behavioral-endocrine negative feedbacks can regulate and often limit the growth of populations of many species of small mammals. Recent laboratory studies are summarized that show how stress, particularly psychogenic, which results in increased adrenocortical secretion also alters gonadotropin secretion and inhibits reproduction. Chronic stress due to crowding, immobilization, et al. inhibits the release of LH and FSH, particularly by abolishing the pulsatile release of LH, and also causes a rise in prolactin (at least acutely). Stimulation of the hypothalamo-pituitary-adrenocortical system is accompanied by an inversely proportional inhibition of growth hormone secretion. Decreasing photoperiod enhances the sensitivity of the hypothalamus to inhibition of gonadotropin secretion by androgens and estrogens. Other endocrine responses to increased density or subordinate social rank also are summarized. How these facts fit into the negative feedback scheme is discussed, including the greatly prolonged effects of diminished lactation. The changed quality of the animals associated with changes in density discussed by Lidicker also can be explained by the above responses to density. Data on changes in growth and reproductive function which are consistent with the behavioral-endocrine feedback hypothesis are presented for several populations of small mammals, including some previously unpublished data for Microtus pennsylvanicus

Activation of phosphoinositide 3-kinase/Akt/mechanistic target of rapamycin pathway and response to everolimus in endocrine receptor-positive metastatic breast cancer – A retrospective pilot analysis and viewpoint

Directory of Open Access Journals (Sweden)

Jyoti Bajpai

2017-01-01

Full Text Available Introduction: Biomarkers predictive of response to mechanistic target of rapamycin (mTOR inhibitor, everolimus, in endocrine receptor (ER-positive metastatic breast cancer (MBC are a work in progress. We evaluated the feasibility of directly measuring mTOR activity and phosphatase and tensin homolog (PTEN expression and correlating their expression with response and survival. Materials and Methods: MBC patients who received everolimus with endocrine therapy (ET after progression on an aromatase inhibitor and had adequate tissue preservation for estimation of mTOR activity and PTEN expression were selected for analysis from a prospectively maintained database. Progression-free survival (PFS and overall survival (OS were estimated by Kaplan–Meier method, and correlation between mTOR activity and PTEN expression with survival was done by log-rank test. Results: Thirteen ER-positive MBC patients were available for analysis. PTEN expression was lost in 11/13 (84.6% patients and retained in 2/13 patients (15.4%. mTOR activity was absent in four patients (30.7%, weak in six patients (46.1%, and moderate in 3 patients (23.2%. Median PFS for the entire population was 2.5 months while median OS was not reached. Patients with an absent mTOR activity showed a longer PFS (5 vs. 1.5 vs. 2 months than those with weak and moderate activity, respectively (P = 0.043. There was no correlation between loss of PTEN expression and PFS. Conclusions: Measurement of direct mTOR activity in patients with MBC receiving everolimus/ET combination appears feasible. Absent mTOR activity may predict for longer PFS with everolimus-ET combination and requires further study.

Cancer therapy leading to state of cancer metabolism depression for efficient operation of small dosage cytotoxic drugs

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Ponizovskiy MR

2015-04-01

Full Text Available “Prolonged medical starvation” as the method of cancer therapy was borrowed from folk healers Omelchenko A and Breuss R. Author was convinced in efficiency of this method of cancer treatment via examination of cured patients and on own experience. The mechanism of this method of cancer therapy operates via Warburg effect targeting that promotes efficient cancer treatment with small cytotoxic drugs. Just it was described the mechanism of Warburg effect as well as mechanism transmutation of mitochondrial function in cancer metabolism which are exhibited in connection with operation of described method cancer therapy. There were described the biochemical and biophysical mechanisms of formations resistance to some cytotoxic drugs and recurrence cancer disease after disease remission which occur sometimes as result of treatment with great dosage of cytotoxic drugs. Also it was described the benefits of use the method “Prolonged medical starvation” with decreased dosage of cytotoxic drugs for cancer treatment. The significance of this work that it was substantiated the mechanism operation of combination “Prolonged medical starvation” with small dosages cytotoxic drugs of cancer treatment, which mechanism leads to prevention recurrence cancer disease and resistance to anticancer drugs in comparison with intensive anticancer chemotherapy with great dosages of cytotoxic drugs in cancer therapy. Also the offered concepts of cancer therapy mechanism gave possibility to explain mechanisms of some results of experiments eliminating the doubts of the authors these experiments.

Radiotherapy of endocrine orbitopathy

International Nuclear Information System (INIS)

Weischedel, U.; Wieland, C.

1985-01-01

After a review of the history and a discussion of recent theories about pathogenesis of endocrine ophthalmopathy the authros give a report on their radiotherapeutical treatment results with cobalt-60-γ-rays in 50 patients. Amelioration was achieved in 50% of the cases, in the other 50% no progression was seen. Radiotherapy is of antiphlogistic and functional effectivity and should be integrated in the treatment regime in early stages. (orig.) [de

Lymphocyte cytotoxicity induced by preincubation with serum from patients with Hashimoto thyroiditis

Science.gov (United States)

Calder, Elizabeth A.; McLeman, Dena; Irvine, W. J.

1973-01-01

Lymphocytes from healthy donors were incubated with serum samples from nine patients with Hashimoto thyroiditis and subsequently shown to be cytotoxic to chicken red blood cells (Ch. RBC) coated with thyroglobulin. Target cell death was estimated using a standard 51Cr release assay system. Lymphocytes pre-incubated with Hashimoto serum caused a mean% 51Cr release of 13·11±2·83 (SEM) from thyroglobulin-coated Ch. RBC and a mean% 51Cr release of 1·22±0·65 from uncoated Ch. RBC. Untreated lymphocytes caused no significant isotope release from either uncoated or thyroglobulin coated target cells. PMID:4800956

Filling and mining the reactive metabolite target protein database.

Science.gov (United States)

Hanzlik, Robert P; Fang, Jianwen; Koen, Yakov M

2009-04-15

The post-translational modification of proteins is a well-known endogenous mechanism for regulating protein function and activity. Cellular proteins are also susceptible to post-translational modification by xenobiotic agents that possess, or whose metabolites possess, significant electrophilic character. Such non-physiological modifications to endogenous proteins are sometimes benign, but in other cases they are strongly associated with, and are presumed to cause, lethal cytotoxic consequences via necrosis and/or apoptosis. The Reactive Metabolite Target Protein Database (TPDB) is a searchable, freely web-accessible (http://tpdb.medchem.ku.edu:8080/protein_database/) resource that attempts to provide a comprehensive, up-to-date listing of known reactive metabolite target proteins. In this report we characterize the TPDB by reviewing briefly how the information it contains came to be known. We also compare its information to that provided by other types of "-omics" studies relevant to toxicology, and we illustrate how bioinformatic analysis of target proteins may help to elucidate mechanisms of cytotoxic responses to reactive metabolites.

Molecular strategies targeting the host component of cancer to enhance tumor response to radiation therapy

International Nuclear Information System (INIS)

Kim, Dong Wook; Huamani, Jessica; Fu, Allie; Hallahan, Dennis E.

2006-01-01

The tumor microenvironment, in particular, the tumor vasculature, as an important target for the cytotoxic effects of radiation therapy is an established paradigm for cancer therapy. We review the evidence that the phosphoinositide 3-kinase (PI3K)/Akt pathway is activated in endothelial cells exposed to ionizing radiation (IR) and is a molecular target for the development of novel radiation sensitizing agents. On the basis of this premise, several promising preclinical studies that targeted the inhibition of the PI3K/Akt activation as a potential method of sensitizing the tumor vasculature to the cytotoxic effects of IR have been conducted. An innovative strategy to guide cytotoxic therapy in tumors treated with radiation and PI3K/Akt inhibitors is presented. The evidence supports a need for further investigation of combined-modality therapy that involves radiation therapy and inhibitors of PI3K/Akt pathway as a promising strategy for improving the treatment of patients with cancer

A comprehensive review of regulatory test methods for endocrine adverse health effects.

Science.gov (United States)

Manibusan, M K; Touart, L W

2017-07-01

Development of new endocrine disruption-relevant test methods has been the subject of intensive research efforts for the past several decades, prompted in part by mandates in the 1996 Food Quality Protection Act (FQPA). While scientific understanding and test methods have advanced, questions remain on whether current scientific methods are capable of adequately addressing the complexities of the endocrine system for regulatory health and ecological risk assessments. The specific objective of this article is to perform a comprehensive, detailed evaluation of the adequacy of current test methods to inform regulatory risk assessments of whether a substance has the potential to perturb endocrine-related pathways resulting in human adverse effects. To that end,  approximately 42 existing test guidelines (TGs) were considered in the evaluation of coverage for endocrine-related adverse effects. In addition to evaluations of whether test methods are adequate to capture endocrine-related effects, considerations of further enhancements to current test methods, along with the need to develop novel test methods to address existing test method gaps are described. From this specific evaluation, up to 35 test methods are capable of informing whether a chemical substance perturbs known endocrine related biological pathways. Based on these findings, it can be concluded that current validated test methods are adequate to discern substances that may perturb the endocrine system, resulting in an adverse health effect. Together, these test methods predominantly form the core data requirements of a typical food-use pesticide registration submission. It is recognized, however, that the current state of science is rapidly advancing and there is a need to update current test methods to include added enhancements to ensure continued coverage and public health and environmental protection.

Role of endocrine-genotoxic switchings in cancer and other human diseases: basic triad.

Science.gov (United States)

Berstein, Lev M

2008-01-01

Cancer is one of the leading causes of human death and belongs to the group of main chronic noncommunicable diseases (NCD). Certain specific features ofNCD have raised the concept of 'normal' and 'successful' aging. The apparent paradox of simultaneous increase with aging of the diseases connected with estrogen deficiency as well as with estrogenic excess can be explained by the existence of the phenomenon of the switching of estrogen effects. An isolated or combined with the weakening of hormonal effect increase in genotoxic action of estrogens can modify the course ofage-associated pathology. In particular, such changes in estrogen effect may alter the biology of tumors to make them less favorable/more aggressive. Two other endocrine-genotoxic switchings (EGS) involving phenomena ofJanus (dual) function of glucose and adipogenotoxicosis may produce similar influences on tumor and other NCD biology. These three phenomena form a'basic triad' and can act independently of each other or in concert. EGS and their inductors may serve as targets for prevention and, probably, treatment of main noncommunicable diseases. The measures to correct components of the 'triad' can be divided into several groups aimed to optimally orchestrate the balance between endocrine and DNA-damagingeffects of estrogens, glucose and adipose tissue-related factors.

Poly(3-hydroxybutyrate-co-R-3-hydroxyhexanoate) nanoparticles with polyethylenimine coat as simple, safe, and versatile vehicles for cell targeting

DEFF Research Database (Denmark)

Wu, Linping; Wang, Danyang; Parhamifar, Ladan

2014-01-01

A simple and highly safe poly(3-hydroxybutyrate-co-R-3-hydroxyhexanoate) nanoparticulate delivery system that targets different cell types is developed. A sub-cytotoxic level of polyethylenimine coat mediates universal cell targeting. Internalized nanoparticles traffic along endolysosomal compart...... compartments, endoplasmic reticulum and the Golgi complex. Nanoparticles have no detrimental effects on cell morphology and respiration.......A simple and highly safe poly(3-hydroxybutyrate-co-R-3-hydroxyhexanoate) nanoparticulate delivery system that targets different cell types is developed. A sub-cytotoxic level of polyethylenimine coat mediates universal cell targeting. Internalized nanoparticles traffic along endolysosomal...

In vitro cytotoxic and in silico activity of piperine isolated from Piper nigrum fruits Linn.

Science.gov (United States)

Paarakh, Padmaa M; Sreeram, Dileep Chandra; D, Shruthi S; Ganapathy, Sujan P S

2015-12-01

Piper nigrum [Piperaceae], commonly known as black pepper is used as medicine fairly throughout the greater part of India and as a spice globally. To isolate piperine and evaluate in vitro cytotoxic [antiproliferative] activity and in silico method. Piperine was isolated from the fruits of P.nigrum. Piperine was characterized by UV,IR, (1)H-NMR, (13)C-NMR and Mass spectrum. Standardization of piperine was done also by HPTLC fingerprinting. In vitro cytotoxic activity was done using HeLa cell lines by MTT assay at different concentrations ranging from 20 to 100 μg/ml in triplicate and in silico docking studies using enzyme EGFR tyrosine kinase. Fingerprinting of isolated piperine were done by HPTLC method. The IC50 value was found to be 61.94 ± 0.054 μg/ml in in vitro cytotoxic activity in HeLa Cell lines. Piperine was subjected to molecular docking studies for the inhibition of the enzyme EGFR tyrosine kinase, which is one of the targets for inhibition of cancer cells. It has shown -7.6 kJ mol(-1) binding and 7.06 kJ mol(-1) docking energy with two hydrogen bonds. piperine has shown to possess in vitro cytotoxic activity and in silico studies.

Development and application of QSAR models for mechanisms related to endocrine disruption

DEFF Research Database (Denmark)

Abildgaard Rosenberg, Sine

Humans are daily exposed to a wide variety of man-made chemicals through food, consumer products, water, air inhalation etc. For the main part of these chemicals no or only very limited information is available on their potential to cause endocrine disruption. Traditionally such information has...... is a background section, comprising 1) an introduction to the endocrine system with a focus on thyroid hormones (THs) and their essential function in neurodevelopment as well as a description of how chemicals may interference with endocrine mechanisms and cause adverse effects, 2) an introduction to the applied...

Radiologic features of cystic, endocrine and other pancreatic neoplasms

International Nuclear Information System (INIS)

Balci, N. Cem; Semelka, Richard C.

2001-01-01

This article presents imaging features of cystic, endocrine and other pancreatic neoplasms. Microcystic adenoma which is composed of small cysts ( 2 cm) are accounted for mucinous cystic neoplasms, its variant along pancreatic duct is ductectatic mucinous cystic neoplasm. Endocrine tumors of pancreas are hypervascular and can be depicted on early dynamic enhanced crosssectional imaging modalities or on angiography when they are <1 cm. Pancreatic metastases and lymphomas are rare neoplasms which should also be included in differential diagnosis for pancreatic masses

X-Ray semiotics of cranial involvement in endocrine diseases

International Nuclear Information System (INIS)

Spuzyak, M.I.; Kramnoj, I.E.; Belaya, L.M.; Tyazhelova, O.V.; Litvinenko, V.M.

1992-01-01

The incidence and type of X-ray semeiotics of the skull involvement were studied in 703 patients with endocrine diseases. Craniorgam analysis involved study of the thickness and structure of the vault bones, shape and size of the skull, status of the sutures, internal plate relief, changes of the base of the skull, of the sella turcica first of all, and facial bone. The characteristic X-ray symprom complexes of the involvement of the skull in some endocrine diseases were distinguished

Cytotoxic Effects of Bangladeshi Medicinal Plant Extracts

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Shaikh J. Uddin

2011-01-01

Full Text Available To investigate the cytotoxic effect of some Bangladeshi medicinal plant extracts, 16 Bangladeshi medicinal plants were successively extracted with n-hexane, dichloromethane, methanol and water. The methanolic and aqueous extracts were screened for cytotoxic activity against healthy mouse fibroblasts (NIH3T3 and three human cancer-cell lines (gastric: AGS; colon: HT-29; and breast: MDA-MB-435S using the MTT assay. Two methanolic extracts (Hygrophila auriculata and Hibiscus tiliaceous and one aqueous extract (Limnophila indica showed no toxicity against healthy mouse fibroblasts, but selective cytotoxicity against breast cancer cells (IC50 1.1–1.6 mg mL−1. Seven methanolic extracts from L. indica, Clerodendron inerme, Cynometra ramiflora, Xylocarpus moluccensis, Argemone mexicana, Ammannia baccifera and Acrostichum aureum and four aqueous extracts from Hygrophila auriculata, Bruguiera gymnorrhiza, X. moluccensis and Aegiceras corniculatum showed low toxicity (IC50 > 2.5 mg mL−1 against mouse fibroblasts but selective cytotoxicity (IC50 0.2–2.3 mg mL−1 against different cancer cell lines. The methanolic extract of Blumea lacera showed the highest cytotoxicity (IC50 0.01–0.08 mg mL−1 against all tested cell lines among all extracts tested in this study. For some of the plants their traditional use as anticancer treatments correlates with the cytotoxic results, whereas for others so far unknown cytotoxic activities were identified.

Central control of glucose homeostasis: the brain--endocrine pancreas axis.

Science.gov (United States)

Thorens, B

2010-10-01

A large body of data gathered over the last decades has delineated the neuronal pathways that link the central nervous system with the autonomic innervation of the endocrine pancreas, which controls alpha- and beta-cell secretion activity and mass. These are important regulatory functions that are certainly keys for preserving the capacity of the endocrine pancreas to control glucose homeostasis over a lifetime. Identifying the cells involved in controlling the autonomic innervation of the endocrine pancreas, in response to nutrient, hormonal and environmental cues and how these cues are detected to activate neuronal activity are important goals of current research. Elucidation of these questions may possibly lead to new means for preserving or restoring defects in insulin and glucagon secretion associated with type 2 diabetes. Copyright © 2010 Elsevier Masson SAS. All rights reserved.

The international spinal cord injury endocrine and metabolic function basic data set

DEFF Research Database (Denmark)

Bauman, W A; Biering-Sørensen, Fin; Krassioukov, A

2011-01-01

To develop the International Spinal Cord Injury (SCI) Endocrine and Metabolic Function Basic Data Set within the framework of the International SCI Data Sets that would facilitate consistent collection and reporting of basic endocrine and metabolic findings in the SCI population....

Changes in serum adhesion molecules, chemokines, cytokines, and tissue remodeling factors in euthyroid women without thyroid antibodies who are at risk for autoimmune thyroid disease: a hypothesis on the early phases of the endocrine autoimmune reaction

NARCIS (Netherlands)

Beumer, Wouter; Effraimidis, Grigoris; Drexhage, Roosmarijn C.; Wiersinga, Wilmar M.; Drexhage, Hemmo A.

2013-01-01

The target glands in spontaneous animal models of endocrine autoimmune disease show, prior to the autoimmune reaction, growth and connective tissue abnormalities, whereas the autoimmune reaction is initiated by an early accumulation of macrophages and dendritic cells in the target glands. The aim of

Integrin Targeting and Toxicological Assessment of Peptide-Conjugated Liposome Delivery Systems to Activated Endothelial Cells

DEFF Research Database (Denmark)

Kermanizadeh, Ali; Villadsen, Klaus; Østrem, Ragnhild Garborg

2017-01-01

constructed with the aim of targeting integrins (i.e. vitronectin and/or fibronectin receptors) on activated endothelial cells. The peptide-conjugated liposomes induced only cytotoxicity at the highest concentration in non-activated or activated endothelial cells, as well as in co-culture of endothelial cells...... and macrophages. There was unaltered secretion of cytokines following exposure of peptide-conjugated liposomes to endothelial cells, indicating that the materials were not inflammogenic. Liposomes with a peptide targeting the fibronectin receptor (integrin α5β1) were more effective in targeting of activated....... Therefore, this study demonstrates the feasibility of constructing a peptide-conjugated cationic liposome, which displays targeting to activated endothelial cells at concentrations that are not cytotoxic or inflammogenic to the cells....

Cysteine Cathepsins as Regulators of the Cytotoxicity of NK and T Cells

Science.gov (United States)

Perišić Nanut, Milica; Sabotič, Jerica; Jewett, Anahid; Kos, Janko

2014-01-01

Cysteine cathepsins are lysosomal peptidases involved at different levels in the processes of the innate and adaptive immune responses. Some, such as cathepsins B, L, and H are expressed constitutively in most immune cells. In cells of innate immunity they play a role in cell adhesion and phagocytosis. Other cysteine cathepsins are expressed more specifically. Cathepsin X promotes dendritic cell maturation, adhesion of macrophages, and migration of T cells. Cathepsin S is implicated in major histocompatibility complex class II antigen presentation, whereas cathepsin C, expressed in cytotoxic T lymphocytes and natural killer (NK) cells, is involved in processing pro-granzymes into proteolytically active forms, which trigger cell death in their target cells. The activity of cysteine cathepsins is controlled by endogenous cystatins, cysteine protease inhibitors. Of these, cystatin F is the only cystatin that is localized in endosomal/lysosomal vesicles. After proteolytic removal of its N-terminal peptide, cystatin F becomes a potent inhibitor of cathepsin C with the potential to regulate pro-granzyme processing and cell cytotoxicity. This review is focused on the role of cysteine cathepsins and their inhibitors in the molecular mechanisms leading to the cytotoxic activity of T lymphocytes and NK cells in order to address new possibilities for regulation of their function in pathological processes. PMID:25520721

Suppression of cytotoxic T lymphocytes by carrageenan-activated macrophage-like cells

International Nuclear Information System (INIS)

Yung, Y.P.; Cudkowicz, G.

1978-01-01

In the presence of 100 μg/ml of carrageenans (CAR), B6D2F 1 responder spleen cells failed to generate antiparent or anti-allogeneic cytotoxic T lymphocytes in vitro, but instead generated suppressor cells. Cultured CAR-treated cells added to mixtures of B6D2F 1 anti-B6 or B6D2F 1 anti-C3H cytotoxic effectors (induced in vitro) and the appropriate 51 Cr-labeled lymphoma targets reduced or abolished cytolysis (measured as 51 Cr release) depending on the ratio of suppressor to effector cells. Cultured spleen cells not exposed to CAR failed to inhibit both types of cytotoxicity. Presuppressor cells were associated with a splenic subpopulation independent of the thymus (i.e., present in spleens of athymic nude mice), were moderately adherent to Sephadex G-10 columns, but were not phagocytic or ''sticky'' to carbonyl iron particles. Activation of such cells by CAR was not prevented by in vitro exposure to 2000 rads of γ-rays before culture, nor facilitated by antigenic stimulation. The matured suppressor cells remained radioresistant and became strongly adherent to Sephadex G-10. The suppressors lacked surface Thy-1 alloantigen detectable by antibody and rabbit complement. Suppressor cell activity was not restricted by the immunologic specificity and major histocompatibility type of effectors

Targeting Antibacterial Agents by Using Drug-Carrying Filamentous Bacteriophages

Science.gov (United States)

Yacoby, Iftach; Shamis, Marina; Bar, Hagit; Shabat, Doron; Benhar, Itai

2006-01-01

Bacteriophages have been used for more than a century for (unconventional) therapy of bacterial infections, for half a century as tools in genetic research, for 2 decades as tools for discovery of specific target-binding proteins, and for nearly a decade as tools for vaccination or as gene delivery vehicles. Here we present a novel application of filamentous bacteriophages (phages) as targeted drug carriers for the eradication of (pathogenic) bacteria. The phages are genetically modified to display a targeting moiety on their surface and are used to deliver a large payload of a cytotoxic drug to the target bacteria. The drug is linked to the phages by means of chemical conjugation through a labile linker subject to controlled release. In the conjugated state, the drug is in fact a prodrug devoid of cytotoxic activity and is activated following its dissociation from the phage at the target site in a temporally and spatially controlled manner. Our model target was Staphylococcus aureus, and the model drug was the antibiotic chloramphenicol. We demonstrated the potential of using filamentous phages as universal drug carriers for targetable cells involved in disease. Our approach replaces the selectivity of the drug itself with target selectivity borne by the targeting moiety, which may allow the reintroduction of nonspecific drugs that have thus far been excluded from antibacterial use (because of toxicity or low selectivity). Reintroduction of such drugs into the arsenal of useful tools may help to combat emerging bacterial antibiotic resistance. PMID:16723570

CONTAMINANT-ASSOCIATED ENDOCRINE DISRUPTION IN REPTILES.

Science.gov (United States)

The data presented suggest that contaminants can alter the endocrine and reproductive system of reptiles by mimicking hormones and by various mechanisms other than direct hormonal mimicry. However, these data indicate, as do many other studies using various vertebrates, that a fo...

Diabetic and endocrine emergencies

OpenAIRE

Kearney, T; Dang, C

2007-01-01

Endocrine emergencies constitute only a small percentage of the emergency workload of general doctors, comprising about 1.5% of all hospital admission in England in 2004–5. Most of these are diabetes related with the remaining conditions totalling a few hundred cases at most. Hence any individual doctor might not have sufficient exposure to be confident in their management. This review discusses the management of diabetic ketoacidosis, hyperosmolar hyperglycaemic state, hypoglycaemia, hyperca...

Endocrine profiles and neuropsychologic correlates of functional hypothalamic amenorrhea in adolescents.

Science.gov (United States)

Bomba, Monica; Gambera, Alessandro; Bonini, Luisa; Peroni, Maria; Neri, Francesca; Scagliola, Pasquale; Nacinovich, Renata

2007-04-01

To determine trigger factors and neuropsychologic correlates of functional hypothalamic amenorrhea (FHA) in adolescence and to evaluate the correlations with the endocrine-metabolic profile. Cross-sectional comparison of adolescents with FHA and eumenorrheic controls Academic medical institution Twenty adolescent girls with FHA (aged <18 years) and 20 normal cycling girls All subjects underwent endocrine-gynecologic (hormone) and neuropsychiatric (tests and interview) investigations. A separate semistructured interview was also used to investigate parents. Gonadotropins, leptin, prolactin, androgens, estrogens, cortisol, carrier proteins (SHBG, insulin-like growth factor-binding protein 1), and metabolic parameters (insulin, insulin-like growth factor 1, thyroid hormones) were assayed in FHA and control subjects. All girls were evaluated using a test for depression, a test for disordered eating, and a psychodynamic semistructured interview. Adolescents with FHA showed a particular susceptibility to common life events, restrictive disordered eating, depressive traits, and psychosomatic disorders. The endocrine-metabolic profile was strictly correlated to the severity of the psychopathology. Functional hypothalamic amenorrhea in adolescence is due to a particular neuropsychologic vulnerability to stress, probably related to familial relationship styles, expressed by a proportional endocrine impairment.

Fluorine-Containing Taxoid Anticancer Agents and Their Tumor-Targeted Drug Delivery

OpenAIRE

Seitz, Joshua; Vineberg, Jacob G.; Zuniga, Edison S.; Ojima, Iwao

2013-01-01

A long-standing problem of conventional chemotherapy is the lack of tumor-specific treatments. Traditional chemotherapy relies on the premise that rapidly proliferating cancer cells are more likely to be killed by a cytotoxic agent. In reality, however, cytotoxic agents have very little or no specificity, which leads to systemic toxicity, causing undesirable severe side effects. Consequently, various “molecularly targeted cancer therapies” have been developed for use in specific cancers, incl...

Cytotoxic constituents of ethyl acetate fraction from Dianthus superbus.

Science.gov (United States)

Ding, Chengli; Zhang, Wu; Li, Jie; Lei, Jiachuan; Yu, Jianqing

2013-01-01

The ethyl acetate fraction (EE-DS) from Dianthus superbus was found to possess the cytotoxic activity against cancer cells in previous study. To investigate cytotoxic constituents, the bioassay-guided isolation of compounds from EE-DS was performed. Two dianthramides (1 and 2), three flavonoids (3-5), two coumarins (6 and 7) and three other compounds (8-10) were obtained. Structures of isolated compounds were identified by spectroscopic analysis. Cytotoxicity of the compounds against HepG2 cells was evaluated. Compound 1 showed the strongest cytotoxicity, compounds 10, 4, 3 and 5 had moderate cytotoxicity.

Association studies in common endocrine diseases (review article

Directory of Open Access Journals (Sweden)

Akrami SM

2007-05-01

Full Text Available Our understanding of the pathogenesis of endocrine disorders increase rapidly by genetic studies at the molecular level. Common endocrine disorders such as diabetes mellitus, obesity, osteoporosis, dyslipidemia and cancer follow the multifactorial model in the genetic aspect. This review tries to clarify the approach in molecular studies of such diseases for clinicians in different specialties. How to evaluate a possible association between a single nucleotide polymorphism and an endocrinopathy or its complication is the main concern of this review. Two approaches for gene mapping will be discussed as well as main challenges regarding each approach. All such genetic studies ideally include some test of the association between genome sequence variation and the phenotype of interest such as the trait itself, the presence of a given complication, or measures of some endocrinopathy-related intermediate trait. Despite different advances in this analysis, there are major concerns regarding the overall performance and robustness of genetic association studies. By using powerful new high-throughput methods, further insights to molecular basis of such endocrine disorders can be expected. Close correlation between geneticists and clinicians can effectively bridge between basic sciences and clinical investigations.

Quantitative structure-cytotoxicity relationship of phenylpropanoid amides.

Science.gov (United States)

Shimada, Chiyako; Uesawa, Yoshihiro; Ishihara, Mariko; Kagaya, Hajime; Kanamoto, Taisei; Terakubo, Shigemi; Nakashima, Hideki; Takao, Koichi; Saito, Takayuki; Sugita, Yoshiaki; Sakagami, Hiroshi

2014-07-01

A total of 12 phenylpropanoid amides were subjected to quantitative structure-activity relationship (QSAR) analysis, based on their cytotoxicity, tumor selectivity and anti-HIV activity, in order to investigate on their biological activities. Cytotoxicity against four human oral squamous cell carcinoma (OSCC) cell lines and three human oral normal cells was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. Tumor selectivity was evaluated by the ratio of the mean CC50 (50% cytotoxic concentration) against normal oral cells to that against OSCC cell lines. Anti-HIV activity was evaluated by the ratio of CC50 to EC50 (50% cytoprotective concentration from HIV infection). Physicochemical, structural, and quantum-chemical parameters were calculated based on the conformations optimized by the LowModeMD method followed by density functional theory (DFT) method. Twelve phenylpropanoid amides showed moderate cytotoxicity against both normal and OSCC cell lines. N-Caffeoyl derivatives coupled with vanillylamine and tyramine exhibited relatively higher tumor selectivity. Cytotoxicity against normal cells was correlated with descriptors related to electrostatic interaction such as polar surface area and chemical hardness, whereas cytotoxicity against tumor cells correlated with free energy, surface area and ellipticity. The tumor-selective cytotoxicity correlated with molecular size (surface area) and electrostatic interaction (the maximum electrostatic potential). The molecular size, shape and ability for electrostatic interaction are useful parameters for estimating the tumor selectivity of phenylpropanoid amides. Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Spreeta-based biosensor for endocrine disruptors

NARCIS (Netherlands)

Marchesini, G.R.; Koopal, K.; Meulenberg, E.; Haasnoot, W.; Irth, H.

2007-01-01

The construction and performance of an automated low-cost Spreeta¿-based prototype biosensor system for the detection of endocrine disrupting chemicals (EDCs) is described. The system consists primarily of a Spreeta miniature liquid sensor incorporated into an aluminum flow cell holder, dedicated to

Ultrastructure of the midgut endocrine cells in Melipona quadrifasciata anthidioides (Hymenoptera, Apidae

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C. A. Neves

Full Text Available In this study we describe the ultrastructure of the endocrine cells observed in the midgut of M. quadrifasciata anthidioides. This bee has two types of endocrine cells, which are numerous on the posterior midgut region. Cells of the closed type are smaller and have irregular secretory granules with lower electrondensity than those of the open cell type. The open cell type has elongated mitochondria mainly on the basal area, where most of the secretory granules are also found. Besides the secretion granules and mitochondria, endocrine cells in this species have well-developed autophagic vacuoles and Golgi complex elements.

Endocrine dysfunction after total body irradiation and bone marrow transplantation

International Nuclear Information System (INIS)

Feyer, P.; Titlbach, O.; Hoffmann, F.A.; Kubel, M.; Helbig, W.; Leipzig Univ.

1989-01-01

Data regarding changes of endocrine parameters after total body irradiation (TBI) and bone marrow transplantation (BMT) are described. Endocrine glands are usually resistant to irradiation under morphological aspects. But new methods of determination and sensitive tests were developed in the last few years. Now it is possible to detect already small functional changes. Endocrine studies in the course of the disease were followed serially in 16 patients with TBI and BMT. Pretransplant conditioning consisted of single-dose irradiation combined with a high-dose, short-term chemotherapy. Reactions of the endocrine system showed a defined temporary order. Changes of ACTH and cortisol were in the beginning. The pituitary-adrenal cortex system responds in a different way. The pituitary-thyroid system develops a short-term 'low-T 3 -syndrome' reflecting the extreme stress of the organism. At the same time we obtained an increase of thyroxine. Testosterone and luteotropic hormone, the sexual steroids showed levels representing a primary gonadal insufficiency. The studies in the posttransplant period yielded a return to the normal range at most of the hormonal levels with the exception of the sexual steroids. Sterility is one of the late effects of TBI. A tendency towards hypothyroidism could be noticed in some cases being only subclinical forms. Reasons and possible therapy are discussed. (author)

The indication of endocrine therapy from the radiological view with mammary carcinoma

International Nuclear Information System (INIS)

Nadji-Esfahani, A.

1982-01-01

Important for the determining of the indication of endocrine treatment with mammary carcinoma is the pre-determination of receptors. A safe method for the choice of patients, for whom endocrine therapy would be appropriate, is not yet available. Patients who have no estrogen receptors, have as good as no chance, to be picked for endocrine therapy. The highest remission rates (around 60%) with endocrine therapy are attained when estrogen and progesterone receptors are both present, which, however, is usually only so in about one-third of the cases. Estrogen receptors are present in about 60 to 70% of the cases. With pre-menopausal women the following would be considered as endocrine procedures after switching off the ovaries: Androgens with abdominal, lung and pleura metastases; anti-estrogens (at best Tamoxifen) with abdominal and visceral metastasis; adrenalectomy with abdominal and bone metastases; and hypophyseal switching-off mostly with skeletal pains. In post-menopause estrogens are the first choice. In combination with progestogen they are indicated for abdominal and lung metastases and for carcinomatic pleura discharges. With abdominal and visceral metastasis Tamoxifen can be considered as first choice. The indications for hypophyseal switching-off, adrenalectomy and androgens are the same as for pre-menopausal women. (TRV) [de

Purinergic receptors in the endocrine and exocrine pancreas

DEFF Research Database (Denmark)

Novak, I

2008-01-01

The pancreas is a complex gland performing both endocrine and exocrine functions. In recent years there has been increasing evidence that both endocrine and exocrine cells possess purinergic receptors, which influence processes such as insulin secretion and epithelial ion transport. Most commonly......, there is also evidence for other P2 and adenosine receptors in beta cells (P2Y(2), P2Y(4), P2Y(6), P2X subtypes and A(1) receptors) and in glucagon-secreting alpha cells (P2X(7), A(2) receptors). In the exocrine pancreas, acini release ATP and ATP-hydrolysing and ATP-generating enzymes. P2 receptors...

The eye as a window to rare endocrine disorders

Science.gov (United States)

Chopra, Rupali; Chander, Ashish; Jacob, Jubbin J.

2012-01-01

The human eye, as an organ, can offer critical clues to the diagnosis of various systemic illnesses. Ocular changes are common in various endocrine disorders such as diabetes mellitus and Graves’ disease. However there exist a large number of lesser known endocrine disorders where ocular involvement is significant. Awareness of these associations is the first step in the diagnosis and management of these complex patients. The rare syndromes involving the pituitary hypothalamic axis with significant ocular involvement include Septo-optic dysplasia, Kallman's syndrome, and Empty Sella syndrome all affecting the optic nerve at the optic chiasa. The syndromes involving the thyroid and parathyroid glands that have ocular manifestations and are rare include Mc Cune Albright syndrome wherein optic nerve decompression may occur due to fibrous dysplasia, primary hyperparathyroidism that may present as red eye due to scleritis and Ascher syndrome wherein ptosis occurs. Allgrove's syndrome, Cushing's disease, and Addison's disease are the rare endocrine syndromes discussed involving the adrenals and eye. Ocular involvement is also seen in gonadal syndromes such as Bardet Biedl, Turner's, Rothmund's, and Klinefelter's syndrome. This review also highlights the ocular manifestation of miscellaneous syndromes such as Werner's, Cockayne's, Wolfram's, Kearns Sayre's, and Autoimmune polyendocrine syndrome. The knowledge of these relatively uncommon endocrine disorders and their ocular manifestations will help an endocrinologist reach a diagnosis and will alert an ophthalmologist to seek specialty consultation of an endocrinologist when encountered with such cases. PMID:22629495

Incidence of endocrine disorders in Indian adult male population

Directory of Open Access Journals (Sweden)

K. V. S. Hari Kumar

2017-01-01

Full Text Available Background: The comprehensive epidemiology of endocrine disorders is lacking from our country. Most of the available data pertain to the prevalence of diabetes and thyroid disorders only. We studied the incidence of endocrine disorders in a cohort of service personnel followed for a long duration. Materials and Methods: The data for this descriptive epidemiologic study were derived from the electronic medical records of the male service personnel enrolled between 1990 and 2015. They were recruited between the ages of 17 and 20 years in good health, and their morbidity data were derived from the medical records. We calculated the incidence rates as per person-years (py using appropriate statistical methods. Results: Our analysis includes 51,217 participants (median: age 33 years, range: 17–54 with a mean follow-up of 12.5 years. Yearly evaluation of the data gave a cumulative follow-up duration of 613,925 py. The incidence of diabetes, obesity, and dyslipidemia was 0.41, 0.23, and 0.12 per 1000 py, respectively. The incidence of thyroid, parathyroid, pituitary, adrenal, and metabolic bone disorders was 3.9, 8.6, 1.6, 0.81, and 0.97 per 100,000 py, respectively. Conclusion: Our cohort had lower incidence rates of endocrine disorders when compared with the Western population. Long-term epidemiological studies are essential to identify the demographic trends of the endocrine disorders in India.

Endocrine function in 97 patients with myotonic dystrophy type 1

DEFF Research Database (Denmark)

Ørngreen, Mette Cathrine; Arlien-Søborg, P.; Duno, M

2012-01-01

. Correlation with CTG(n) expansion size was investigated with the Pearson correlation test. Eighteen percent of the DM1 patients had hyperparathyroidism with increased PTH compared with 0.5% in the background population. Of these, 16% had normocalcemia and 2% had hypercalcemia. An additional 3% had...... LH, but normal testosterone levels, indicating relative insufficiency. Numbers of CTG repeats correlated directly with plasma PTH, phosphate, LH, and tended to correlate with plasma testosterone for males. This is the largest study of endocrine dysfunction in a cohort of Caucasian patients with DM1....... We found that patients with DM1 have an increased risk of abnormal endocrine function, particularly calcium metabolism disorders. However, the endocrine dysfunction appears not to be of clinical significance in all of the cases. Finally, we found correlations between CTG(n) expansion size and plasma...

Poly(ADP-ribose) polymerase-independent potentiation of nitrosourea cytotoxicity by 3-aminobenzamide in human malignant glioma cells.

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Winter, S; Weller, M

2000-06-16

Poly(ADP-ribose) polymerase is a zinc-finger DNA-binding protein that detects specifically DNA strand breaks generated by genotoxic agents and is thought to be involved in DNA repair. Here, we examined the effects of 3-aminobenzamide, a poly(ADP-ribose) polymerase inhibitor, on the chemosensitivity of human malignant glioma cells. 3-Aminobenzamide selectively potentiated the cytotoxicity of the nitrosoureas, nimustine, carmustine and lomustine in 10 of 12 human malignant glioma cell lines. In contrast, 3-aminobenzamide did not modulate the cytotoxic effects of doxorubicine, teniposide, vincristine, camptothecin or cytarabine. The nitrosoureas did not induce poly(ADP-ribose) polymerase activity in the glioma cells. Ectopic expression of truncated poly(ADP-ribose) polymerase containing the poly(ADP-ribose) polymerase DNA-binding domain, which acts as a dominant-negative mutant, in LN-18 or LN-229 cells did not alter the 3-aminobenzamide effect on nitrosourea-mediated cytotoxicity. Thus, 3-aminobenzamide may target another nicotinamide adenine dinucleotide (NAD)-requiring enzyme, but not poly(ADP-ribose) polymerase, when enhancing nitrosourea cytotoxicity in human malignant glioma cells. Carmustine cytotoxicity was associated with a G2/M arrest. Coexposure to carmustine and 3-aminobenzamide overcame this G2/M arrest in T98G cells, which are sensitized to carmustine by 3-aminobenzamide, but not in U251MG cells, which are refractory to 3-aminobenzamide-mediated sensitization to carmustine. Thus, 3-aminobenzamide-mediated sensitization to carmustine cytotoxicity may result from interference with the stable G2/M arrest response to carmustine in human glioma cells.

ENDOCRINE-DISRUPTING CHEMICALS: PREPUBERTAL EXPOSURES AND EFFECTS ON SEXUAL MATURATION AND THYROID FUNCTION IN THE MALE RAT. A FOCUS ON THE EDSTAC RECOMMENDATIONS. ENDOCRINE DISRUPTER SCREENING AND TESTING ADVISORY COMMITTEE

Science.gov (United States)

Endocrine-disrupting chemicals: prepubertal exposures and effects on sexual maturation and thyroid function in the male rat. A focus on the EDSTAC recommendations. Endocrine Disrupter Screening and Testing Advisory Committee.Stoker TE, Parks LG, Gray LE, Cooper RL.

Localized field conformation radiotherapy combined with endocrine therapy for the treatment of prostate cancer

International Nuclear Information System (INIS)

Karasawa, Katsuyuki; Kaizu, Toshihide; Kurosaki, Hiromasa; Tanaka, Yoshiaki

1999-01-01

To improve the quality of life (QOL) of the patients with prostate cancer, we limit the radiotherapy target volume to the prostate and seminal vesicles while using endocrine therapy towards the disease outside the target volume. Radiotherapy technique was rotation conformation technique with computer-controlled multileaf collimators to the total doses of up to 66-70 Gy. Among 145 evaluable cases with the median age of 74, overall and cause-specific 5-year survival rates were 59.3% and 84.1%, respectively, and the relative survival rate of the Stage A-C cases was 100%. The two thirds (33/50) of the deaths were not of prostate cancer. The rate of severe complication was 1.4%. As for QOL, the rate of impotence was 90%, however, the patients' overall satisfaction towards the treatment was 90%. From this analysis, this combined treatment seems beneficial in the treatment of prostate cancer. (author)

Lineage-related cytotoxicity and clonogenic profile of 1,4-benzoquinone-exposed hematopoietic stem and progenitor cells

Energy Technology Data Exchange (ETDEWEB)

Chow, Paik Wah [Biomedical Science Programme, School of Diagnostic & Applied Health Sciences, Faculty of Health Sciences, Universiti Kebangsaan Malaysia, Jalan Raja Abdul Muda Aziz, 50300 Kuala Lumpur, Wilayah Persekutuan (Malaysia); Toxicology Laboratory, Faculty of Health Sciences, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, 50300 Kuala Lumpur (Malaysia); Abdul Hamid, Zariyantey, E-mail: zyantey@ukm.edu.my [Biomedical Science Programme, School of Diagnostic & Applied Health Sciences, Faculty of Health Sciences, Universiti Kebangsaan Malaysia, Jalan Raja Abdul Muda Aziz, 50300 Kuala Lumpur, Wilayah Persekutuan (Malaysia); Toxicology Laboratory, Faculty of Health Sciences, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, 50300 Kuala Lumpur (Malaysia); Chan, Kok Meng [Environmental Health and Industrial Safety Programme, School of Diagnostic & Applied Health Sciences, Faculty of Health Sciences, Universiti Kebangsaan Malaysia, Jalan Raja Abdul Muda Aziz, 50300 Kuala Lumpur, Wilayah Persekutuan (Malaysia); Toxicology Laboratory, Faculty of Health Sciences, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, 50300 Kuala Lumpur (Malaysia); Inayat-Hussain, Salmaan Hussain [Environmental Health and Industrial Safety Programme, School of Diagnostic & Applied Health Sciences, Faculty of Health Sciences, Universiti Kebangsaan Malaysia, Jalan Raja Abdul Muda Aziz, 50300 Kuala Lumpur, Wilayah Persekutuan (Malaysia); Rajab, Nor Fadilah [Biomedical Science Programme, School of Diagnostic & Applied Health Sciences, Faculty of Health Sciences, Universiti Kebangsaan Malaysia, Jalan Raja Abdul Muda Aziz, 50300 Kuala Lumpur, Wilayah Persekutuan (Malaysia); Toxicology Laboratory, Faculty of Health Sciences, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, 50300 Kuala Lumpur (Malaysia)

2015-04-01

Hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) are sensitive targets for benzene-induced hematotoxicity and leukemogenesis. The impact of benzene exposure on the complex microenvironment of HSCs and HPCs remains elusive. This study aims to investigate the mechanism linking benzene exposure to targeting HSCs and HPCs using phenotypic and clonogenic analyses. Mouse bone marrow (BM) cells were exposed ex vivo to the benzene metabolite, 1,4-benzoquinone (1,4-BQ), for 24 h. Expression of cellular surface antigens for HSC (Sca-1), myeloid (Gr-1, CD11b), and lymphoid (CD45, CD3e) populations were confirmed by flow cytometry. The clonogenicity of cells was studied using the colony-forming unit (CFU) assay for multilineage (CFU-GM and CFU-GEMM) and single-lineage (CFU-E, BFU-E, CFU-G, and CFU-M) progenitors. 1,4-BQ demonstrated concentration-dependent cytotoxicity in mouse BM cells. The percentage of apoptotic cells increased (p < 0.05) following 1,4-BQ exposure. Exposure to 1,4-BQ showed no significant effect on CD3e{sup +} cells but reduced the total counts of Sca-1{sup +}, CD11b{sup +}, Gr-1{sup +}, and CD45{sup +} cells at 7 and 12 μM (p < 0.05). Furthermore, the CFU assay showed reduced (p < 0.05) clonogenicity in 1,4-BQ-treated cells. 1,4-BQ induced CFU-dependent cytotoxicity by significantly inhibiting colony growth for CFU-E, BFU-E, CFU-G, and CFU-M starting at a low concentration of exposure (5 μM); whereas for the CFU-GM and CFU-GEMM, the inhibition of colony growth was remarkable only at 7 and 12 μM of 1,4-BQ, respectively. Taken together, 1,4-BQ caused lineage-related cytotoxicity in mouse HPCs, demonstrating greater toxicity in single-lineage progenitors than in those of multi-lineage. - Highlights: • We examine 1,4-BQ toxicity targeting mouse hematopoietic cell lineages. • 1,4-BQ induces concentration-dependent cytotoxicity in bone marrow (BM) cells. • 1,4-BQ shows lineage-related toxicity on hematopoietic stem and

Lineage-related cytotoxicity and clonogenic profile of 1,4-benzoquinone-exposed hematopoietic stem and progenitor cells

International Nuclear Information System (INIS)

Chow, Paik Wah; Abdul Hamid, Zariyantey; Chan, Kok Meng; Inayat-Hussain, Salmaan Hussain; Rajab, Nor Fadilah

2015-01-01

Hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) are sensitive targets for benzene-induced hematotoxicity and leukemogenesis. The impact of benzene exposure on the complex microenvironment of HSCs and HPCs remains elusive. This study aims to investigate the mechanism linking benzene exposure to targeting HSCs and HPCs using phenotypic and clonogenic analyses. Mouse bone marrow (BM) cells were exposed ex vivo to the benzene metabolite, 1,4-benzoquinone (1,4-BQ), for 24 h. Expression of cellular surface antigens for HSC (Sca-1), myeloid (Gr-1, CD11b), and lymphoid (CD45, CD3e) populations were confirmed by flow cytometry. The clonogenicity of cells was studied using the colony-forming unit (CFU) assay for multilineage (CFU-GM and CFU-GEMM) and single-lineage (CFU-E, BFU-E, CFU-G, and CFU-M) progenitors. 1,4-BQ demonstrated concentration-dependent cytotoxicity in mouse BM cells. The percentage of apoptotic cells increased (p < 0.05) following 1,4-BQ exposure. Exposure to 1,4-BQ showed no significant effect on CD3e + cells but reduced the total counts of Sca-1 + , CD11b + , Gr-1 + , and CD45 + cells at 7 and 12 μM (p < 0.05). Furthermore, the CFU assay showed reduced (p < 0.05) clonogenicity in 1,4-BQ-treated cells. 1,4-BQ induced CFU-dependent cytotoxicity by significantly inhibiting colony growth for CFU-E, BFU-E, CFU-G, and CFU-M starting at a low concentration of exposure (5 μM); whereas for the CFU-GM and CFU-GEMM, the inhibition of colony growth was remarkable only at 7 and 12 μM of 1,4-BQ, respectively. Taken together, 1,4-BQ caused lineage-related cytotoxicity in mouse HPCs, demonstrating greater toxicity in single-lineage progenitors than in those of multi-lineage. - Highlights: • We examine 1,4-BQ toxicity targeting mouse hematopoietic cell lineages. • 1,4-BQ induces concentration-dependent cytotoxicity in bone marrow (BM) cells. • 1,4-BQ shows lineage-related toxicity on hematopoietic stem and progenitors. • 1,4-BQ

Autophagy plays a critical role in ChLym-1-induced cytotoxicity of non-hodgkin's lymphoma cells.

Directory of Open Access Journals (Sweden)

Jiajun Fan

Full Text Available Autophagy is a critical mechanism in both cancer therapy resistance and tumor suppression. Monoclonal antibodies have been documented to kill tumor cells via apoptosis, antibody-dependent cellular cytotoxicity (ADCC and complement-dependent cytotoxicity (CDC. In this study, we report for the first time that chLym-1, a chimeric anti-human HLA-DR monoclonal antibody, induces autophagy in Raji Non-Hodgkin's Lymphoma (NHL cells. Interestingly, inhibition of autophagy by pharmacological inhibitors (3-methyladenine and NH4Cl or genetic approaches (siRNA targeting Atg5 suppresses chLym-1-induced growth inhibition, apoptosis, ADCC and CDC in Raji cells, while induction of autophagy could accelerate cytotoxic effects of chLym-1 on Raji cells. Furthermore, chLym-1-induced autophagy can mediate apoptosis through Caspase 9 activation, demonstrating the tumor-suppressing role of autophagy in antilymphoma effects of chLym-1. Moreover, chLym-1 can activate several upstream signaling pathways of autophagy including Akt/mTOR and extracellular signal-regulated kinase 1/2 (Erk1/2. These results elucidate the critical role of autophagy in cytotoxicity of chLym-1 antibody and suggest a potential therapeutic strategy of NHL therapy by monoclonal antibody chLym-1 in combination with autophagy inducer.

Psycho-Neuro-Endocrine-Immunology: A Psychobiological Concept.

Science.gov (United States)

França, Katlein; Lotti, Torello M

2017-01-01

Psycho-Neuro-Endocrine-Immunology (P.N.E.I.) is a scientific field of study that investigates the link between bidirectional communications among the nervous system, the endocrine system, and the immune system and the correlations of this cross-talk with physical health. The P.N.E.I. innovative medical approach represents a paradigm shift from a strictly biomedical view of health and disease taken as hermetically sealed compartments to a more interdisciplinary one. The key element of P.N.E.I. approach is represented by the concept of bidirectional cross-talk between the psychoneuroendocrine and immune systems. The Low Dose Medicine is one of the most promising approaches able to allow the researchers to design innovative therapeutic strategies for the treatment of skin diseases based on the rebalance of the immune response.

Endocrine cells in the denervated intestine

Science.gov (United States)

Santos, Gilda C; Zucoloto, Sérgio; Garcia, Sérgio B

2000-01-01

This study deals with the effects of myenteric denervation of the proximal jejunum on endocrine cell population of the crypt-villus unit, 5 months after treatment with benzalkonium chloride (BAC). Male Wistar albino rats weighing on average 100 g were allocated to two groups: the BAC group − the proximal jejunal serosa was treated with 2 mm BAC for 30 min, and the control group − treated with saline solution (0,9% NaCl). There was a significant reduction in neurone number in the jejunal myenteric plexus of the BAC group and the endocrine cell population (serotoninergic and argyrophilic cells) was significantly increased in this intestine segment. In conclusion, the present findings provide further evidence that the myenteric denervation induced by BAC may lead to the development of a local imbalance of the neurotransmitters, with a consequent induction of enteroendocrine cell (argyrophilic and serotoninergic cells) hyperplasia in the crypt and villus. PMID:10971748

How immunoglobulin G antibodies kill target cells: revisiting an old paradigm.

Science.gov (United States)

Biburger, Markus; Lux, Anja; Nimmerjahn, Falk

2014-01-01

The capacity of immunoglobulin G (IgG) antibodies to eliminate virtually any target cell has resulted in the widespread introduction of cytotoxic antibodies into the clinic in settings of cancer therapy, autoimmunity, and transplantation, for example. More recently, it has become apparent that also the protection from viral infection via IgG antibodies may require cytotoxic effector functions, suggesting that antibody-dependent cellular cytotoxicity (ADCC) directed against malignant or virally infected cells is one of the most essential effector mechanisms triggered by IgG antibodies to protect the host. A detailed understanding of the underlying molecular and cellular pathways is critical, therefore, to make full use of this antibody effector function. Several studies over the last years have provided novel insights into the effector pathways and innate immune effector cells responsible for ADCC reactions. One of the most notable outcomes of many of these reports is that cells of the mononuclear phagocytic system rather than natural killer cells are critical for removal of IgG opsonized target cells in vivo. © 2014 Elsevier Inc. All rights reserved.

Destabilization of mitochondrial functions as a target against breast cancer progression: Role of TPP+-linked-polyhydroxybenzoates

International Nuclear Information System (INIS)

Sandoval-Acuña, Cristian; Fuentes-Retamal, Sebastián; Guzmán-Rivera, Daniela; Peredo-Silva, Liliana; Madrid-Rojas, Matías; Rebolledo, Solange; Castro-Castillo, Vicente; Pavani, Mario; Catalán, Mabel; Maya, Juan Diego; Jara, José A.; Parra, Eduardo; Calaf, Gloria M.

2016-01-01

Mitochondrion is an accepted molecular target in cancer treatment since it exhibits a higher transmembrane potential in cancer cells, making it susceptible to be targeted by lipophilic-delocalized cations of triphenylphosphonium (TPP + ). Thus, we evaluated five TPP + -linked decyl polyhydroxybenzoates as potential cytotoxic agents in several human breast cancer cell lines that differ in estrogen receptor and HER2/neu expression, and in metabolic profile. Results showed that all cell lines tested were sensitive to the cytotoxic action of these compounds. The mechanism underlying the cytotoxicity would be triggered by their weak uncoupling effect on the oxidative phosphorylation system, while having a wider and safer therapeutic range than other uncouplers and a significant lowering in transmembrane potential. Noteworthy, while the TPP + -derivatives alone led to almost negligible losses of ATP, when these were added in the presence of an AMP-activated protein kinase inhibitor, the levels of ATP fell greatly. Overall, data presented suggest that decyl polyhydroxybenzoates-TPP + and its derivatives warrant future investigation as potential anti-tumor agents. - Highlights: • TPP + -polyhydroxybenzoates are cytotoxic to various subtypes of breast cancer cells. • Cytotoxicity is not-dependent on the expression of estrogen/growth factor receptors. • Cytotoxicity appears to be triggered by a weak mitochondrial uncoupling effect. • Effects include loss of transmembrane potential and apoptosis was detected. • TPP + -polyhydroxybenzoates inhibit migration of highly metastatic cells.

The Current Role of Venous Sampling in the Localization of Endocrine Disease

International Nuclear Information System (INIS)

Lau, Jeshen H. G.; Drake, William; Matson, Matthew

2007-01-01

Endocrine venous sampling plays a specific role in the diagnosis of endocrine disorders. In this article, we cover inferior petrosal sinus sampling, selective parathyroid venous sampling, hepatic venous sampling with arterial stimulation, adrenal venous sampling, and ovarian venous sampling. We review their indications and the scientific evidence justifying these indications in the diagnosis and management of Cushing's syndrome, hyperparathyroidism, pancreatic endocrine tumors, Conn's syndrome, primary hyperaldosteronism, pheochromocytomas, and androgen-secreting ovarian tumors. For each sampling technique, we compare its diagnostic accuracy with that of other imaging techniques and, where possible, look at how it impacts patient management. Finally, we incorporate venous sampling into diagnostic algorithms used at our institution

Somatostatin-receptor imaging in the localization of endocrine tumors

International Nuclear Information System (INIS)

Lamberts, S.W.; Bakker, W.H.; Reubi, J.C.; Krenning, E.P.

1990-01-01

A number of different tumors have receptors for somatostatin. We evaluated the efficacy of scanning with 123 I-labeled Tyr3-octreotide, a somatostatin analogue, for tumor localization in 42 patients with carcinoid tumors, pancreatic endocrine tumors, or paragangliomas. We then evaluated the response to octreotide therapy in some of these patients. Primary tumors or metastases, often previously unrecognized, were visualized in 12 of 13 patients with carcinoid tumors and in 7 of 9 patients with pancreatic endocrine tumors. The endocrine symptoms of these patients responded well to therapy with octreotide. Among 20 patients with paragangliomas, 8 of whom had more than one tumor, 10 temporal (tympanic or jugular), 9 carotid, and 10 vagal tumors could be visualized. One small tympanic tumor and one small carotid tumor were not seen on the scan. The 123 I-labeled Tyr3-octreotide scanning technique is a rapid and safe procedure for the visualization of some tumors with somatostatin receptors. A positive scan may predict the ability of octreotide therapy to control symptoms of hormonal hypersecretion

Fluoride caused thyroid endocrine disruption in male zebrafish (Danio rerio).

Science.gov (United States)

Jianjie, Chen; Wenjuan, Xue; Jinling, Cao; Jie, Song; Ruhui, Jia; Meiyan, Li

2016-02-01

Excessive fluoride in natural water ecosystem has the potential to detrimentally affect thyroid endocrine system, but little is known of such effects or underlying mechanisms in fish. In the present study, we evaluated the effects of fluoride on growth performance, thyroid histopathology, thyroid hormone levels, and gene expressions in the HPT axis in male zebrafish (Danio rerio) exposed to different determined concentrations of 0.1, 0.9, 2.0 and 4.1 M of fluoride to investigate the effects of fluoride on thyroid endocrine system and the potential toxic mechanisms caused by fluoride. The results indicated that the growth of the male zebrafish used in the experiments was significantly inhibited, the thyroid microtrastructure was changed, and the levels of T3 and T4 were disturbed in fluoride-exposed male fish. In addition, the expressional profiles of genes in HPT axis displayed alteration. The expressions of all studied genes were significantly increased in all fluoride-exposed male fish after exposure for 45 days. The transcriptional levels of corticotrophin-releasing hormone (CRH), thyroid-stimulating hormone (TSH), thyroglobulin (TG), sodium iodide symporter (NIS), iodothyronine I (DIO1), and thyroid hormone receptor alpha (TRα) were also elevated in all fluoride-exposed male fish after 90 days of exposure, while the inconsistent expressions were found in the mRNA of iodothyronineⅡ (DIO2), UDP glucuronosyltransferase 1 family a, b (UGT1ab), transthyretin (TTR), and thyroid hormone receptor beta (TRβ). These results demonstrated that fluoride could notably inhibit the growth of zebrafish, and significantly affect thyroid endocrine system by changing the microtrastructure of thyroid, altering thyroid hormone levels and endocrine-related gene expressions in male zebrafish. All above indicated that fluoride could pose a great threat to thyroid endocrine system, thus detrimentally affected the normal function of thyroid of male zebrafish. Copyright © 2015

Review: the role of neural crest cells in the endocrine system.

Science.gov (United States)

Adams, Meghan Sara; Bronner-Fraser, Marianne

2009-01-01

The neural crest is a pluripotent population of cells that arises at the junction of the neural tube and the dorsal ectoderm. These highly migratory cells form diverse derivatives including neurons and glia of the sensory, sympathetic, and enteric nervous systems, melanocytes, and the bones, cartilage, and connective tissues of the face. The neural crest has long been associated with the endocrine system, although not always correctly. According to current understanding, neural crest cells give rise to the chromaffin cells of the adrenal medulla, chief cells of the extra-adrenal paraganglia, and thyroid C cells. The endocrine tumors that correspond to these cell types are pheochromocytomas, extra-adrenal paragangliomas, and medullary thyroid carcinomas. Although controversies concerning embryological origin appear to have mostly been resolved, questions persist concerning the pathobiology of each tumor type and its basis in neural crest embryology. Here we present a brief history of the work on neural crest development, both in general and in application to the endocrine system. In particular, we present findings related to the plasticity and pluripotency of neural crest cells as well as a discussion of several different neural crest tumors in the endocrine system.

Mathematical modeling of antibody drug conjugates with the target and tubulin dynamics to predict AUC.

Science.gov (United States)

Byun, Jong Hyuk; Jung, Il Hyo

2018-04-14

Antibody drug conjugates (ADCs)are one of the most recently developed chemotherapeutics to treat some types of tumor cells. They consist of monoclonal antibodies (mAbs), linkers, and potent cytotoxic drugs. Unlike common chemotherapies, ADCs combine selectively with a target at the surface of the tumor cell, and a potent cytotoxic drug (payload) effectively prevents microtubule polymerization. In this work, we construct an ADC model that considers both the target of antibodies and the receptor (tubulin) of the cytotoxic payloads. The model is simulated with brentuximab vedotin, one of ADCs, and used to investigate the pharmacokinetic (PK) characteristics of ADCs in vivo. It also predicts area under the curve (AUC) of ADCs and the payloads by identifying the half-life. The results show that dynamical behaviors fairly coincide with the observed data and half-life and capture AUC. Thus, the model can be used for estimating some parameters, fitting experimental observations, predicting AUC, and exploring various dynamical behaviors of the target and the receptor. Copyright © 2018 Elsevier Ltd. All rights reserved.

Career Advancement: Meeting the Challenges Confronting the Next Generation of Endocrinologists and Endocrine Researchers.

Science.gov (United States)

Santen, Richard J; Joham, Anju; Fishbein, Lauren; Vella, Kristen R; Ebeling, Peter R; Gibson-Helm, Melanie; Teede, Helena

2016-12-01

Challenges and opportunities face the next generation (Next-Gen) of endocrine researchers and clinicians, the lifeblood of the field of endocrinology for the future. A symposium jointly sponsored by The Endocrine Society and the Endocrine Society of Australia was convened to discuss approaches to addressing the present and future Next-Gen needs. Data collection by literature review, assessment of previously completed questionnaires, commissioning of a new questionnaire, and summarization of symposium discussions were studied. Next-Gen endocrine researchers face diminishing grant funding in inflation-adjusted terms. The average age of individuals being awarded their first independent investigator funding has increased to age 45 years. For clinicians, a workforce gap exists between endocrinologists needed and those currently trained. Clinicians in practice are increasingly becoming employees of integrated hospital systems, resulting in greater time spent on nonclinical issues. Workforce data and published reviews identify challenges specifically related to early career women in endocrinology. Strategies to Address Issues: Recommendations encompassed the areas of grant support for research, mentoring, education, templates for career development, specific programs for Next-Gen members by senior colleagues as outlined in the text, networking, team science, and life/work integration. Endocrine societies focusing on Next-Gen members provide a powerful mechanism to support these critical areas. A concerted effort to empower, train, and support the next generation of clinical endocrinologists and endocrine researchers is necessary to ensure the viability and vibrancy of our discipline and to optimize our contributions to improving health outcomes. Collaborative engagement of endocrine societies globally will be necessary to support our next generation moving forward.

The antioxidant properties, cytotoxicity and monoamine oxidase ...

African Journals Online (AJOL)

ajl yemi

2011-11-28

Nov 28, 2011 ... and the nitroblue tetrazolium (NBT) assay. The cytotoxicity ... The antioxidant activity and cytotoxic effect of the extracts increased with increase ... supplements are concoctions of plants and/or plant .... In vitro antioxidant assay.

Virus-specific HLA-restricted lysis of herpes simplex virus-infected human monocytes and macrophages mediated by cytotoxic T lymphocytes

Energy Technology Data Exchange (ETDEWEB)

Torpey, D.J. III

1987-01-01

Freshly-isolated peripheral blood human monocytes and 5 day in vitro cultured macrophages were infected with herpes simplex virus type 1 (HSV-1), labeled with /sup 51/Cr, and used as target cells in a 12-14 hour cell-mediated cytotoxicity assay. Mononuclear leukocytes (MNL) from HSV-1 non-immune individuals, whether unstimulated or stimulated with HSV-1 antigen, did not mediate significant lysis of either target cell. HSV-immune MNL, both freshly-isolated and cultured for 5 days without antigen, demonstrated only low levels of natural killer (NK) cell-mediate lysis. MNL from HSV-immune individuals incubated for 5 days in vitro with HSV-1 antigen mediated significant virus-specific lysis of both target cells. Mean virus-specific lysis of autologous monocytes was 8.5(/+-/2.0)% compared to a three-fold greater virus-specific lysis of autologous macrophages. Greater than 70% of this lytic activity was mediated by Leu-11-negative, T3-positive cytotoxic T lymphocytes (CTL). Allogeneic target cells lacking a common HLA determinant were not significantly lysed while T8-positive CTL mediated infrequent lysis of target cells sharing a common HLA-A and/or HLA-B determinant. T4-positive lymphocytes were demonstrated to be the predominant cell mediating lysis of autologous target cells and allogeneic target cells sharing both HLA-A and/or HLA-B plus HLA-DR determinants with the CTL; the T4-positive cell was the sole CTL mediator of lysis of allogeneic target cells having a common HLA-DR determinant.

Virus-specific HLA-restricted lysis of herpes simplex virus-infected human monocytes and macrophages mediated by cytotoxic T lymphocytes

International Nuclear Information System (INIS)

Torpey, D.J. III.

1987-01-01

Freshly-isolated peripheral blood human monocytes and 5 day in vitro cultured macrophages were infected with herpes simplex virus type 1 (HSV-1), labeled with 51 Cr, and used as target cells in a 12-14 hour cell-mediated cytotoxicity assay. Mononuclear leukocytes (MNL) from HSV-1 non-immune individuals, whether unstimulated or stimulated with HSV-1 antigen, did not mediate significant lysis of either target cell. HSV-immune MNL, both freshly-isolated and cultured for 5 days without antigen, demonstrated only low levels of natural killer (NK) cell-mediate lysis. MNL from HSV-immune individuals incubated for 5 days in vitro with HSV-1 antigen mediated significant virus-specific lysis of both target cells. Mean virus-specific lysis of autologous monocytes was 8.5(/+-/2.0)% compared to a three-fold greater virus-specific lysis of autologous macrophages. Greater than 70% of this lytic activity was mediated by Leu-11-negative, T3-positive cytotoxic T lymphocytes (CTL). Allogeneic target cells lacking a common HLA determinant were not significantly lysed while T8-positive CTL mediated infrequent lysis of target cells sharing a common HLA-A and/or HLA-B determinant. T4-positive lymphocytes were demonstrated to be the predominant cell mediating lysis of autologous target cells and allogeneic target cells sharing both HLA-A and/or HLA-B plus HLA-DR determinants with the CTL; the T4-positive cell was the sole CTL mediator of lysis of allogeneic target cells having a common HLA-DR determinant

Histologic, immunologic and endocrine biomarkers indicate contaminant effects in fishes of the Ashtabula River.

Science.gov (United States)

Iwanowicz, Luke R; Blazer, Vicki S; Hitt, Nathaniel P; McCormick, Stephen D; DeVault, David S; Ottinger, Christopher A

2012-01-01

The use of fish as sentinels of aquatic ecosystem health is a biologically relevant approach to environmental monitoring and assessment. We examined the health of the Ashtabula River using histologic, immunologic, and endocrine biomarkers in brown bullhead (BB; Ameiurus nebulosus) and largemouth bass (Micropterus salmoides) and compared fish collected from a reference site (Conneaut Creek). Seasonal analysis was necessary to distinguish differences in fish between the two rivers. Overall BB from the Ashtabula River had a lower condition factor and significantly more macrophage aggregates than those from the reference site. Reduced bactericidal and cytotoxic-cell activity was observed in anterior kidney leukocytes from both BB and largemouth bass from the Ashtabula River. Lower plasma thyroxine and triiodo-L-thyronine in both species in the Ashtabula River indicated disruption of the thyroid axis. Differences in physiological biomarker responses were supported by body burden chemical concentrations when data were analyzed on a seasonal basis. The use of two fish species added a level of rigor that demonstrated biological effects were not exclusive to a single species. The results provide strong evidence that contaminants have affected fish in the Ashtabula River, a Great Lakes Area of Concern, and provide a baseline by which to evaluate remediation activities.

Endocrine alterations in HIV-infected patients

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Sujit Kumar Tripathy

2015-01-01

Full Text Available Aims and objectives: To study the frequency of thyroid, adrenal and gonadal dysfunction in newly diagnosed HIV-infected patients and to correlate them at different levels of CD4 cell counts. Materials and Methods: Forty-three HIV-positive cases were included in the study group. Cases were divided into three groups on the basis of CD4 cell count. Serum free T3, free T4, TSH, Cortisol, FSH, LH, testosterone and estradiol were estimated by the radioimmunoassay method. Hormone levels between cases were compared and their correlation with CD4 count was analyzed. Results: Prevalence of gonadal dysfunction (88.3% was the most common endocrine dysfunction followed by thyroid (60.4% and adrenal dysfunction (27.9%. Secondary hypogonadism (68.4% was more common than primary (31.6%. Low T3 syndrome, that is, isolated low free T3, was the most common (25.6% thyroid dysfunction followed by secondary hypothyroidism (16.2% and subclinical hypothyroidism (11.6%. Adrenal excess (16.3% was more common than adrenal insufficiency (11.6%. The difference in hormonal dysfunction between male and female was statistically insignificant (P > 0.05. 27.9% of patients had multiple hormone deficiency. There was negligible or no correlation between CD4 count and serum hormone level. Conclusion: In our study, endocrine dysfunction was quite common among HIV-infected patients but there was no correlation between hormone levels and CD4 count. Endocrine dysfunctions and role of hormone replacement therapy in HIV-infected patient needs to be substantiated by large longitudinal study, so that it will help to reduce morbidity, improve quality of life.

ELISPOT Assay for Monitoring Cytotoxic T Lymphocytes (CTL Activity in Cancer Vaccine Clinical Trials

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Thomas J. Sayers

2012-05-01

Full Text Available The profiling and monitoring of immune responses are key elements in the evaluation of the efficacy and development of new biotherapies, and a number of assays have been introduced for analyzing various immune parameters before, during, and after immunotherapy. The choice of immune assays for a given clinical trial depends on the known or suggested immunomodulating mechanisms associated with the tested therapeutic modality. Cell-mediated cytotoxicity represents a key mechanism in the immune response to various pathogens and tumors. Therefore, the selection of monitoring methods for the appropriate assessment of cell-mediated cytotoxicity is thought to be crucial. Assays that can detect both cytotoxic T lymphocytes (CTL frequency and function, such as the IFN-γ enzyme-linked immunospot assay (ELISPOT have gained increasing popularity for monitoring clinical trials and in basic research. Results from various clinical trials, including peptide and whole tumor cell vaccination and cytokine treatment, have shown the suitability of the IFN-γ ELISPOT assay for monitoring T cell responses. However, the Granzyme B ELISPOT assay and Perforin ELISPOT assay may represent a more direct analysis of cell-mediated cytotoxicity as compared to the IFN-γ ELISPOT, since Granzyme B and perforin are the key mediators of target cell death via the granule-mediated pathway. In this review we analyze our own data and the data reported by others with regard to the application of various modifications of ELISPOT assays for monitoring CTL activity in clinical vaccine trials.

Endocrine disorders in pregnancy

DEFF Research Database (Denmark)

Feldt-Rasmussen, Ulla; Mathiesen, Elisabeth R

2011-01-01

The endocrinology of pregnancy involves endocrine and metabolic changes as a consequence of physiological alterations at the foetoplacental boundary between mother and foetus. The vast changes in maternal hormones and their binding proteins complicate assessment of the normal level of most hormones...... during gestation. The neuroendocrine events and their timing in the placental, foetal and maternal compartments are critical for initiation and maintenance of pregnancy, for foetal growth and development, and for parturition. As pregnancy advances, the relative number of trophoblasts increase...

Activating Transcription Factor 3 regulates in part the enhanced tumour cell cytotoxicity of the histone deacetylase inhibitor M344 and cisplatin in combination

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St Germain Carly

2010-09-01

Full Text Available Abstract Background Activating Transcription Factor (ATF 3 is a key regulator of the cellular integrated stress response whose expression has also been correlated with pro-apoptotic activities in tumour cell models. Combination treatments with chemotherapeutic drugs, such as cisplatin, and histone deacetylase (HDAC inhibitors have been demonstrated to enhance tumour cell cytotoxicity. We recently demonstrated a role for ATF3 in regulating cisplatin-induced apoptosis and others have shown that HDAC inhibition can also induce cellular stress. In this study, we evaluated the role of ATF3 in regulating the co-operative cytotoxicity of cisplatin in combination with an HDAC inhibitor. Results The HDAC inhibitor M344 induced ATF3 expression at the protein and mRNA level in a panel of human derived cancer cell lines as determined by Western blot and quantitative RT-PCR analyses. Combination treatment with M344 and cisplatin lead to increased induction of ATF3 compared with cisplatin alone. Utilizing the MTT cell viability assay, M344 treatments also enhanced the cytotoxic effects of cisplatin in these cancer cell lines. The mechanism of ATF3 induction by M344 was found to be independent of MAPKinase pathways and dependent on ATF4, a known regulator of ATF3 expression. ATF4 heterozygote (+/- and knock out (-/- mouse embryonic fibroblast (MEF as well as chromatin immunoprecipitation (ChIP assays were utilized in determining the mechanistic induction of ATF3 by M344. We also demonstrated that ATF3 regulates the enhanced cytotoxicity of M344 in combination with cisplatin as evidenced by attenuation of cytotoxicity in shRNAs targeting ATF3 expressing cells. Conclusion This study identifies the pro-apoptotic factor, ATF3 as a novel target of M344, as well as a mediator of the co-operative effects of cisplatin and M344 induced tumour cell cytotoxicity.

Metabolic syndrome, endocrine disruptors and prostate cancer associations: biochemical and pathophysiological evidences

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Quagliariello, Vincenzo; Rossetti, Sabrina; Cavaliere, Carla; Di Palo, Rossella; Lamantia, Elvira; Castaldo, Luigi; Nocerino, Flavia; Ametrano, Gianluca; Cappuccio, Francesca; Malzone, Gabriella; Montanari, Micaela; Vanacore, Daniela; Romano, Francesco Jacopo; Piscitelli, Raffaele; Iovane, Gelsomina; Pepe, Maria Filomena; Berretta, Massimiliano; D'Aniello, Carmine; Perdonà, Sisto; Muto, Paolo; Botti, Gerardo; Ciliberto, Gennaro; Veneziani, Bianca Maria; De Falco, Francesco; Maiolino, Piera; Caraglia, Michele; Montella, Maurizio; Iaffaioli, Rosario Vincenzo; Facchini, Gaetano

2017-01-01

This review summarizes the main pathophysiological basis of the relationship between metabolic syndrome, endocrine disruptor exposure and prostate cancer that is the most common cancer among men in industrialized countries. Metabolic syndrome is a cluster of metabolic and hormonal factors having a central role in the initiation and recurrence of many western chronic diseases including hormonal-related cancers and it is considered as the worlds leading health problem in the coming years. Many biological factors correlate metabolic syndrome to prostate cancer and this review is aimed to focus, principally, on growth factors, cytokines, adipokines, central obesity, endocrine abnormalities and exposure to specific endocrine disruptors, a cluster of chemicals, to which we are daily exposed, with a hormone-like structure influencing oncogenes, tumor suppressors and proteins with a key role in metabolism, cell survival and chemo-resistance of prostate cancer cells. Finally, this review will analyze, from a molecular point of view, how specific foods could reduce the relative risk of incidence and recurrence of prostate cancer or inhibit the biological effects of endocrine disruptors on prostate cancer cells. On the basis of these considerations, prostate cancer remains a great health problem in terms of incidence and prevalence and interventional studies based on the treatment of metabolic syndrome in cancer patients, minimizing exposure to endocrine disruptors, could be a key point in the overall management of this disease. PMID:28389628

Nuclear medicine procedures to diagnose endocrine pancreatic tumours

International Nuclear Information System (INIS)

Bares, R.; Besenfelder, H.; Eschmann, S.M.; Pfannenberg, C.

2003-01-01

The typical clinical features of endocrine pancreatic tumours are either symptoms caused by excessive hormone production or progressive tumour growth. In several prospective studies it has been shown that somatostatin receptor scintigraphy is the most accurate imaging technique currently available to detect endocrine pancreatic tumours. Therefore it should be used whenever curative surgical treatment appears to be feasible. Furthermore it should be applied if a radionuclide treatment of inoperable tumours is considered. In this situation scintigraphy with 123 I-mIBG might be useful, too. Future developments include the use of PET with labelled somatostatin analogues or DOPA derivatives as well as image fusion techniques to optimize preoperative tumour localization. (orig.) [de

Endocrine responses to water restriction in desert sheep

International Nuclear Information System (INIS)

Ahmed, Muna M.M.

1994-01-01

For ruminants grazing in semi-arid areas, the maintenance of balanced water and energy metabolism is challenging to productivity.The metabolic effects of water restriction usually stimulate endocrine which control metabolic activity depending on the thermal environment.Radioimmunoasay technique was used to determine the level of endocrine hormones, namely thyroid stimulating hormone(TSH),thyroxine(T4) and cortisol in desert sheep.Intermittent watering every 24h, 48h and 72h increased TSH level during the morning but decreased it during the afternoon.T4 level decreased during both morning and afternoon.The cortisol level was depressed by water restriction during the morning and afternoon but showed an overlapping pattern with that of the control during the afternoon. (Author)

The eye as a window to rare endocrine disorders

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Rupali Chopra

2012-01-01

Full Text Available The human eye, as an organ, can offer critical clues to the diagnosis of various systemic illnesses. Ocular changes are common in various endocrine disorders such as diabetes mellitus and Graves′ disease. However there exist a large number of lesser known endocrine disorders where ocular involvement is significant. Awareness of these associations is the first step in the diagnosis and management of these complex patients. The rare syndromes involving the pituitary hypothalamic axis with significant ocular involvement include Septo-optic dysplasia, Kallman′s syndrome, and Empty Sella syndrome all affecting the optic nerve at the optic chiasa. The syndromes involving the thyroid and parathyroid glands that have ocular manifestations and are rare include Mc Cune Albright syndrome wherein optic nerve decompression may occur due to fibrous dysplasia, primary hyperparathyroidism that may present as red eye due to scleritis and Ascher syndrome wherein ptosis occurs. Allgrove′s syndrome, Cushing′s disease, and Addison′s disease are the rare endocrine syndromes discussed involving the adrenals and eye. Ocular involvement is also seen in gonadal syndromes such as Bardet Biedl, Turner′s, Rothmund′s, and Klinefelter′s syndrome. This review also highlights the ocular manifestation of miscellaneous syndromes such as Werner′s, Cockayne′s, Wolfram′s, Kearns Sayre′s, and Autoimmune polyendocrine syndrome. The knowledge of these relatively uncommon endocrine disorders and their ocular manifestations will help an endocrinologist reach a diagnosis and will alert an ophthalmologist to seek specialty consultation of an endocrinologist when encountered with such cases.

Update: Systemic Diseases and the Cardiovascular System (II). The endocrine system and the heart: a review.

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Rhee, Soo S; Pearce, Elizabeth N

2011-03-01

Normal endocrine function is essential for cardiovascular health. Disorders of the endocrine system, consisting of hormone hyperfunction and hypofunction, have multiple effects on the cardiovascular system. In this review, we discuss the epidemiology, diagnosis, and management of disorders of the pituitary, thyroid, parathyroid, and adrenal glands, with respect to the impact of endocrine dysfunction on the cardiovascular system. We also review the cardiovascular benefits of restoring normal endocrine function. Copyright © 2010 Sociedad Española de Cardiología. Published by Elsevier Espana. All rights reserved.

C22:0- and C24:0-dihydroceramides confer mixed cytotoxicity in T-cell acute lymphoblastic leukemia cell lines.

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Michael W Holliday

Full Text Available We previously reported that fenretinide (4-HPR was cytotoxic to acute lymphoblastic leukemia (ALL cell lines in vitro in association with increased levels of de novo synthesized dihydroceramides, the immediate precursors of ceramides. However, the cytotoxic potentials of native dihydroceramides have not been defined. Therefore, we determined the cytotoxic effects of increasing dihydroceramide levels via de novo synthesis in T-cell ALL cell lines and whether such cytotoxicity was dependent on an absolute increase in total dihydroceramide mass versus an increase of certain specific dihydroceramides. A novel method employing supplementation of individual fatty acids, sphinganine, and the dihydroceramide desaturase-1 (DES inhibitor, GT-11, was used to increase de novo dihydroceramide synthesis and absolute levels of specific dihydroceramides and ceramides. Sphingolipidomic analyses of four T-cell ALL cell lines revealed strong positive correlations between cytotoxicity and levels of C22:0-dihydroceramide (ρ = 0.74-0.81, P ≤ 0.04 and C24:0-dihydroceramide (ρ = 0.84-0.90, P ≤ 0.004, but not between total or other individual dihydroceramides, ceramides, or sphingoid bases or phosphorylated derivatives. Selective increase of C22:0- and C24:0-dihydroceramide increased level and flux of autophagy marker, LC3B-II, and increased DNA fragmentation (TUNEL assay in the absence of an increase of reactive oxygen species; pan-caspase inhibition blocked DNA fragmentation but not cell death. C22:0-fatty acid supplemented to 4-HPR treated cells further increased C22:0-dihydroceramide levels (P ≤ 0.001 and cytotoxicity (P ≤ 0.001. These data demonstrate that increases of specific dihydroceramides are cytotoxic to T-cell ALL cells by a caspase-independent, mixed cell death mechanism associated with increased autophagy and suggest that dihydroceramides may contribute to 4-HPR-induced cytotoxicity. The targeted increase of specific acyl chain dihydroceramides

A cytotoxic serine proteinase isolated from mouse submandibular gland.

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Shimamura, T; Nagumo, N; Ikigai, H; Murakami, K; Okubo, S; Toda, M; Ohnishi, R; Tomita, M

1989-08-01

We have isolated a novel cytotoxic factor from the submandibular glands of male BALB/c mice by Sephadex G-50 gel filtration chromatography and reverse-phase HPLC. The cytotoxic factor is a serine proteinase, which belongs to the mouse glandular kallikrein (mGK) family, with an Mr of approximately 27,000. The purified serine proteinase showed cytotoxic activity against mouse thymocytes in a dose-dependent manner, and a serine proteinase inhibitor, diisopropyl fluorophosphate, blocked its cytotoxic activity.

Potential genotoxic and cytotoxicity of emamectin benzoate in human normal liver cells.

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Zhang, Zhijie; Zhao, Xinyu; Qin, Xiaosong

2017-10-10

Pesticide residue inducing cancer-related health problems draw people more attention recently. Emamectin benzoate (EMB) has been widely used in agriculture around the world based on its specificity targets. Although potential risk and the molecular mechanism of EMB toxicity to human liver has not been well-characterized. Unlike well-reported toxicity upon central nervous system, potential genotoxic and cytotoxicity of EMB in human liver cell was ignored and very limited. In this study, we identify genotoxicity and cytotoxicity of EMB to human normal liver cells (QSG7701 cell line) in vitro . We demonstrate that EMB inhibited the viability of QSG7701 cells and induced the DNA damage. Established assays of cytotoxicity were performed to characterize the mechanism of EMB toxicity on QSG7701 cells. Typical chromatin condensation and DNA fragmentation indicated the apoptosis of QSG7701 cells induced by EMB. And the intracellular biochemical results demonstrated that EMB-enhanced apoptosis of QSG7701 cells concurrent with generated ROS, a loss of mitochondrial membrane potential, the cytochrome-c release, up regulate the Bax/Bcl-2 and the activation of caspase-9/-3. Our results of EMB induces the death of QSG7701 cells maybe via mitochondrial-mediated intrinsic apoptotic pathways would contribute to promote the awareness of EMB as an extensive used pesticide to human being effects and reveal the underlying mechanisms of potential genotoxic.

System chemical biology studies of endocrine disruptors

DEFF Research Database (Denmark)

Taboureau, Olivier; Oprea, Tudor I.

Endocrine disrupting chemicals (EDCs) alter hormonal balance and other physiological systems through inappropriate developmental or adult exposure, perturbing the reproductive function of further generations. While disruption of key receptors (e.g., estrogen, androgen, and thyroid) at the ligand...

Monogenic autoimmune diseases of the endocrine system.

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Johnson, Matthew B; Hattersley, Andrew T; Flanagan, Sarah E

2016-10-01

The most common endocrine diseases, type 1 diabetes, hyperthyroidism, and hypothyroidism, are the result of autoimmunity. Clustering of autoimmune endocrinopathies can result from polygenic predisposition, or more rarely, may present as part of a wider syndrome due to a mutation within one of seven genes. These monogenic autoimmune diseases show highly variable phenotypes both within and between families with the same mutations. The average age of onset of the monogenic forms of autoimmune endocrine disease is younger than that of the common polygenic forms, and this feature combined with the manifestation of other autoimmune diseases, specific hallmark features, or both, can inform clinicians as to the relevance of genetic testing. A genetic diagnosis can guide medical management, give an insight into prognosis, inform families of recurrence risk, and facilitate prenatal diagnoses. Copyright © 2016 Elsevier Ltd. All rights reserved.

Endoplasmic Reticulum (ER Stress and Endocrine Disorders

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Daisuke Ariyasu

2017-02-01

Full Text Available The endoplasmic reticulum (ER is the organelle where secretory and membrane proteins are synthesized and folded. Unfolded proteins that are retained within the ER can cause ER stress. Eukaryotic cells have a defense system called the “unfolded protein response” (UPR, which protects cells from ER stress. Cells undergo apoptosis when ER stress exceeds the capacity of the UPR, which has been revealed to cause human diseases. Although neurodegenerative diseases are well-known ER stress-related diseases, it has been discovered that endocrine diseases are also related to ER stress. In this review, we focus on ER stress-related human endocrine disorders. In addition to diabetes mellitus, which is well characterized, several relatively rare genetic disorders such as familial neurohypophyseal diabetes insipidus (FNDI, Wolfram syndrome, and isolated growth hormone deficiency type II (IGHD2 are discussed in this article.

Endoplasmic Reticulum (ER) Stress and Endocrine Disorders

Science.gov (United States)

Ariyasu, Daisuke; Yoshida, Hiderou; Hasegawa, Yukihiro

2017-01-01

The endoplasmic reticulum (ER) is the organelle where secretory and membrane proteins are synthesized and folded. Unfolded proteins that are retained within the ER can cause ER stress. Eukaryotic cells have a defense system called the “unfolded protein response” (UPR), which protects cells from ER stress. Cells undergo apoptosis when ER stress exceeds the capacity of the UPR, which has been revealed to cause human diseases. Although neurodegenerative diseases are well-known ER stress-related diseases, it has been discovered that endocrine diseases are also related to ER stress. In this review, we focus on ER stress-related human endocrine disorders. In addition to diabetes mellitus, which is well characterized, several relatively rare genetic disorders such as familial neurohypophyseal diabetes insipidus (FNDI), Wolfram syndrome, and isolated growth hormone deficiency type II (IGHD2) are discussed in this article. PMID:28208663