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Sample records for spexin inhibits adrenocortical

  1. Spexin is a Novel Human Peptide that Reduces Adipocyte Uptake of Long Chain Fatty Acids and Causes Weight Loss in Rodents with Diet-induced Obesity*

    Science.gov (United States)

    Walewski, José L.; Ge, Fengxia; Lobdell, Harrison; Levin, Nancy; Schwartz, Gary J.; Vasselli, Joseph; Pomp, Afons; Dakin, Gregory; Berk, Paul D.

    2014-01-01

    Objective Microarray studies identified Ch12:orf39 (Spexin) as the most dysregulated gene in obese human fat. Therefore we examined its role in obesity pathogenesis. Design and Methods Spexin effects on food intake, meal patterns, body weight, Respiratory Exchange Ratio (RER), and locomotor activity were monitored electronically in C57BL/6J mice or Wistar rats with dietary-induced obesity (DIO). Its effects on adipocyte [3H]-oleate uptake were determined. Results In humans, Spexin gene expression was down-regulated 14.9-fold in obese omental and subcutaneous fat. Circulating Spexin changed in parallel, correlating (r = −0.797) with Leptin. In rats, Spexin (35 μg/kg/day s.c) reduced caloric intake ~32% with corresponding weight loss. Meal patterns were unaffected. In mice, Spexin (25 μg/kg/day i.p.) significantly reduced the RER at night, and increased locomotion. Spexin incubation in vitro significantly inhibited facilitated fatty acid (FA) uptake into DIO mouse adipocytes. Conditioned taste aversion testing (70μg/kg/day i.p.) demonstrated no aversive Spexin effects. Conclusions Spexin gene expression is markedly down-regulated in obese human fat. The peptide produces weight loss in DIO rodents. Its effects on appetite and energy regulation are presumably central; those on adipocyte FA uptake appear direct and peripheral. Spexin is a novel hormone involved in weight regulation, with potential for obesity therapy. PMID:24550067

  2. Spexin is a novel human peptide that reduces adipocyte uptake of long chain fatty acids and causes weight loss in rodents with diet-induced obesity.

    Science.gov (United States)

    Walewski, José L; Ge, Fengxia; Lobdell, Harrison; Levin, Nancy; Schwartz, Gary J; Vasselli, Joseph R; Pomp, Afons; Dakin, Gregory; Berk, Paul D

    2014-07-01

    Microarray studies identified Ch12:orf39 (Spexin) as the most down-regulated gene in obese human fat. Therefore, we examined its role in obesity pathogenesis. Spexin effects on food intake, meal patterns, body weight, respiratory exchange ratio (RER), and locomotor activity were monitored electronically in C57BL/6J mice or Wistar rats with diet-induced obesity (DIO). Its effects on adipocyte [(3)H]-oleate uptake were determined. In humans, Spexin gene expression was down-regulated 14.9-fold in obese omental and subcutaneous fat. Circulating Spexin changed in parallel, correlating (r = -0.797) with Leptin. In rats, Spexin (35 µg/kg/day SC) reduced caloric intake ∼32% with corresponding weight loss. Meal patterns were unaffected. In mice, Spexin (25 µg/kg/day IP) significantly reduced the RER at night, and increased locomotion. Spexin incubation in vitro significantly inhibited facilitated fatty acid (FA) uptake into DIO mouse adipocytes. Conditioned taste aversion testing (70 µg/kg/day IP) demonstrated no aversive Spexin effects. Spexin gene expression is markedly down-regulated in obese human fat. The peptide produces weight loss in DIO rodents. Its effects on appetite and energy regulation are presumably central; those on adipocyte FA uptake appear direct and peripheral. Spexin is a novel hormone involved in weight regulation, with potential for obesity therapy. Copyright © 2014 The Obesity Society.

  3. Resveratrol inhibits steroidogenesis in human fetal adrenocortical cells at the end of first trimester

    DEFF Research Database (Denmark)

    Savchuk, Iuliia; Morvan, Marie-Line; Søeborg, Tue

    2017-01-01

    SCOPE: Resveratrol has a diverse array of healthful effects on metabolic parameters in different experimental paradigms but has also potential to inhibit steroidogenesis in rodent adrenals. The aim of the present study was to characterize the effects of resveratrol on human fetal adrenal...... steroidogenesis at gestational weeks (GW) 9-12. METHODS AND RESULTS: Adrenals from aborted fetuses (GW10-12) were used to prepare primary cultures of human fetal adrenocortical cells (HFAC). HFAC were treated in the presence or absence of ACTH (10 ng/ml) with or without resveratrol (10 μM) for 24 hours....... The production of steroids by HFAC was analyzed by gas and liquid chromatography coupled to tandem/mass spectrometry. The expression of steroidogenic enzymes at GW 9-12 was quantified by automated Western blotting. We observed that resveratrol significantly suppressed synthesis of dehydroepiandrosterone (DHEA...

  4. Rosiglitazone Inhibits Adrenocortical Cancer Cell Proliferation by Interfering with the IGF-IR Intracellular Signaling

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    Luconi Michaela

    2008-07-01

    Full Text Available Rosiglitazone (RGZ, a thiazolidinedione ligand of the peroxisome proliferator-activated receptor (PPAR-γ, has been recently described as possessing antitumoral properties. We investigated RGZ effect on cell proliferation in two cell line models (SW13 and H295R of human adrenocortical carcinoma (ACC and its interaction with the signaling pathways of the activated IGF-I receptor (IGF-IR. We demonstrate a high expression of IGF-IR in the two cell lines and in ACC. Cell proliferation is stimulated by IGF-I in a dose- and time-dependent manner and is inhibited by RGZ. The analysis of the main intracellular signaling pathways downstream of the activated IGF-IR, phosphatidyl inositol 3-kinase (PI3K-Akt, and extracellular signal-regulated kinase (ERK1/2 cascades reveals that RGZ rapidly interferes with the Akt and ERK1/2 phosphorylation/activation which mediates IGF-I stimulated proliferation. In conclusion, our results suggest that RGZ exerts an inhibitory effect on human ACC cell proliferation by interfering with the PI3K/Akt and ERK1/2 signaling pathways downstream of the activated IGF-IR.

  5. The N-terminal neurotensin fragment, NT1-11, inhibits cortisol secretion by human adrenocortical cells.

    Science.gov (United States)

    Sicard, Flavie; Contesse, Vincent; Lefebvre, Hervé; Ait-Ali, Djida; Gras, Marjorie; Cartier, Dorthe; Decker, Annick; Chartrel, Nicolas; Anouar, Youssef; Vaudry, Hubert; Delarue, Catherine

    2006-08-01

    Neurotensin (NT) modulates corticosteroid secretion from the mammalian adrenal gland. The objective of this study was to investigate the possible involvement of NT in the control of cortisol secretion in the human adrenal gland. In vitro studies were conducted on cultured human adrenocortical cells. This study was conducted in a university research laboratory. Adrenal explants from patients undergoing expanded nephrectomy for kidney cancer were studied. Cortisol secretion from cultured adrenocortical cells was measured. NT1-11, the N-terminal fragment of NT, dose-dependently inhibited basal and ACTH-stimulated cortisol production by human adrenocortical cells in primary culture. In contrast, NT had no influence on cortisol output at concentrations up to 10(-6) m. HPLC and RT-PCR analyses failed to detect any significant amounts of NT and NT mRNA, respectively, in adrenal extracts. Molecular and pharmacological studies were performed to determine the type of NT receptor involved in the corticostatic effect of NT1-11. RT-PCR analysis revealed the expression of NT receptor type (NTR) 3 mRNA but not NTR1 and NTR2 mRNAs in the human adrenal tissue. However, the pharmacological profile of the adrenal NT1-11 receptor was different from that of NTR3, indicating that this receptor type is not involved in the action of NT1-11 on corticosteroidogenesis. Our results indicate that NT1-11 may act as an endocrine factor to inhibit cortisol secretion through activation of a receptor distinct from the classical NTR1, NTR2, and NTR3.

  6. Adrenocortical cancer

    DEFF Research Database (Denmark)

    Payabyab, Eden C.; Balasubramaniam, Sanjeeve; Edgerly, Maureen

    2016-01-01

    The development of new therapies has lagged behind for rare cancers without defined therapeutic targets. Adrenocortical cancer is no exception. Mitotane, an older agent considered "adrenolytic," is used both to control symptoms in advanced disease and as adjuvant therapy after surgical resection....... Molecular characterization of adrenocortical cancer has deepened our understanding of this genetically complex disease while identifying subgroups whose importance remains to be determined. Unfortunately, such studies have yet to demonstrate a therapeutic target for drug development, and to date......, no targeted therapy has achieved meaningful outcomes. Consequently, first-line therapy for metastatic disease remains a combination regimen of etoposide, doxorubicin, and cisplatinum established in a randomized clinical trial. In addition to evaluating recent studies in adrenocortical cancer, we raise one...

  7. Circulating Spexin Levels Negatively Correlate With Age, BMI, Fasting Glucose, and Triglycerides in Healthy Adult Women.

    Science.gov (United States)

    Lin, Cheng-Yuan; Huang, Tao; Zhao, Ling; Zhong, Linda L D; Lam, Wai Ching; Fan, Bao-Min; Bian, Zhao-Xiang

    2018-05-01

    Spexin is a newly identified neuropeptide that is involved in satiety control, glucose, and lipids metabolism. It has also been related to human diseases, such as obesity and type 2 diabetes. However, whether spexin changes with age or not is still unclear. The aim of this study is to investigate the relationship between circulating spexin levels and age and to study their interaction effects on body mass index (BMI), fasting glucose, and -lipids. This is a cross-sectional study, including 68 healthy adult women whose ages are in a wide range (minimum: 23; median: 38.5; maximum: 64). The serum spexin levels were measured by an enzyme-linked immunosorbent assay. Fasting glucose, total cholesterol, triglycerides (TG), alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, urea, and creatinine were measured by routine biochemical test. Shapiro-Wilk's test, Spearman and Pearson correlation analyses, χ 2 test, and two-way analysis of variance were used to interpret the data. Serum spexin levels are significantly correlated with age (Spearman r = -0.277, P = 0.022), BMI (Spearman r = -0.445, P glucose (Spearman r = -0.302, P = 0.014), and TG (Spearman r = -0.324, P = 0.008). Spexin levels independently predict the risk of high BMI and high fasting glucose. No interaction effects of spexin and age on BMI and fasting glucose were found. Circulating spexin levels decrease with age, suggesting a possible role of this peptide in aging-related functions and disorders. Further investigations are needed to expand the clinical significance of this finding.

  8. Spexin peptide is expressed in human endocrine and epithelial tissues and reduced after glucose load in type 2 diabetes.

    Science.gov (United States)

    Gu, Liping; Ma, Yuhang; Gu, Mingyu; Zhang, Ying; Yan, Shuai; Li, Na; Wang, Yufan; Ding, Xiaoying; Yin, Jiajing; Fan, Nengguang; Peng, Yongde

    2015-09-01

    Spexin mRNA and protein are widely expressed in rat tissues and associate with weight loss in rodents of diet-induced obesity. Its location in endocrine and epithelial cells has also been suggested. Spexin is a novel peptide that involves weight loss in rodents of diet-induced obesity. Therefore, we aimed to examine its expression in human tissues and test whether spexin could have a role in glucose and lipid metabolism in type 2 diabetes mellitus (T2DM). The expression of the spexin gene and immunoreactivity in the adrenal gland, skin, stomach, small intestine, liver, thyroid, pancreatic islets, visceral fat, lung, colon, and kidney was higher than that in the muscle and connective tissue. Immunoreactive serum spexin levels were reduced in T2DM patients and correlated with fasting blood glucose (FBG, r=-0.686, Pepithelial tissues, indicating that spexin may be involved in physiological functions of endocrine and in several other tissues. Circulating spexin levels are low in T2DM patients and negatively related to blood glucose and lipids suggesting that the peptide may play a role in glucose and lipid metabolism in T2DM. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  9. Adrenocortical Carcinoma—Health Professional Version

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    Adrenocortical carcinoma is also called cancer of the adrenal cortex. A tumor of the adrenal cortex may be functioning or nonfunctioning. Most adrenocortical tumors are functioning. Find evidence-based information on adrenocortical carcinoma including treatment and research.

  10. Adrenocortical tumors in children

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    R.C. Ribeiro

    2000-10-01

    Full Text Available Childhood adrenocortical tumors (ACT are rare. In the USA, only about 25 new cases occur each year. In Southern Brazil, however, approximately 10 times that many cases are diagnosed each year. Most cases occur in the contiguous states of São Paulo and Paraná. The cause of this higher rate has not been identified. Familial genetic predisposition to cancer (p53 mutations and selected genetic syndromes (Beckwith-Wiedemann syndrome have been associated with childhood ACT in general but not with the Brazilian counterpart. Most of the affected children are young girls with classic endocrine syndromes (virilizing and/or Cushing. Levels of urinary 17-ketosteroids and plasma dehydroepiandrosterone sulfate (DHEA-S, which are abnormal in approximately 90% of the cases, provide the pivotal clue to a diagnosis of ACT. Typical imaging findings of pediatric ACT consist of a large, well-defined suprarenal tumor containing calcifications with a thin capsule and central necrosis or hemorrhage. The pathologic classification of pediatric ACT is troublesome. Even an experienced pathologist can find it difficult to differentiate carcinoma from adenoma. Surgery is the single most important procedure in the successful treatment of ACT. The role of chemotherapy in the management of childhood ACT has not been established although occasional tumors are responsive to mitotane or cisplatin-containing regimens. Because of the heterogeneity and rarity of the disease, prognostic factors have been difficult to establish in pediatric ACT. Patients with incomplete tumor resection or with metastatic disease at diagnosis have a dismal prognosis. In patients with localized and completely resected tumors, the size of the tumor has predictive value. Patients with large tumors have a much higher relapse rate than those with small tumors.

  11. Primary pigmented nodular adrenocortical disease

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    Marie T Manipadam

    2011-01-01

    Full Text Available Primary pigmented nodular adrenocortical disease (PPNAD is a rare cause of ACTH-independent Cushing′s syndrome and has characteristic gross and microscopic pathologic findings. We report a case of PPNAD in a 15-year-old boy, which was not associated with Carney′s complex. Bilateral adrenalectomy is the treatment of choice.

  12. Isolation of rat adrenocortical mitochondria

    Energy Technology Data Exchange (ETDEWEB)

    Solinas, Paola [Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106 (United States); Department of Medicine, Center for Mitochondrial Disease, School of Medicine, Case Western Reserve University, Cleveland, OH 44106 (United States); Fujioka, Hisashi [Electron Microscopy Facility, Department of Pharmacology, Center for Mitochondrial Disease, School of Medicine, Case Western Reserve University, Cleveland, OH 44106 (United States); Tandler, Bernard [Department of Biological Sciences, School of Dental Medicine, Center for Mitochondrial Disease, School of Medicine, Case Western Reserve University, Cleveland, OH 44106 (United States); Hoppel, Charles L., E-mail: charles.hoppel@case.edu [Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106 (United States); Department of Medicine, Center for Mitochondrial Disease, School of Medicine, Case Western Reserve University, Cleveland, OH 44106 (United States)

    2012-10-12

    Highlights: Black-Right-Pointing-Pointer A method for isolation of adrenocortical mitochondria from the adrenal gland of rats is described. Black-Right-Pointing-Pointer The purified isolated mitochondria show excellent morphological integrity. Black-Right-Pointing-Pointer The properties of oxidative phosphorylation are excellent. Black-Right-Pointing-Pointer The method increases the opportunity of direct analysis of adrenal mitochondria from small animals. -- Abstract: This report describes a relatively simple and reliable method for isolating adrenocortical mitochondria from rats in good, reasonably pure yield. These organelles, which heretofore have been unobtainable in isolated form from small laboratory animals, are now readily accessible. A high degree of mitochondrial purity is shown by the electron micrographs, as well as the structural integrity of each mitochondrion. That these organelles have retained their functional integrity is shown by their high respiratory control ratios. In general, the biochemical performance of these adrenal cortical mitochondria closely mirrors that of typical hepatic or cardiac mitochondria.

  13. MicroRNAs as potential biomarkers in adrenocortical cancer: progress and challenges

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    Nadia eCHERRADI

    2016-01-01

    Full Text Available Adrenocortical carcinoma is a rare malignancy with poor prognosis and limited therapeutic options. Over the last decade, pan-genomic analyses of genetic and epigenetic alterations and genome-wide expression profile studies allowed major advances in the understanding of the molecular genetics of adrenocortical carcinoma. Besides the well-known dysfunctional molecular pathways in adrenocortical tumors such as the IGF2 pathway, the Wnt pathway and TP53, high-throughput technologies enabled a more comprehensive genomic characterization of adrenocortical cancer. Integration of expression profile data with exome sequencing, SNP array analysis, methylation and microRNA profiling led to the identification of subgroups of malignant tumors with distinct molecular alterations and clinical outcomes. MicroRNAs post-transcriptionally silence their target gene expression either by degrading mRNA or by inhibiting translation. Although our knowledge of the contribution of deregulated microRNAs to the pathogenesis of adrenocortical carcinoma is still in its infancy, recent studies support their relevance in gene expression alterations in these tumors. Some microRNAs have been shown to carry potential diagnostic and prognostic values while others may be good candidates for therapeutic interventions. With the emergence of disease-specific blood-borne microRNAs signatures, analyses of small cohorts of patients with adrenocortical carcinoma suggest that circulating microRNAs represent promising non-invasive biomarkers of malignancy or recurrence. However, some technical challenges still remain, and most of the microRNAs reported in the literature have not yet been validated in sufficiently powered and longitudinal studies. In this review, we discuss the current knowledge regarding the deregulation of tumor-associated and circulating microRNAs in adrenocortical carcinoma patients, while emphasizing their potential significance in adrenocortical carcinoma pathogenic

  14. Feminizing Adrenocortical Carcinoma Without Gynecomastia

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    Farida Chentli1*,

    2017-07-01

    Full Text Available Malignant feminizing adrenocortical tumors are exceedingly rare. Their main presentation is gynecomastia. In these estrogen secreting tumors (with or without other adrenocortical hormones lack of gynecomastia is exceptional as in our case. A 44-year-old man presented with abdominal pain. Radiological assessment revealed a tumor measuring 120 × 95 mm in the retroperitoneal area with numerous metastases. Pathological examination pleaded for an adrenal origin with a Weiss’s score of 5. Six months later, the tumor relapsed, and he had a second surgery and was sent for hormone assessment. Clinical examination showed a skinny man with severe fatigue. He had no Cushingoid features. Gynecomastia and galactorrhea were absent. Penile length, testicular volume, and body hair growth were normal. Several cutaneous nodules were present. Biological assessment showed high morning plasma cortisol, which failed to be suppressed by treatment with 2 mg dexamethasone. Plasma estradiol and 17OH progesterone levels were high, but his testosterone levels were low. Radiological exploration showed numerous metastases: pleural, pulmonary, retroperitoneal, and abdominal. He was treated with classical chemotherapy, but he died four months after diagnosis.

  15. Adrenocortical zonation, renewal, and remodeling

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    Marjut ePihlajoki

    2015-03-01

    Full Text Available The adrenal cortex is divided into concentric zones. In humans the major cortical zones are the zona glomerulosa, zona fasciculata, and zona reticularis. The adrenal cortex is a dynamic organ in which senescent cells are replaced by newly differentiated ones. This constant renewal facilitates organ remodeling in response to physiological demand for steroids. Cortical zones can reversibly expand, contract, or alter their biochemical profiles to accommodate needs. Pools of stem/progenitor cells in the adrenal capsule, subcapsular region, and juxtamedullary region can differentiate to repopulate or expand zones. Some of these pools appear to be activated only during specific developmental windows or in response to extreme physiological demand. Senescent cells can also be replenished through direct lineage conversion; for example, cells in the zona glomerulosa can transform into cells of the zona fasciculata. Adrenocortical cell differentiation, renewal, and function are regulated by a variety of endocrine/paracrine factors including adrenocorticotropin, angiotensin II, insulin-related growth hormones, luteinizing hormone, activin, and inhibin. Additionally, zonation and regeneration of the adrenal cortex are controlled by developmental signaling pathways, such as the sonic hedgehog, delta-like homologue 1, fibroblast growth factor, and WNT/β-catenin pathways. The mechanisms involved in adrenocortical remodeling are complex and redundant so as to fulfill the offsetting goals of organ homeostasis and stress adaptation.

  16. Fluconazole inhibits human adrenocortical steroidogenesis in vitro

    NARCIS (Netherlands)

    R. van der Pas (Rob); L.J. Hofland (Leo); J. Hofland (Johannes); A.E. Taylor (A.); W. Arlt (Wiebke); J. Steenbergen (Jacobie); P.M. van Koetsveld (Peter); W.W. de Herder (Wouter); F.H. de Jong (Frank); R.A. Feelders (Richard)

    2012-01-01

    textabstractThe antifungal agent ketoconazole is often used to suppress cortisol production in patients with Cushing's syndrome (CS). However, ketoconazole has serious side effects and is hepatotoxic. Here, the in vitro effects of ketoconazole and fluconazole, which might be less toxic, on human

  17. Childhood Adrenocortical Tumours: a Review

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    Marques-Pereira Rosana

    2006-05-01

    Full Text Available Abstract Childhood adrenocortical tumour (ACT is not a common disease, but in southern Brazil the prevalence is 15 times higher than in other parts of the world. One hundred and thirty-seven patients have been identified and followed by our group over the past four decades. Affected children are predominantly girls, with a female-to-male ratio of 3.5:1 in patients below 4 years of age. Virilization alone (51.6% or mixed with Cushing's syndrome (42.0% was the predominant clinical picture observed in these patients. Tumours are unilateral, affecting both glands equally. TP53 R337H germline mutations underlie most childhood ACTs in southern Brazil. Epidemiological data from our casuistic studies revealed that this mutation has ~10% penetrance for ACT. Surgery is the definitive treatment, and a complete resection should always be attempted. Although adjuvant chemotherapy has shown some encouraging results, its influence on overall outcome is small. The survival rate is directly correlated to tumour size; patients with small, completely excised tumours have survival rates close to 90%, whereas in those patients with inoperable tumours and/or metastatic disease it is less than 10%. In the group of patients with large, excisable tumours, half of them have an intermediate outcome. Recent molecular biology techniques and genomic approaches may help us to better understand the pathogenesis of ACT, the risk of developing a tumour when TP53 R337H is present, and to predict its outcome. An ongoing pilot study consisting of close monitoring of healthy carriers of the TP53 R337H mutation - siblings and first-degree relatives of known affected cases - aims at the early detection of ACTs and an improvement of the cure rate.

  18. Adrenocortical function in hospitalised patients with active ...

    African Journals Online (AJOL)

    2006-05-17

    May 17, 2006 ... Tuberculosis (TB) is a major cause of morbidity and mortality in sub-Sah aran Africa, ... To assess whether adrenocortical function was compromised in patients with active tuberculosis. (TB) during the first 5 days of ..... Hernandez-Pando R, de la Luz Streber M, Orozco H, et al. Emergent immunoregulatory.

  19. Adjuvant and Definitive Radiotherapy for Adrenocortical Carcinoma

    International Nuclear Information System (INIS)

    Sabolch, Aaron; Feng, Mary; Griffith, Kent; Hammer, Gary; Doherty, Gerard; Ben-Josef, Edgar

    2011-01-01

    Purpose: To evaluate the impact of both adjuvant and definitive radiotherapy on local control of adrenocortical carcinoma. Methods and Materials: Outcomes were analyzed from 58 patients with 64 instances of treatment for adrenocortical carcinoma at the University of Michigan's Multidisciplinary Adrenal Cancer Clinic. Thirty-seven of these instances were for primary disease, whereas the remaining 27 were for recurrent disease. Thirty-eight of the treatment regimens involved surgery alone, 10 surgery plus adjuvant radiotherapy, and 16 definitive radiotherapy for unresectable disease. The effects of patient, tumor, and treatment factors were modeled simultaneously using multiple variable Cox proportional hazards regression for associations with local recurrence, distant recurrence, and overall survival. Results: Local failure occurred in 16 of the 38 instances that involved surgery alone, in 2 of the 10 that consisted of surgery plus adjuvant radiotherapy, and in 1 instance of definitive radiotherapy. Lack of radiotherapy use was associated with 4.7 times the risk of local failure compared with treatment regimens that involved radiotherapy (95% confidence interval, 1.2-19.0; p = 0.030). Conclusions: Radiotherapy seems to significantly lower the risk of local recurrence/progression in patients with adrenocortical carcinoma. Adjuvant radiotherapy should be strongly considered after surgical resection.

  20. Diagnosis of bilateral adrenocortical hemorrhage by computed tomography

    International Nuclear Information System (INIS)

    Liu, L.; Haskin, M.E.; Rose, L.I.; Bemis, C.E.

    1982-01-01

    Adrenocortical hemorrhage has been diagnosed on the basis of the clinical presentation and response to steroids or autopsy findings. Prompt recognition of the disease has been difficult because of its similarity to other disorders. We report the diagnosis of a bilateral adrenocortical hemorrhage by computed tomography (CT), followed by biochemical confirmation of the diagnosis

  1. Morphological changes in the pituitary-adrenocortical axis in natives of La Paz

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    Gosney, John; Heath, Donald; Williams, David; Rios-Dalenz, Jaime

    1991-03-01

    Increased activity of the hypothalamic-pituitary-adrenocortical axis is part of the response to the stress of initial exposure to hypoxia, but there is evidence to suggest that it persists after homeostatic stability has been regained and acclimatization achieved. The adrenal glands of five lifelong residents of La Paz, Bolivia, who had lived at altitudes in the range 3600 3800 m, were significantly larger than those in age-matched controls from sea level (15.3g vs 10.4g; Ppituitary glands of the highlanders were not significantly different in size from those of the controls (0.67 g vs 0.51 g), but contained larger populations of corticotrophs expressed in terms of the total cell population of their anterior lobes (25.6% vs 19.4%; P<0.001). In conjunction with other studies of this endocrine axis in man and animals exposed to a hypoxic environment, these data suggest that greater amounts of adrenocorticotrophic hormone (ACTH) are required to maintain normal adrenocortical function under such circumstances, probably as a result of hypoxic inhibition of adrenocortical sensitivity to stimulation. Physiological hyperplasia of the adrenal cortex may be common in people living at high altitude.

  2. High-density lipoprotein is a potential growth factor for adrenocortical cells

    International Nuclear Information System (INIS)

    Murao, Koji; Imachi, Hitomi; Cao, Wenming; Yu, Xiao; Li, Junhua; Yoshida, Kazuya; Ahmed, Rania A.M.; Matsumoto, Kensuke; Nishiuchi, Takamasa; Wong, Norman C.W.; Ishida, Toshihiko

    2006-01-01

    The entry of cholesterol contained within high-density lipoprotein (HDL) into adrenocortical cells is mediated by a human homologue of SR-BI, CD36, and LIMPII Analogous-1 (CLA-1) and thus augmenting their growth. To address the role of CLA-1, we created a mutant mCLA that lacked the C-terminal tail. HDL CE selective uptake by cells carrying the mCLA-1 receptor was fully active and equivalent to those transfected with full-length CLA-1 (fCLA-1). Expression of mCLA inhibited the proliferation of an adrenocortical cell line and the incorporation of [ 3 H]thymidine into the cells. This effect was sensitive to wortmannin, an inhibitor of phosphoinositide 3-kinase (PI3K). Our transcriptional studies revealed that the inhibitory action of mCLA required the transcriptional factor AP-1 and the effect of HDL on AP-1 activation was also abrogated by wortmannin. These findings raise the possibility that the inhibitors of the effects of HDL may be of therapeutic value for adrenocortical tumor

  3. Visualization of adrenocortical carcinoma with 131I-Adosterol

    International Nuclear Information System (INIS)

    Maruoka, Shin; Nakamura, Mamoru

    1987-01-01

    There are very few literatures on successful visualization of adrenocortical carcinoma by means of 131 I-iodocholesterol scintigraphy, although many reports have referred to utility of 131 I-iodocholesterol scintigraphy for adrenal disorders. Since 1976, we have experienced 4 cases of adrenocortical carcinoma which were delineated by 131 I-6β-iodomethyl-19-norcholesterol ( 131 I-Adosterol). Three of 4 cases were adrenocortical carcinoma with Cushing's syndrome, and one was adrenocortical carcinoma with adrenogenital syndrome. In 3 cases of cortisol secreting adrenocortical carcinoma, uptake in the tumor and lack of uptake in the contralateral adrenal gland were seen. Faint to moderate uptakes were observed in the 2 cases, but another one showed as high uptake as seen in adenoma. Patient with androgen secreting adrenocortical carcinoma had increased uptake in the tumor and showed faint uptake in the contralateral adrenal gland. Intensity of 131 I-Adosterol uptake in adrenocortical carcinoma seems to depend on the extent of tumor necrosis, cell differentiation and function. (author)

  4. Visualization of adrenocortical carcinoma with /sup 131/I-Adosterol

    Energy Technology Data Exchange (ETDEWEB)

    Maruoka, Shin; Nakamura, Mamoru

    1987-01-01

    There are very few literatures on successful visualization of adrenocortical carcinoma by means of /sup 131/I-iodocholesterol scintigraphy, although many reports have referred to utility of /sup 131/I-iodocholesterol scintigraphy for adrenal disorders. Since 1976, we have experienced 4 cases of adrenocortical carcinoma which were delineated by /sup 131/I-6US -iodomethyl-19-norcholesterol (/sup 131/I-Adosterol). Three of 4 cases were adrenocortical carcinoma with Cushing's syndrome, and one was adrenocortical carcinoma with adrenogenital syndrome. In 3 cases of cortisol secreting adrenocortical carcinoma, uptake in the tumor and lack of uptake in the contralateral adrenal gland were seen. Faint to moderate uptakes were observed in the 2 cases, but another one showed as high uptake as seen in adenoma. Patient with androgen secreting adrenocortical carcinoma had increased uptake in the tumor and showed faint uptake in the contralateral adrenal gland. Intensity of /sup 131/I-Adosterol uptake in adrenocortical carcinoma seems to depend on the extent of tumor necrosis, cell differentiation and function.

  5. Primary pigmented nodular adrenocortical disease presenting with a unilateral adrenocortical nodule treated with bilateral laparoscopic adrenalectomy: a case report

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    Kaltsas Gregory

    2010-07-01

    Full Text Available Abstract Introduction Primary pigmented nodular adrenocortical disease is a rare cause of adrenocorticotropic hormone-independent Cushing's syndrome. We report an uncommon primary pigmented nodular adrenocortical disease case presenting with a unilateral adrenocortical nodule and provide a brief overview of the existing literature. Case presentation A 27-year-old Caucasian woman was admitted to our Department with adrenocorticotropic hormone-independent Cushing's syndrome. Its cause was initially considered a left adrenocortical adenoma based on computer tomography imaging. The patient underwent left laparoscopic adrenalectomy and histological examination revealed pigmented micronodular adrenal hyperplasia. Evaluation for the presence of Carney complex was negative. Six months later recurrence of hypercortisolism was documented and a right laparoscopic adrenalectomy was performed further establishing the diagnosis of primary pigmented nodular adrenocortical disease. After a nine-year follow-up there is no evidence of residual disease. Conclusions Even though primary pigmented nodular adrenocortical disease is a rare cause of Cushing's syndrome, it should be included in the differential diagnosis of adrenocorticotropic hormone-independent Cushing's syndrome, especially because adrenal imaging can be misleading mimicking other adrenocortical diseases. Bilateral laparoscopic adrenalectomy is the preferred treatment in these subjects.

  6. Feminizing adrenocortical carcinoma with distant metastases: can surgery be considered?

    Directory of Open Access Journals (Sweden)

    Alessandro Fancellu

    2014-07-01

    Full Text Available Functioning adrenocortical carcinomas are rare diseases with dismal prognosis. A 41-year-old man presenting with gynecomastia had a giant feminizing adrenocortical carcinoma at stage IV. Although surgical resection was controversial, we removed the primary tumor to reduce the mass effects. He lived for 12 months with an acceptable quality of life. Gynecomastia may be the first sign of feminizing adrenal malignancies. Surgery may ameliorate the quality of life in selected patients with metastatic disease.

  7. Cell cycle dependent RRM2 may serve as proliferation marker and pharmaceutical target in adrenocortical cancer.

    Science.gov (United States)

    Grolmusz, Vince Kornél; Karászi, Katalin; Micsik, Tamás; Tóth, Eszter Angéla; Mészáros, Katalin; Karvaly, Gellért; Barna, Gábor; Szabó, Péter Márton; Baghy, Kornélia; Matkó, János; Kovalszky, Ilona; Tóth, Miklós; Rácz, Károly; Igaz, Péter; Patócs, Attila

    2016-01-01

    Adrenocortical cancer (ACC) is a rare, but agressive malignancy with poor prognosis. Histopathological diagnosis is challenging and pharmacological options for treatment are limited. By the comparative reanalysis of the transcriptional malignancy signature with the cell cycle dependent transcriptional program of ACC, we aimed to identify novel biomarkers which may be used in the histopathological diagnosis and for the prediction of therapeutical response of ACC. Comparative reanalysis of publicly available microarray datasets included three earlier studies comparing transcriptional differences between ACC and benign adrenocortical adenoma (ACA) and one study presenting the cell cycle dependent gene expressional program of human ACC cell line NCI-H295R. Immunohistochemical analysis was performed on ACC samples. In vitro effects of antineoplastic drugs including gemcitabine, mitotane and 9-cis-retinoic acid alone and in combination were tested in the NCI-H295R adrenocortical cell line. Upon the comparative reanalysis, ribonucleotide reductase subunit 2 (RRM2), responsible for the ribonucleotide dezoxyribonucleotide conversion during the S phase of the cell cycle has been validated as cell cycle dependently expressed. Moreover, its expression was associated with the malignancy signature, as well. Immunohistochemical analysis of RRM2 revealed a strong correlation with Ki67 index in ACC. Among the antiproliferative effects of the investigated compounds, gemcitabine showed a strong inhibition of proliferation and an increase of apoptotic events. Additionally, RRM2 has been upregulated upon gemcitabine treatment. Upon our results, RRM2 might be used as a proliferation marker in ACC. RRM2 upregulation upon gemcitabine treatment might contribute to an emerging chemoresistance against gemcitabine, which is in line with its limited therapeutical efficacy in ACC, and which should be overcome for successful clinical applications.

  8. Adrenocortical scintigraphy with {sup 131}I-6-beta-iodomethyl-norcholesterol (NP 59) in bilateral adrenocortical carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Ruiz Hernandez, G.; Pallares, F.J.C.; Avila y Avalos, C.R. de [Hospital Clinic Universitari de Valencia (Spain). Servei de Medicina Nuclear; Bartual, A.R.; Rodrigo, S.T.; Ampudia-Blasco, F.J. [Hospital Clinic Universitari de Valencia (Spain). Servei d`Endocrinologia

    1998-06-01

    A case of a 49-year-old man suffering from bilateral adrenocortical carcinoma with local and secondary rapid progression is reported. The results of adrenocortical scintigraphy (NP 59) and histological findings allowed the diagnosis. This case report and a literature review showed the importance of using adrenocortical scintigraphy as a complementary imaging procedure of CT or MR images. (orig.) [Deutsch] Es wird ueber einen 49jaehrigen Mann berichtet, der an einem beidseitigen Nebennierenrinden-Karzinom mit schneller lokaler und sekundaerer Progression leidet. Die Ergebnisse der Nebennierenrinden-Szintigraphie (NP 59) und Histologie ermoeglichten die Diagnose: Dieser Fallbericht und ein Literaturueberblick zeigen die Bedeutung der Nebennierenrinden-Szintigraphie als ein zusaetzliches bildgebendes Verfahren neben CT und NMR. (orig.)

  9. Rosiglitazone induces autophagy in H295R and cell cycle deregulation in SW13 adrenocortical cancer cells

    International Nuclear Information System (INIS)

    Cerquetti, Lidia; Sampaoli, Camilla; Amendola, Donatella; Bucci, Barbara; Masuelli, Laura; Marchese, Rodolfo; Misiti, Silvia; De Venanzi, Agostino; Poggi, Maurizio; Toscano, Vincenzo; Stigliano, Antonio

    2011-01-01

    Thiazolidinediones, specific peroxisome proliferator-activated receptor-γ (PPAR-γ) ligands, used in type-2 diabetes therapy, show favourable effects in several cancer cells. In this study we demonstrate that the growth of H295R and SW13 adrenocortical cancer cells is inhibited by rosiglitazone, a thiazolidinediones member, even though the mechanisms underlying this effect appeared to be cell-specific. Treatment with GW9662, a selective PPAR-γ-inhibitor, showed that rosiglitazone acts through both PPAR-γ-dependent and -independent mechanisms in H295R, while in SW13 cells the effect seems to be independent of PPAR-γ. H295R cells treated with rosiglitazone undergo an autophagic process, leading to morphological changes detectable by electron microscopy and an increased expression of specific proteins such as AMPKα and beclin-1. The autophagy seems to be independent of PPAR-γ activation and could be related to an increase in oxidative stress mediated by reactive oxygen species production with the disruption of the mitochondrial membrane potential, triggered by rosiglitazone. In SW13 cells, flow cytometry analysis showed an arrest in the G0/G1 phase of the cell cycle with a decrease of cyclin E and cdk2 activity, following the administration of rosiglitazone. Our data show the potential role of rosiglitazone in the therapeutic approach to adrenocortical carcinoma and indicate the molecular mechanisms at the base of its antiproliferative effects, which appear to be manifold and cell-specific in adrenocortical cancer lines.

  10. Rosiglitazone induces autophagy in H295R and cell cycle deregulation in SW13 adrenocortical cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Cerquetti, Lidia; Sampaoli, Camilla [Endocrinology, Department of Clinical and Molecular Medicine, Sant' Andrea Hospital, Faculty of Medicine and Psychology ' Sapienza' University of Rome, Via di Grottarossa, 1035-00189 Rome (Italy); Research Center S. Pietro Hospital, Via Cassia, 600-00189 Rome (Italy); Amendola, Donatella; Bucci, Barbara [Research Center S. Pietro Hospital, Via Cassia, 600-00189 Rome (Italy); Masuelli, Laura [Department of Experimental Medicine, ' Sapienza' University of Rome, Rome (Italy); Marchese, Rodolfo [Research Center S. Pietro Hospital, Via Cassia, 600-00189 Rome (Italy); Misiti, Silvia [Endocrinology, Department of Clinical and Molecular Medicine, Sant' Andrea Hospital, Faculty of Medicine and Psychology ' Sapienza' University of Rome, Via di Grottarossa, 1035-00189 Rome (Italy); Research Center S. Pietro Hospital, Via Cassia, 600-00189 Rome (Italy); De Venanzi, Agostino; Poggi, Maurizio; Toscano, Vincenzo [Endocrinology, Department of Clinical and Molecular Medicine, Sant' Andrea Hospital, Faculty of Medicine and Psychology ' Sapienza' University of Rome, Via di Grottarossa, 1035-00189 Rome (Italy); Stigliano, Antonio, E-mail: antonio.stigliano@uniroma1.it [Endocrinology, Department of Clinical and Molecular Medicine, Sant' Andrea Hospital, Faculty of Medicine and Psychology ' Sapienza' University of Rome, Via di Grottarossa, 1035-00189 Rome (Italy); Research Center S. Pietro Hospital, Via Cassia, 600-00189 Rome (Italy)

    2011-06-10

    Thiazolidinediones, specific peroxisome proliferator-activated receptor-{gamma} (PPAR-{gamma}) ligands, used in type-2 diabetes therapy, show favourable effects in several cancer cells. In this study we demonstrate that the growth of H295R and SW13 adrenocortical cancer cells is inhibited by rosiglitazone, a thiazolidinediones member, even though the mechanisms underlying this effect appeared to be cell-specific. Treatment with GW9662, a selective PPAR-{gamma}-inhibitor, showed that rosiglitazone acts through both PPAR-{gamma}-dependent and -independent mechanisms in H295R, while in SW13 cells the effect seems to be independent of PPAR-{gamma}. H295R cells treated with rosiglitazone undergo an autophagic process, leading to morphological changes detectable by electron microscopy and an increased expression of specific proteins such as AMPK{alpha} and beclin-1. The autophagy seems to be independent of PPAR-{gamma} activation and could be related to an increase in oxidative stress mediated by reactive oxygen species production with the disruption of the mitochondrial membrane potential, triggered by rosiglitazone. In SW13 cells, flow cytometry analysis showed an arrest in the G0/G1 phase of the cell cycle with a decrease of cyclin E and cdk2 activity, following the administration of rosiglitazone. Our data show the potential role of rosiglitazone in the therapeutic approach to adrenocortical carcinoma and indicate the molecular mechanisms at the base of its antiproliferative effects, which appear to be manifold and cell-specific in adrenocortical cancer lines.

  11. Non-invasive measurement of adrenocortical activity in a ...

    African Journals Online (AJOL)

    Measuring physiological stress reactions through the quantification of plasma cortisol often involves physical restraint, which acts as a stressor itself. Here, we present the validation of a non-invasive method for assessing adrenocortical activity as an indicator of stress in the bat-eared fox (Otocyon megalotis). By conducting ...

  12. Pathogenesis of canine cortisol-secreting adrenocortical tumors

    NARCIS (Netherlands)

    Kool, Miriam

    2015-01-01

    In dogs, hypercortisolism is one of the most frequently observed endocrine disorders, with an estimated incidence of about 1-2 cases per 1000 dogs per year. Approximately 15% of these cases is due to a cortisol-secreting adrenocortical tumor (AT). Cortisol-secreting ATs are characterized by

  13. Mouse Models Recapitulating Human Adrenocortical Tumors: What is lacking?

    Directory of Open Access Journals (Sweden)

    Felicia Leccia

    2016-07-01

    Full Text Available Adrenal cortex tumors are divided into benign forms such as primary hyperplasias and adrenocortical adenomas (ACAs, and malignant forms or adrenocortical carcinomas (ACCs. Primary hyperplasias are rare causes of ACTH-independent hypercortisolism. ACAs are the most common type of adrenal gland tumors and they are rarely functional, i.e producing steroids. When functional, adenomas result in endocrine disorders such as Cushing’s syndrome (hypercortisolism or Conn’s syndrome (hyperaldosteronism. In contrast, ACCs are extremely rare but highly aggressive tumors that may also lead to hypersecreting syndromes. Genetic analyses of patients with sporadic or familial forms of adrenocortical tumors led to the identification of potentially causative genes, most of them being involved in PKA, Wnt/β-catenin and P53 signaling pathways. Development of mouse models is a crucial step to firmly establish the functional significance of candidate genes, to dissect mechanisms leading to tumors and endocrine disorders and in fine to provide in vivo tools for therapeutic screens. In this article we will provide an overview on the existing mouse models (xenografted and genetically engineered of adrenocortical tumors by focusing on the role of PKA and Wnt/β-catenin pathways in this context. We will discuss the advantages and limitations of models that have been developed heretofore and we will point out necessary improvements in the development of next generation mouse models of adrenal diseases.

  14. Surgical resection of synchronously metastatic adrenocortical cancer.

    Science.gov (United States)

    Dy, Benzon M; Strajina, Veljko; Cayo, Ashley K; Richards, Melanie L; Farley, David R; Grant, Clive S; Harmsen, William S; Evans, Doug B; Grubbs, Elizabeth G; Bible, Keith C; Young, William F; Perrier, Nancy D; Que, Florencia G; Nagorney, David M; Lee, Jeffrey E; Thompson, Geoffrey B

    2015-01-01

    Metastatic adrenocortical carcinoma (ACC) is rapidly fatal, with few options for treatment. Patients with metachronous recurrence may benefit from surgical resection. The survival benefit in patients with hematogenous metastasis at initial presentation is unknown. A review of all patients undergoing surgery (European Network for the Study of Adrenal Tumors) stage IV ACC between January 2000 and December 2012 from two referral centers was performed. Kaplan-Meier estimates were analyzed for disease-free and overall survival (OS). We identified 27 patients undergoing surgery for stage IV ACC. Metastases were present in the lung (19), liver (11), and brain (1). A complete resection (R0) was achieved in 11 patients. The median OS was improved in patients undergoing R0 versus R2 resection (860 vs. 390 days; p = 0.02). The 1- and 2-year OS was also improved in patients undergoing R0 versus R2 resection (69.9 %, 46.9 % vs. 53.0 %, 22.1 %; p = 0.02). Patients undergoing neoadjuvant therapy (eight patients) had a trend towards improved survival at 1, 2, and 5 years versus no neoadjuvant therapy (18 patients) [83.3 %, 62.5 %, 41.7 % vs. 56.8 %, 26.6 %, 8.9 %; p = 0.1]. Adjuvant therapy was associated with improved recurrence-free survival at 6 months and 1 year (67 %, 33 % vs. 40 %, 20 %; p = 0.04) but not improved OS (p = 0.63). Sex (p = 0.13), age (p = 0.95), and location of metastasis (lung, p = 0.51; liver, p = 0.67) did not correlate with OS after operative intervention. Symptoms of hormonal excess improved in 86 % of patients. Operative intervention, especially when an R0 resection can be achieved, following systemic therapy may improve outcomes, including OS, in select patients with stage IV ACC. Response to neoadjuvant chemotherapy may be of use in defining which patients may benefit from surgical intervention. Adjuvant therapy was associated with decreased recurrence but did not improve OS.

  15. Mitotane treatment in patients with adrenocortical cancer causes central hypothyroidism.

    Science.gov (United States)

    Russo, Marco; Scollo, Claudia; Pellegriti, Gabriella; Cotta, Oana Ruxandra; Squatrito, Sebastiano; Frasca, Francesco; Cannavò, Salvatore; Gullo, Damiano

    2016-04-01

    Mitotane, a steroidogenesis inhibitor with adrenolytic properties used to treat adrenocortical cancer (ACC), can affect thyroid function. A reduction of FT4 levels with normal FT3 and TSH has been described in these patients. Using an in vitro murine model, the secretory capacity of thyrotrophic cells has been shown to be inhibited by mitotane. To investigate the pathogenesis of thyroid abnormalities in mitotane-treated patients with ACC. In five female patients with ACC (median age 47; range 31-65) treated with mitotane (dosage 1·5 g/day; 1·0-3·0), we analysed the pattern of TSH and thyroid function index (FT4, FT3 and FT3/FT4 ratio) compared to an age- and gender-matched control group. The in vivo secretory activity of the thyrotrophic cells was evaluated using a standard TRH test (200 μg), and the response was compared to both a group of age-matched female controls (n = 10) and central hypothyroid patients (n = 10). Basal TSH (median 1·54 mU/l; range 1·20-2·17) was normal and scattered around our median reference value, FT3 levels (median 3·80 pmol/l; 3·30-4·29) were normal but below the median reference value of 4·37 pmol/l and FT4 levels were below the normal range in all patients (median 8·40 pmol/l; 7·6-9·9). FT3/FT4 ratio was in the upper range in 4 patients and higher than normal in one patient. A blunted TSH response to TRH was observed in mitotane-treated patients. ΔTSH (absolute TSH response, peak TSH minus basal TSH) was 3·65 (range 3·53-5·26), 12·37 (range 7·55-19·97) and 1·32 mU/l (range 0·52-4·66) in mitotane-treated patients, controls and central hypothyroid patients, respectively. PRL secretion was normal. Mitotane-treated patients with ACC showed low FT4, normal FT3 and TSH and impaired TSH response to TRH, characteristic of central hypothyroidism. Furthermore, the elevated FT3/FT4 ratio of these subjects reflects an enhanced T4 to T3 conversion rate, a compensatory mechanism characteristic of thyroid function changes

  16. Adrenocortical carcinoma, an unusual cause of secondary hypertension.

    Science.gov (United States)

    Veron Esquivel, Daniel; Batiz, Fernando; Farias Vega, Alfonso; Carrillo Gonzalez, Perla A

    2016-12-07

    We present the case of a female patient aged 39 years who was admitted to our hospital due to hypertension, severe hypokalaemia and metabolic alkalosis; physical examination was remarkable for plethoric moon face, centripetal obesity and bilateral lower extremity oedema. She was admitted for intravenous potassium replacement and further assessment of hypertension and associated clinical findings. Laboratory testing showed increased levels of aldosterone, renin, cortisol, testosterone and androstenedione. An abdominal CT revealed a large mass in the right adrenal gland with hepatic involvement. The patient was started on antihypertensive medications and underwent laparoscopic surgery for mass and liver biopsy. The pathological diagnosis was adrenocortical carcinoma with liver metastasis. Hyperaldosteronism is a cause of secondary hypertension and its diagnosis is usually benign. Adrenocortical carcinoma is a rare condition and aldosterone secreting tumours are even rarer; associated hypertension usually improves after tumour resection, but with the presence of metastasis, blood pressure control is difficult. 2016 BMJ Publishing Group Ltd.

  17. Adrenocortical oncocytic neoplasm presenting with Cushing's syndrome: a case report

    Directory of Open Access Journals (Sweden)

    Kabayegit Ozlem

    2008-07-01

    Full Text Available Abstract Introduction Oncocytic neoplasms occur in several organs and are most commonly found in the thyroid, kidneys and salivary glands. Oncocytic neoplasms of the adrenal cortex are extremely rare and are usually non-functioning. Case presentation We report the case of an adrenocortical oncocytic neoplasm with uncertain malignant potential in a 31-year-old man with Cushing's syndrome. The patient had been operated on following diagnosis of a 7 cm adrenal mass. Following surgery, the Cushing's syndrome resolved. The patient is still alive with no metastases one year after the surgery. Conclusion Adrenocortical oncocytic neoplasms must be considered in the differential diagnosis of both functioning and non-functioning adrenal masses.

  18. Marital Conflict Predicts Mother-to-Infant Adrenocortical Transmission.

    Science.gov (United States)

    Hibel, Leah C; Mercado, Evelyn

    2017-12-21

    Employing an experimental design, mother-to-infant transmission of stress was examined. Mothers (N = 117) were randomized to either have a positive or conflictual discussion with their marital partners, after which infants (age = 6 months) participated in a fear and frustration task. Saliva samples were collected to assess maternal cortisol responses to the discussion and infant cortisol responses to the challenge task. Results indicate maternal cortisol reactivity and recovery to the conflict (but not positive) discussion predicted infant cortisol reactivity to the infant challenge. Mothers' positive affect during the discussion buffered, and intrusion during the free-play potentiated, mother-to-infant adrenocortical transmission. These findings advance our understanding of the social and contextual regulation of adrenocortical activity in early childhood. © 2017 The Authors. Child Development © 2017 Society for Research in Child Development, Inc.

  19. Virilizing Adrenocortical Carcinoma Advancing to Central Precocious Puberty after Surgery

    OpenAIRE

    Kim, Min Sun; Yang, Eu Jeen; Cho, Dong Hyu; Hwang, Pyung Han; Lee, Dae-Yeol

    2015-01-01

    Adrenocortical carcinoma (ACC) in pediatric and adolescent patients is rare, and it is associated with various clinical symptoms. We introduce the case of an 8-year-old boy with ACC who presented with peripheral precocious puberty at his first visit. He displayed penis enlargement with pubic hair and facial acne. His serum adrenal androgen levels were elevated, and abdominal computed tomography revealed a right suprarenal mass. After complete surgical resection, the histological diagnosis was...

  20. Clinical results of the use of mitotane for adrenocortical carcinoma

    Directory of Open Access Journals (Sweden)

    Kasperlik-Zaluska A.A.

    2000-01-01

    Full Text Available Mitotane (o,p'-DDD acts mainly as an inhibitor of intramitochondrial pregnenolone and cortisol synthesis. Its adrenolytic effect depends on metabolic activation due to conversion to o,p'-DDA and o,p'-DDE. The drug has been used for 40 years in the treatment of adrenocortical carcinoma, mainly its regional and metastatic stage, as an adjuvant to surgical resection of the tumor. In the medical literature there are controversial opinions about its efficacy for the treatment of adrenocortical carcinoma. In our experience, mitotane administered immediately after surgery appeared to be much more efficient than when administered later. We have administered this drug in all cases of microscopically confirmed adrenocortical carcinoma, irrespectively of stage at the time of surgery, for fear of a false too optimistic classification. In our series of 82 patients with adrenocortical carcinoma, 59 patients have been treated with mitotane, 32 of them immediately after surgery, and 27 with a delay of 2 to 24 months. Today there are 18 survivors in the group of patients treated with mitotane soon after the operation and only 6 survivors in the group receiving mitotane with a delay. All patients were simultaneously given replacement therapy. Undesired effects of mitotane administration included increased aminotransferase and alkaline phosphatase activity, decreased white cell, platelet or red cell number, and myasthenia. Furthermore, we used mitotane with good results in Cushing's syndrome of non-malignant origin as pre-treatment before surgery or in long-term treatment for patients with poor tolerance of other adrenal inhibitors.

  1. Plurihormonal Cosecretion by a Case of Adrenocortical Oncocytic Neoplasm

    Directory of Open Access Journals (Sweden)

    J. J. Corrales

    2016-01-01

    Full Text Available Adrenocortical oncocytic neoplasms (oncocytomas are extremely rare; only approximately 159 cases have been described so far. The majority are nonfunctional and benign. We describe an unusual case of a functional oncocytoma secreting an excess of glucocorticoids (cortisol and androgens (androstenedione and DHEAS, a pattern of plurihormonal cosecretion previously not reported in men, presenting with endocrine manifestations of Cushing’s syndrome. The neoplasm was considered to be of uncertain malignant potential (borderline according to the Lin-Weiss-Bisceglia criteria.

  2. Pediatric adrenocortical neoplasms: can imaging reliably discriminate adenomas from carcinomas?

    International Nuclear Information System (INIS)

    Flynt, Kelsey A.; Dillman, Jonathan R.; Smith, Ethan A.; Strouse, Peter J.; Davenport, Matthew S.; Caoili, Elaine M.; Else, Tobias

    2015-01-01

    There is a paucity of literature describing and comparing the imaging features of adrenocortical adenomas and carcinomas in children and adolescents. To document the CT and MRI features of adrenocortical neoplasms in a pediatric population and to determine whether imaging findings (other than metastatic disease) can distinguish adenomas from carcinomas. We searched institutional medical records to identify pediatric patients with adrenocortical neoplasms. Pre-treatment CT and MRI examinations were reviewed by two radiologists in consensus, and pertinent imaging findings were documented. We also recorded relevant histopathological, demographic, clinical follow-up and survival data. We used the Student's t-test and Wilcoxon rank sum test to compare parametric and nonparametric continuous data, and the Fisher exact test to compare proportions. We used receiver operating characteristic (ROC) curve analyses to evaluate the diagnostic performances of tumor diameter and volume for discriminating carcinoma from adenoma. A P-value ≤0.05 was considered statistically significant. Among the adrenocortical lesions, 9 were adenomas, 15 were carcinomas, and 1 was of uncertain malignant potential. There were no differences in mean age, gender or sidedness between adenomas and carcinomas. Carcinomas were significantly larger than adenomas based on mean estimated volume (581 ml, range 16-2,101 vs. 54 ml, range 3-197 ml; P-value = 0.003; ROC area under the curve = 0.92) and mean maximum transverse plane diameter (9.9 cm, range 3.0-14.9 vs. 4.4 cm, range 1.9-8.2 cm; P-value = 0.0001; ROC area under the curve = 0.92). Carcinomas also were more heterogeneous than adenomas on post-contrast imaging (13/14 vs. 2/9; odds ratio [OR] = 45.5; P-value = 0.001). Six of 13 carcinomas and 1 of 8 adenomas contained calcification at CT (OR = 6.0; P-value = 0.17). Seven of 15 children with carcinomas exhibited metastatic disease at diagnosis, and three had inferior vena cava invasion. Median

  3. Pediatric adrenocortical neoplasms: can imaging reliably discriminate adenomas from carcinomas?

    Energy Technology Data Exchange (ETDEWEB)

    Flynt, Kelsey A.; Dillman, Jonathan R.; Smith, Ethan A.; Strouse, Peter J. [University of Michigan Health System, Section of Pediatric Radiology, C. S. Mott Children' s Hospital, Department of Radiology, Ann Arbor, MI (United States); Davenport, Matthew S.; Caoili, Elaine M. [University of Michigan Health System, Division of Abdominal Imaging, Department of Radiology, Ann Arbor, MI (United States); Else, Tobias [University of Michigan Health System, Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, Ann Arbor, MI (United States)

    2015-08-15

    There is a paucity of literature describing and comparing the imaging features of adrenocortical adenomas and carcinomas in children and adolescents. To document the CT and MRI features of adrenocortical neoplasms in a pediatric population and to determine whether imaging findings (other than metastatic disease) can distinguish adenomas from carcinomas. We searched institutional medical records to identify pediatric patients with adrenocortical neoplasms. Pre-treatment CT and MRI examinations were reviewed by two radiologists in consensus, and pertinent imaging findings were documented. We also recorded relevant histopathological, demographic, clinical follow-up and survival data. We used the Student's t-test and Wilcoxon rank sum test to compare parametric and nonparametric continuous data, and the Fisher exact test to compare proportions. We used receiver operating characteristic (ROC) curve analyses to evaluate the diagnostic performances of tumor diameter and volume for discriminating carcinoma from adenoma. A P-value ≤0.05 was considered statistically significant. Among the adrenocortical lesions, 9 were adenomas, 15 were carcinomas, and 1 was of uncertain malignant potential. There were no differences in mean age, gender or sidedness between adenomas and carcinomas. Carcinomas were significantly larger than adenomas based on mean estimated volume (581 ml, range 16-2,101 vs. 54 ml, range 3-197 ml; P-value = 0.003; ROC area under the curve = 0.92) and mean maximum transverse plane diameter (9.9 cm, range 3.0-14.9 vs. 4.4 cm, range 1.9-8.2 cm; P-value = 0.0001; ROC area under the curve = 0.92). Carcinomas also were more heterogeneous than adenomas on post-contrast imaging (13/14 vs. 2/9; odds ratio [OR] = 45.5; P-value = 0.001). Six of 13 carcinomas and 1 of 8 adenomas contained calcification at CT (OR = 6.0; P-value = 0.17). Seven of 15 children with carcinomas exhibited metastatic disease at diagnosis, and three had inferior vena cava invasion. Median

  4. PRKACA: the catalytic subunit of protein kinase A and adrenocortical tumors

    Directory of Open Access Journals (Sweden)

    Annabel Sophie Berthon

    2015-05-01

    Full Text Available Cyclic-AMP (cAMP-dependent protein kinase (PKA is the main effector of cAMP signaling in all tissues. Inactivating mutations of the PRKAR1A gene, coding for the type 1A regulatory subunit of PKA, are responsible for Carney complex and primary pigmented nodular adrenocortical disease (PPNAD. PRKAR1A inactivation and PKA dysregulation have been implicated in various types of adrenocortical pathologies associated with ACTH-independent Cushing syndrome (AICS from PPNAD to adrenocortical adenomas and cancer, and other forms of bilateral adrenocortical hyperplasias (BAH. More recently, mutations of PRKACA, the gene coding for the catalytic subunit C alpha (Cα, were also identified in the pathogenesis of adrenocortical tumors. PRKACA copy number gain was found in the germline of several patients with cortisol-producing BAH, whereas the somatic Leu206Arg (c.617A>C recurrent PRKACA mutation was found in as many as half of all adrenocortical adenomas associated with AICS. In vitro analysis demonstrated that this mutation led to constitutive Cα activity, unregulated by its main partners, the PKA regulatory subunits. In this review, we summarize the current understanding of the involvement of PRKACA in adrenocortical tumorigenesis, and our understanding of PKA’s role in adrenocortical lesions. We also discuss potential therapeutic advances that can be made through targeting of PRKACA and the PKA pathway.

  5. Effects of centrifugation on gonadal and adrenocortical steroids in rats

    Science.gov (United States)

    Kakihana, R.; Butte, J. C.

    1980-01-01

    Many endocrine systems are sensitive to external changes in the environment. Both the pituitary adrenal and pituitary gonadal systems are affected by stress including centrifugation stress. The effect of centrifugation on the pituitary gonadal and pituitary adrenocortical systems was examined by measuring the gonadal and adrenal steroids in the plasma and brain following different duration and intensity of centrifugation stress in rats. Two studies were completed and the results are presented. The second study was carried out to describe the developmental changes of brain, plasma and testicular testosterone and dihydrotestosterone in Sprague Dawley rats so that the effect of centrifugation stress on the pituitary gonadal syatem could be better evaluated in future studies.

  6. Transcription factor GATA-4 is a marker of anaplasia in adrenocortical neoplasms of the domestic ferret (Mustela putorius furo).

    Science.gov (United States)

    Peterson, R A; Kiupel, M; Bielinska, M; Kiiveri, S; Heikinheimo, M; Capen, C C; Wilson, D B

    2004-07-01

    Adrenocortical neoplasms are a common cause of morbidity in neutered ferrets. Recently we showed that gonadectomized DBA/2J mice develop adrenocortical tumors that express transcription factor GATA-4. Therefore, we screened archival specimens of adrenocortical neoplasms from neutered ferrets to determine whether GATA-4 could be used as a tumor marker in this species. Nuclear immunoreactivity for GATA-4 was evident in 19/22 (86%) of ferret adrenocortical carcinomas and was prominent in areas exhibiting myxoid differentiation. Normal adrenocortical cells lacked GATA-4 expression. Two other markers of adrenocortical tumors in gonadectomized mice, inhibin-alpha and luteinizing hormone receptor, were coexpressed with GATA-4 in some of the ferret tumors. No GATA-4 expression was observed in three cases of nodular hyperplasia, but patches of anaplastic cells expressing GATA-4 were evident in 7/14 (50%) of tumors classified as adenomas. We conclude that GATA-4 can function as a marker of anaplasia in ferret adrenocortical tumors.

  7. StAR Protein Stability in Y1 and Kin-8 Mouse Adrenocortical Cells.

    Science.gov (United States)

    Clark, Barbara J; Hudson, Elizabeth A

    2015-03-04

    The steroidogenic acute regulatory protein (STAR) protein expression is required for cholesterol transport into mitochondria to initiate steroidogenesis in the adrenal and gonads. STAR is synthesized as a 37 kDa precursor protein which is targeted to the mitochondria and imported and processed to an intra-mitochondrial 30 kDa protein. Tropic hormone stimulation of the cAMP-dependent protein kinase A (PKA) signaling pathway is the major contributor to the transcriptional and post-transcriptional regulation of STAR synthesis. Many studies have focused on the mechanisms of cAMP-PKA mediated control of STAR synthesis while there are few reports on STAR degradation pathways. The objective of this study was to determine the effect of cAMP-PKA-dependent signaling on STAR protein stability. We have used the cAMP-PKA responsive Y1 mouse adrenocortical cells and the PKA-deficient Kin-8 cells to measure STAR phosphorylation and protein half-life. Western blot analysis and standard radiolabeled pulse-chase experiments were used to determine STAR phosphorylation status and protein half-life, respectively. Our data demonstrate that PKA-dependent STAR phosphorylation does not contribute to 30 kDa STAR protein stability in the mitochondria. We further show that inhibition of the 26S proteasome does not block precursor STAR phosphorylation or steroid production in Y1 cells. These data suggest STAR can maintain function and promote steroidogenesis under conditions of proteasome inhibition.

  8. A Case of Cushing's Syndrome with Multiple Adrenocortical Adenomas Composed of Compact Cells and Clear Cells.

    Science.gov (United States)

    Asakawa, Masahiro; Yoshimoto, Takanobu; Ota, Mitsutane; Numasawa, Mitsuyuki; Sasahara, Yuriko; Takeuchi, Takato; Nakano, Yujiro; Oohara, Norihiko; Murakami, Masanori; Bouchi, Ryotaro; Minami, Isao; Tsuchiya, Kyoichiro; Hashimoto, Koshi; Izumiyama, Hajime; Kawamura, Naoko; Kihara, Kazunori; Negi, Mariko; Akashi, Takumi; Eishi, Yoshinobu; Sasano, Hironobu; Ogawa, Yoshihiro

    2016-06-01

    A 58-year-old woman was referred to our hospital for Cushingoid features and diagnosed as adrenal Cushing's syndrome due to a right adrenocortical mass (60 × 55 mm). The mass was composed of three different tumors; the first one was homogeneously lipid-poor neoplasm measuring 20 × 13 mm located at the most dorsal region, the second one was heterogeneous and lipid-rich tumor containing multiple foci of calcification measuring 50 × 32 mm located at the central region, and the last one was heterogeneous harboring dilated and tortuous vessels and lipid-poor one measuring 35 × 18 mm at the most ventral region of the adrenal gland. A right adrenalectomy was subsequently performed by open surgery. Macroscopic and microscopic analyses revealed that all three tumors were adrenocortical adenomas; the first one represents a pigmented adrenocortical adenoma, the second one adrenocortical adenoma associated with degeneration, and the third one adrenocortical adenoma harboring extensive degeneration. Immunohistochemical analysis of the steroidogenic enzymes also revealed that all of the tumors had the capacity of synthesizing cortisol. This is a very rare case of Cushing's syndrome caused by multiple adrenocortical adenomas including a pigmented adenoma. Immunohistochemical analysis of steroidogenic enzymes contributed to understanding of steroidogenesis in each of these three different adrenocortical adenomas in this case.

  9. Global gene expression response to telomerase in bovine adrenocortical cells

    International Nuclear Information System (INIS)

    Perrault, Steven D.; Hornsby, Peter J.; Betts, Dean H.

    2005-01-01

    The infinite proliferative capability of most immortalized cells is dependent upon the presence of the enzyme telomerase and its ability to maintain telomere length and structure. However, telomerase may be involved in a greater system than telomere length regulation, as recent evidence has shown it capable of increasing wound healing in vivo, and improving cellular proliferation rate and survival from apoptosis in vitro. Here, we describe the global gene expression response to ectopic telomerase expression in an in vitro bovine adrenocortical cell model. Telomerase-immortalized cells showed an increased ability for proliferation and survival in minimal essential medium above cells transgenic for GFP. cDNA microarray analyses revealed an altered cell state indicative of increased adrenocortical cell proliferation regulated by the IGF2 pathway and alterations in members of the TGF-B family. As well, we identified alterations in genes associated with development and wound healing that support a model that high telomerase expression induces a highly adaptable, progenitor-like state

  10. Chloroquine enhances the efficacy of cisplatin by suppressing autophagy in human adrenocortical carcinoma treatment

    Directory of Open Access Journals (Sweden)

    Qin L

    2016-03-01

    effective in restraining SW13 cell proliferation. DDP could promote cell apoptosis and induce autophagy in SW13 cells. Concomitant therapy further promoted cell apoptosis by inhibiting autophagy. In vivo, we found that concomitant therapy was more potent than DDP monotherapy in inhibiting the growth of xenografted tumors and prolonging the survival of tumor-bearing mice.Conclusion: The antitumor ability of DDP was related to autophagy activity, and the concomitant therapy (DDP and CQ could be an optimal strategy for treating ACC. Keywords: adrenocortical carcinoma, chloroquine, cisplatin, apoptosis, autophagy

  11. Immunoglobulins of patients with Cushing's syndrome due to pigmented adrenocortical micronodular dysplasia stimulate in vitro steroidogenesis

    NARCIS (Netherlands)

    Wulffraat, N. M.; Drexhage, H. A.; Wiersinga, W. M.; van der Gaag, R. D.; Jeucken, P.; Mol, J. A.

    1988-01-01

    The putative stimulation of adrenal steroid production by immunoglobulins (Igs) of five patients with pigmented adrenocortical micronodular dysplasia and clinical Cushing's syndrome was investigated. Ascorbate depletion, a process linked to steroid production, was measured by a cyto-chemical

  12. Effect of acupuncture on adrenocortical hormone production in rabbits with a central lesion

    Energy Technology Data Exchange (ETDEWEB)

    Liao, Y.Y.; Seto, K.; Saitoh, H.; Kawakami, M.

    A study was made of adrenocortical hormone production under electroacupuncture stimulation of the Tsu-San-Li locus in rabbits with a lesion in the fornix, stria terminalis, ventromedial nucleus or arcuate nucleus. In rabbits with a lesion in the stria terminalis or ventromedial nucleus, electroacupuncture stimulation of Tsu-San-Li resulted in no increase in phase 1 but an increase in phase 2 of adrenocortical hormone production. In rabbits with a lesion in the fornix or arcuate nucleus electroacupuncture stimulation of Tsu-San-Li was followed by increased adrenocortical hormone production in the both phases. These results show that the stria terminalis and the ventromedial nucleus play a major role in the augmentation of adrenocortical hormone production by electroacupuncture stimulation of Tsu-San-Li.

  13. Virilizing adrenocortical carcinoma advancing to central precocious puberty after surgery.

    Science.gov (United States)

    Kim, Min Sun; Yang, Eu Jeen; Cho, Dong Hyu; Hwang, Pyung Han; Lee, Dae-Yeol

    2015-05-01

    Adrenocortical carcinoma (ACC) in pediatric and adolescent patients is rare, and it is associated with various clinical symptoms. We introduce the case of an 8-year-old boy with ACC who presented with peripheral precocious puberty at his first visit. He displayed penis enlargement with pubic hair and facial acne. His serum adrenal androgen levels were elevated, and abdominal computed tomography revealed a right suprarenal mass. After complete surgical resection, the histological diagnosis was ACC. Two months after surgical removal of the mass, he subsequently developed central precocious puberty. He was treated with a gonadotropin-releasing hormone agonist to delay further pubertal progression. In patients with functioning ACC and surgical removal, clinical follow-up and hormonal marker examination for the secondary effects of excessive hormone secretion may be a useful option at least every 2 or 3 months after surgery.

  14. Virilization in a Girl with Adrenocortical Adenoma: A Case Report

    Directory of Open Access Journals (Sweden)

    Tahniyah Haq

    2012-07-01

    Full Text Available We present a case of Cushing’s syndrome and virilization in a 15 year old girl which was suspected to be due to an adrenal carcinoma. She presented with features of virilization in addition to those of hypercortisilism. Her high androgen levels especially dehydroepiandrosterone sulfate (DHEAS were also in favor of an adrenal carcinoma. An unenhanced computerized tomography (CT scan showed a mass (size: 5.3 cm in the right adrenal gland with a soft tissue intensity of more than 10 HU which was suggestive of adrenal carcinoma. But, histopathology of the resected mass revealed a benign adrenocortical adenoma. Ibrahim Med. Coll. J. 2012; 6(2: 70-72

  15. A black adrenocortical adenoma causing Cushing's syndrome not imaged by radiocholesterol scintigraphy

    International Nuclear Information System (INIS)

    Reschini, E.; Baldini, M.; Cantalamessa, L.

    1990-01-01

    In a 33-year-old female patient with left adrenal tumour and Cushing's syndrome, adrenocortical scintigraphy with radiocholesterol did not image the tumour nor the suppressed contralateral gland. Histology showed a black adrenocortical adenoma composed only of compact cells; there was no evidence of malignancy. This demonstrates that non-visualization of the adrenal glands in a patient with Cushing's syndrome is not invariably due to adrenal carcinoma. The literature on black adrenal adenomas causing Cushing's syndrome is reviewed. (orig.)

  16. Analysis of adrenocortical tumours morphology as regards their structure and potential malignancy

    International Nuclear Information System (INIS)

    Kajor, M.; Ciupinska-Kajor, M.; Dobrosz, Z.; Ziaja, J.; Krol, R.; Heitzman, M.; Cierpka, L.

    2006-01-01

    Introduction: A consequence of diagnosis of adrenocortical carcinoma (ACC) is introduction of pharmacological therapy, precise monitoring of the patients and in some cases re-operation. The aim of the study is to analyse morphology of adrenocortical tumours as regards their malignancy by use of criteria proposed by Weiss. Material and methods: 110 adrenocortical tumours in 107 patients were analysed (M 27.1%, F 72.9%; age 32 to 77 years, mean 55.2 ± 9.7). Conn syndrome was diagnosed in 16 patients (14.9%), Cushing syndrome in 12 (11.2%), and virilisation in 3 (2.8%). In 76 patients (71.0%) biochemical tests did not reveal hormonal hyperactivity of the tumour. Results: In routine histopathological examination ACC was diagnosed in 6 tumours (5.4%), adrenocortical adenoma (ACA) in 92 (83.6%) and adrenocortical hyperplasia in 12 (10.9%). Nuclear grade III or IV was observed in 8 tumours (7.3%), mitotic rate > 5/50 high power fields in 6 (5.4%), atypical mitoses in 5 (4.5%), clear cells constituting < 25% of the tumour in 10 (9.1%), diffuse architecture in 8 (7.3%), necrosis in 16 (14.5%), veins infiltration in 4 (3.6%), sinusoids infiltration in 7 (6.3%), and tumour capsule infiltration in 5 (4.5%). Among ACC tumours 4 - 9 features of malignancy were present, among ACA - 0 - 3 features. Statistical analysis revealed correlation between number of criteria proposed by Weiss and maximal tumour size (p < 0.05). Conclusion: The structure and cell arrangement in adrenocortical adenoma are heterogeneous. Application of criteria proposed by Weiss in histopathological examination of adrenocortical tumours can be useful in differentiating adrenocortical adenoma from carcinoma. (author)

  17. Canine hyperadrenocorticism due to adrenocortical neoplasia: pretreatment evaluation of 41 dogs

    International Nuclear Information System (INIS)

    Reusch, C.E.; Feldman, E.C.

    1991-01-01

    This retrospective study identifies parameters that might separate dogs with hyperadrenocorticism caused by adrenocortical tumors from dogs with pituitary-dependent hyperadrenocorticism. Further, an attempt was made to identify factors that could separate dogs with adrenocortical adenomas from dogs with carcinomas. The records of 41 dogs with hyperadrenocorticism caused by adrenocortical neoplasia were reviewed. The history, physical examination, urinalysis, hemogram (CBC), chemistry profile adrenocorticotrophic hormone (ACTH) stimulation and low dose dexamethasone test results were typical of the nonspecific diagnosis of hyperadrenocorticism. The preceding information on the 41 dogs with adrenocortical tumors was compared with that from 44 previously diagnosed pituitary-dependent hyperadrenocorticoid dogs. There was no parameter which aided in separating these two groups of dogs. Thirty dogs with adrenocortical tumors were tested with a high-dose dexamethasone test and none had suppressed plasma cortisol concentrations 8 hours after IV administration of 0.1 mg/kg of dexamethasone. In 29 of the 41 adrenal tumor dogs, plasma endogenous ACTH was not detectable on at least one measurement (less than 20 pg/ml). The remaining 12 dogs from this group had nondiagnostic concentrations (20-45 pg/ml). Thirteen of 22 dogs (59%) with adrenocortical carcinomas had adrenal masses identified on abdominal radiographs and seven of 13 dogs (54%) with adrenocortical adenomas had radiographically visible adrenal masses. Thirteen of 17 adrenocortical carcinomas (76%) and five of eight adenomas (62%) were identified with ultrasonography. Radiographs of the thorax and ultrasonography of the abdomen identified most of the dogs (8 of 11) with metastatic lesions

  18. Noninvasive monitoring of adrenocortical function in captive jaguars (Panthera onca).

    Science.gov (United States)

    Conforti, Valéria A; Morato, Ronaldo G; Augusto, Anderson M; de Oliveira e Sousa, Lúcio; de Avila, David M; Brown, Janine L; Reeves, Jerry J

    2012-01-01

    Jaguars are threatened with extinction throughout their range. A sustainable captive population can serve as a hedge against extinction, but only if they are healthy and reproduce. Understanding how jaguars respond to stressors may help improve the captive environment and enhance their wellbeing. Thus, our objectives were to: (1) conduct an adrenocorticotrophic hormone (ACTH) challenge to validate a cortisol radioimmunoassay (RIA) for noninvasive monitoring of adrenocortical function in jaguars; (2) investigate the relationship between fecal corticoid (FCM) and androgen metabolite (FAM) concentrations in males during the ACTH challenge; and (3) establish a range of physiological concentrations of FCMs for the proposed protocol. Seven jaguars (3 M, 4 F) received 500 IU/animal of ACTH. Pre- and post-ACTH fecal samples were assayed for corticoid (M and F) and androgen metabolites (M) by RIA. Concentrations of FCMs increased (P80.01) after ACTH injection (pre-ACTH: 0.90 ± 0.12 µg/g dry feces; post-ACTH: 2.55 ± 0.25 µg/g). Considering pre- and post-ACTH samples, FCM concentrations were higher (P80.01) in males (2.15 ± 0.20 µg/g) than in females (1.30 ± 0.20 µg/g), but the magnitude of the response to ACTH was comparable (P>0.05) between genders. After ACTH injection, FAMs increased in two (of 3) males; in one male, FCMs and FAMs were positively correlated (0.60; P80.01). Excretion of FCMs was assessed in 16 jaguars (7 M, 9 F) and found to be highly variable (range, 80.11-1.56 µg/g). In conclusion, this study presents a cortisol RIA for monitoring adrenocortical function in jaguars noninvasively. © 2011 Wiley Periodicals, Inc.

  19. Blood Transfusion and Survival for Resected Adrenocortical Carcinoma: A Study from the United States Adrenocortical Carcinoma Group.

    Science.gov (United States)

    Poorman, Caroline E; Postlewait, Lauren M; Ethun, Cecilia G; Tran, Thuy B; Prescott, Jason D; Pawlik, Timothy M; Wang, Tracy S; Glenn, Jason; Hatzaras, Ioannis; Shenoy, Rivfka; Phay, John E; Keplinger, Kara; Fields, Ryan C; Jin, Linda X; Weber, Sharon M; Salem, Ahmed; Sicklick, Jason K; Gad, Shady; Yopp, Adam C; Mansour, John C; Duh, Quan-Yang; Seiser, Natalie; Solorzano, Carmen C; Kiernan, Colleen M; Votanopoulos, Konstantinos I; Levine, Edward A; Staley, Charles A; Poultsides, George A; Maithel, Shishir K

    2017-07-01

    Perioperative blood transfusion is associated with decreased survival in pancreatic, gastric, and liver cancer. The effect of transfusion in adrenocortical carcinoma (ACC) has not been studied. Patients with available transfusion data undergoing curative-intent resection of ACC from 1993 to 2014 at 13 institutions comprising the United States Adrenocortical Carcinoma Group were included. Factors associated with blood transfusion were determined. Primary and secondary end points were recurrence-free survival (RFS) and overall survival (OS), respectively. Out of 265 patients, 149 were included for analysis. Out of these, 57 patients (38.3%) received perioperative transfusions. Compared to nontransfused patients, transfused patients more commonly had stage 4 disease (46% vs 24%, P = 0.01), larger tumors (15.8 vs 10.2 cm, P Transfusion was associated with decreased RFS (8.9 vs 24.7 months, P = 0.006) and OS (22.8 vs 91.0 months, P transfusion, stage IV, hormonal hypersecretion, and adjuvant therapy were associated with decreased RFS. On multivariable analysis, only transfusion [hazard ratio (HR) = 1.7, 95% confidence interval (CI) =1.0-2.9, P = 0.04], stage IV (HR = 3.2, 95% CI = 1.7-5.9, P transfusion HR = 2.0, 95% CI = 1.1-3.8, P = 0.02; stage 4 HR = 6.2, 95% CI = 3.1-12.4, P 2 units of packed red blood cells in median RFS (8.9 vs 8.4 months, P = 0.95) or OS (26.5 vs 18.6 months, P = 0.63). Perioperative transfusion is associated with earlier recurrence and decreased survival after curative-intent resection of ACC. Strategies and protocols to minimize blood transfusion should be developed and followed.

  20. Characterization of differential gene expression in adrenocortical tumors harboring beta-catenin (CTNNB1) mutations.

    Science.gov (United States)

    Durand, Julien; Lampron, Antoine; Mazzuco, Tania L; Chapman, Audrey; Bourdeau, Isabelle

    2011-07-01

    Mutations of β-catenin gene (CTNNB1) are frequent in adrenocortical adenomas (AA) and adrenocortical carcinomas (ACC). However, the target genes of β-catenin have not yet been identified in adrenocortical tumors. Our objective was to identify genes deregulated in adrenocortical tumors harboring CTNNB1 genetic alterations and nuclear accumulation of β-catenin. Microarray analysis identified a dataset of genes that were differently expressed between AA with CTNNB1 mutations and wild-type (WT) tumors. Within this dataset, the expression profiles of five genes were validated by real time-PCR (RT-PCR) in a cohort of 34 adrenocortical tissues (six AA and one ACC with CTNNB1 mutations, 13 AA and four ACC with WT CTNNB1, and 10 normal adrenal glands) and two human ACC cell lines. We then studied the effects of suppressing β-catenin transcriptional activity with the T-cell factor/β-catenin inhibitors PKF115-584 and PNU74654 on gene expression in H295R and SW13 cells. RT-PCR analysis confirmed the overexpression of ISM1, RALBP1, and PDE2A and the down-regulation of PHYHIP in five of six AA harboring CTNNB1 mutations compared with WT AA (n = 13) and normal adrenal glands (n = 10). RALBP1 and PDE2A overexpression was also confirmed at the protein level by Western blotting analysis in mutated tumors. ENC1 was specifically overexpressed in three of three AA harboring CTNNB1 point mutations. mRNA expression and protein levels of RALBP1, PDE2A, and ENC1 were decreased in a dose-dependent manner in H295R cells after treatment with PKF115-584 or PNU74654. This study identified candidate genes deregulated in CTNNB1-mutated adrenocortical tumors that may lead to a better understanding of the role of the Wnt-β-catenin pathway in adrenocortical tumorigenesis.

  1. Primary aldosteronism and hypercortisolism due to bilateral functioning adrenocortical adenomas.

    Science.gov (United States)

    Oki, Kenji; Yamane, Kiminori; Sakashita, Yu; Kamei, Nozomu; Watanabe, Hiroshi; Toyota, Naoyuki; Shigeta, Masanobu; Sasano, Hironobu; Kohno, Nobuoki

    2008-10-01

    A 50-year-old male patient with a 15-year history of hypertension was referred to our hospital for evaluation of bilateral adrenal tumors. No Cushingoid features were observed. Computed tomographic scan showed 10-mm masses in each adrenal gland. Preoperative endocrinological examinations revealed autonomous cortisol and aldosterone secretion in this patient. The results of a subsequent adrenal venous catheterization study were consistent with the presence of a left cortisol-producing tumor and a right aldosterone-producing tumor. A left partial adrenalectomy was performed initially, but cortisol and aldosterone over-secretion persisted. Accordingly, the patient underwent a right adrenalectomy. Pathological examination of the resected specimens, including immunohistochemical analysis, demonstrated that both adenomas possibly produced cortisol and aldosterone. This is an extremely rare case of bilateral adrenal tumors, in which the left adrenocortical tumor produced and secreted cortisol or both cortisol and aldosterone and the right one produced and secreted both aldosterone and cortisol, as confirmed by clinical findings and pathological studies using immunohistochemical analysis.

  2. Surgical management and clinical prognosis of adrenocortical carcinoma.

    Science.gov (United States)

    Dong, Dexin; Li, Hanzhong; Yan, Weigang; Ji, Zhigang; Mao, Quanzong

    2012-01-01

    To study the relationship between surgical management and prognosis of adrenocortical carcinoma (ACC) in order to guide the surgical management of ACC. Clinical data of 45 cases of ACC treated in our hospital were retrospectively analyzed. The 45 cases included 3 cases in stage I, 12 cases in stage II, 7 cases in stage III, and 23 cases in stage IV. 17 cases underwent complete excision, 14 cases underwent palliative excision, 8 cases had non-operative treatment and 6 cases gave up treatment. All patients were followed up from 2 to 141 months. The average survival time of 31 patients with surgery was 32.46 months, and the average survival time of 14 patients without surgery was 4.75 months. There were statistically significant differences between the two groups (p 0.05). Surgery is considered to be the only method to cure ACC. For ACC in stage I and II, tumor resection is the most effective treatment, and second surgical operation is recommended for local recurrence. For ACC in stage III, extensive surgical operation is recommended, and for ACC in stage IV, surgical operation has no effect on the prognosis. Copyright © 2012 S. Karger AG, Basel.

  3. Percutaneous laser ablation of unresectable primary and metastatic adrenocortical carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Pacella, Claudio M. [Regina Apostolorum Hospital, Department of Diagnostic Imaging and Interventional Radiology, Via San Francesco 50, Albano Laziale, Rome 00041 (Italy)], E-mail: claudiomaurizio.pacella@fastwebnet.it; Stasi, Roberto; Bizzarri, Giancarlo; Pacella, Sara; Graziano, Filomena Maria; Guglielmi, Rinaldo; Papini, Enrico [Regina Apostolorum Hospital, Department of Diagnostic Imaging and Interventional Radiology, Via San Francesco 50, Albano Laziale, Rome 00041 (Italy)

    2008-04-15

    Purpose: To evaluate the feasibility, safety, and clinical benefits of percutaneous laser ablation (PLA) in patients with unresectable primary and metastatic adrenocortical carcinoma (ACC). Patients and methods: Four patients with hepatic metastases from ACC and a Cushing's syndrome underwent ultrasound-guided PLA. In one case the procedure was performed also on the primary tumor. Results: After three sessions of PLA, the primary tumor of 15 cm was ablated by 75%. After 1-4 (median 1) sessions of PLA, five liver metastases ranging from 2 to 5 cm were completely ablated, while the sixth tumor of 12 cm was ablated by 75%. There were no major complications. Treatment resulted in an improvement of performance status and a reduction of the daily dosage of mitotane in all patients. The three patients with liver metastases presented a marked decrease of 24-h urine cortisol levels, an improved control of hypertension and a mean weight loss of 2.8 kg. After a median follow-up after PLA of 27.0 months (range, 9-48 months), two patients have died of tumor progression, while two other patients remain alive and free of disease. Conclusions: Percutaneous laser ablation is a feasible, safe and well tolerated procedure for the palliative treatment of unresectable primary and metastatic ACC. Further study is required to evaluate the impact of PLA on survival.

  4. Percutaneous laser ablation of unresectable primary and metastatic adrenocortical carcinoma

    International Nuclear Information System (INIS)

    Pacella, Claudio M.; Stasi, Roberto; Bizzarri, Giancarlo; Pacella, Sara; Graziano, Filomena Maria; Guglielmi, Rinaldo; Papini, Enrico

    2008-01-01

    Purpose: To evaluate the feasibility, safety, and clinical benefits of percutaneous laser ablation (PLA) in patients with unresectable primary and metastatic adrenocortical carcinoma (ACC). Patients and methods: Four patients with hepatic metastases from ACC and a Cushing's syndrome underwent ultrasound-guided PLA. In one case the procedure was performed also on the primary tumor. Results: After three sessions of PLA, the primary tumor of 15 cm was ablated by 75%. After 1-4 (median 1) sessions of PLA, five liver metastases ranging from 2 to 5 cm were completely ablated, while the sixth tumor of 12 cm was ablated by 75%. There were no major complications. Treatment resulted in an improvement of performance status and a reduction of the daily dosage of mitotane in all patients. The three patients with liver metastases presented a marked decrease of 24-h urine cortisol levels, an improved control of hypertension and a mean weight loss of 2.8 kg. After a median follow-up after PLA of 27.0 months (range, 9-48 months), two patients have died of tumor progression, while two other patients remain alive and free of disease. Conclusions: Percutaneous laser ablation is a feasible, safe and well tolerated procedure for the palliative treatment of unresectable primary and metastatic ACC. Further study is required to evaluate the impact of PLA on survival

  5. Cushing Syndrome in a 6-Month-Old Infant due to Adrenocortical Tumor

    Directory of Open Access Journals (Sweden)

    Volmar KeithE

    2009-09-01

    Full Text Available Cushing syndrome is rare in infancy and usually due to an adrenocortical tumor (ACT. We report an infant with Cushing syndrome due to adrenocortical carcinoma. The patient presented at six months of age with a three-month history of growth failure, rapid weight gain, acne, and irritability. Physical examination showed obesity, hypertension, and Cushingoid features. Biochemical evaluation showed very high serum cortisol, mildly elevated testosterone, and suppressed ACTH. Abdominal MRI revealed a heterogeneous right adrenal mass extending into the inferior vena cava. Evaluation for metastases was negative. The tumor was removed surgically en bloc. Pathologic examination demonstrated low mitotic rate, but capsular and vascular invasion. She received no adjuvant therapy. Her linear growth has improved and Cushingoid features resolved. Hormonal markers and quarterly PET scans have been negative for recurrence 24 months postoperatively. In conclusion, adrenocortical neoplasms in children are rare, but should be considered in the differential diagnosis of Cushing syndrome.

  6. Species-specific sensitivity to selenium-induced impairment of cortisol secretion in adrenocortical cells of rainbow trout (Oncorhynchus mykiss) and brook trout (Salvelinus fontinalis)

    International Nuclear Information System (INIS)

    Miller, L.L.; Hontela, A.

    2011-01-01

    Species differences in physiological and biochemical attributes exist even among closely related species and may underlie species-specific sensitivity to toxicants. Rainbow trout (RT) are more sensitive than brook trout (BT) to the teratogenic effects of selenium (Se), but it is not known whether all tissues exhibit this pattern of vulnerability. In this study, primary cultures of RT and BT adrenocortical cells were exposed to selenite (Na 2 SO 3 ) and selenomethionine (Se-Met) to compare cell viability and ACTH-stimulated cortisol secretion in the two fish species. Cortisol, the primary stress hormone in fish, facilitates maintenance of homeostasis when fish are exposed to stressors, including toxicants. Cell viability was not affected by Se, but selenite impaired cortisol secretion, while Se-Met did not (RT and BT EC 50 > 2000 mg/L). RT cells were more sensitive (EC 50 = 8.7 mg/L) to selenite than BT cells (EC 50 = 90.4 mg/L). To identify the targets where Se disrupts cortisol synthesis, selenite-impaired RT and BT cells were stimulated with ACTH, dbcAMP, OH-cholesterol, and pregnenolone. Selenite acted at different steps in the cortisol biosynthesis pathway in RT and BT cells, confirming a species-specific toxicity mechanism. To test the hypothesis that oxidative stress mediates Se-induced toxicity, selenite-impaired RT cells were exposed to NAC, BSO and antioxidants (DETCA, ATA, Vit A, and Vit E). Inhibition of SOD by DETCA enhanced selenite-induced cortisol impairment, indicating that oxidative stress plays a role in Se toxicity; however, modifying GSH content of the cells did not have an effect. The results of this study, with two closely related salmonids, provided additional evidence for species-specific differences in sensitivity to Se which should be considered when setting thresholds and water quality guidelines. - Research Highlights: → We investigated species-specific sensitivity to Se in trout adrenocortical cells. → Selenite, not Se-Met, disrupts

  7. 18F-Labelled metomidate analogues as adrenocortical imaging agents

    International Nuclear Information System (INIS)

    Erlandsson, Maria; Karimi, Farhad; Lindhe, Orjan; Langstroem, Bengt

    2009-01-01

    Introduction: Two- and one-step syntheses of 18 F-labelled analogues of metomidate, such as 2-[ 18 F]fluoroethyl 1-[(1R)-1-phenylethyl]-1H-imidazole-5-carboxylate (1), 2-[ 18 F]fluoroethyl 1-[(1R)-1-(4-chlorophenyl)ethyl]-1H-imidazole-5-carboxylate (2), 2-[ 18 F]fluoroethyl 1-[(1R)-1-(4-bromophenyl)ethyl]-1H-imidazole-5-carboxylate (3), 3-[ 18 F]fluoropropyl 1-[(1R)-1-(4-bromophenyl)ethyl]-1H-imidazole-5-carboxylate (4) and 3-[ 18 F]fluoropropyl 1-[(1R)-1-phenylethyl]-1H-imidazole-5-carboxylate (5) are presented. Methods: Analogues 1-5 were prepared by a two-step reaction sequence that started with the synthesis of either 2-[ 18 F]fluoroethyl 4-methylbenzenesulfonate or 3-[ 18 F]fluoropropyl 4-methylbenzenesulfonate. These were used as 18 F-alkylating agents in the second step, in which they reacted with the ammonium salt of a 1-[(1R)-1-phenylethyl]-1H-imidazole-5-carboxylic acid. One-step-labelling syntheses of 1, 2 and 5 were also explored. Analogues 1-4 were biologically validated by frozen-section autoradiography and organ distribution. Metabolite analysis was performed for 2 and 3. Results: The radiochemical yield of the two-step synthesis was in the range of 10-29% and that of the one-step synthesis was 25-37%. Using microwave irradiation in the one-step synthesis of 1 and 2 increased the radiochemical yield to 46±3% and 79±30%, respectively. Conclusion: Both the frozen-section autoradiography and organ distribution results indicated that analogue 2 has a potential as an adrenocortical imaging agent, having the highest degree of specific adrenal binding and best ratio of adrenal to organ uptake among the compounds studied.

  8. Hair cortisol measurement in mitotane-treated adrenocortical cancer patients.

    Science.gov (United States)

    Manenschijn, L; Quinkler, M; van Rossum, E F C

    2014-04-01

    The only approved drug for the treatment of adrenocortical cancer (ACC) is mitotane. Mitotane is adrenolytic and therefore, hydrocortisone replacement therapy is necessary. Since mitotane increases cortisol binding globulin (CBG) and induces CYP3A4 activity, high doses of hydrocortisone are thought to be required. Evaluation of hydrocortisone therapy in mitotane-treated patients has been difficult since there is no good marker to evaluate hydrocortisone therapy. Measurement of cortisol in scalp hair is a novel method that offers the opportunity to measure long-term cortisol levels. Our aim was to evaluate whether hair cortisol measurements could be useful in evaluating recent hydrocortisone treatment in mitotane-treated ACC patients. Hair cortisol levels were measured in 15 mitotane-treated ACC patients on hydrocortisone substitution and 96 healthy individuals. Cortisol levels were measured in 3 cm hair segments, corresponding to a period of 3 months. Hair cortisol levels were higher in ACC patients compared to healthy individuals (pcortisol levels above the reference range. None of the patients had hair cortisol levels below normal. In contrast to hydrocortisone doses (β=0.03, p=0.93), hair cortisol levels were associated with BMI (β=0.53, p=0.042). There was no correlation between hair cortisol levels and hydrocortisone doses (β=0.41, p=0.13). Almost half of the ACC patients had high hair cortisol levels, suggesting long-term over-substitution of hydrocortisone in some of the patients, whereas none of the patients was under-substituted. Hair cortisol measurements might be useful in long-term monitoring hydrocortisone treatment in mitotane-treated ACC patients. © Georg Thieme Verlag KG Stuttgart · New York.

  9. Synthetic high-density lipoprotein nanodisks for targeted withalongolide delivery to adrenocortical carcinoma

    Directory of Open Access Journals (Sweden)

    Kuai R

    2017-09-01

    .115 µM, P<0.05. Fluorescent dye-loaded sHDL nanodisks efficiently accumulated in H295R adrenal carcinoma xenografts 24 hours following dosing. Moreover, daily intraperitoneal administration of 7 mg/kg WGA-TA-loaded sHDL nanodisks significantly inhibited tumor growth during 21-day administration to H295R xenograft-bearing mice compared to placebo (P<0.01. Collectively, these results suggest that WGA-TA-loaded nanodisks may represent a novel and beneficial therapeutic strategy for the treatment of ACC. Keywords: synthetic high-density lipoproteins, scavenger receptor class B1, targeted delivery, nanodisks, withalongolides, adrenocortical carcinomas

  10. DNA methylation is an independent prognostic marker of survival in adrenocortical cancer

    NARCIS (Netherlands)

    Jouinot, Anne; Assie, Guillaume; Libe, Rossella; Fassnacht, Martin; Papathomas, Thomas; Barreau, Olivia; De La Villeon, Bruno; Faillot, Simon; Hamzaoui, Nadim; Neou, Mario; Perlemoine, Karine; Rene-Corail, Fernande; Rodriguez, Stephanie; Sibony, Mathilde; Tissier, Frederique; Dousset, Bertrand; Sbiera, Silviu; Ronchi, Cristina; Kroiss, Matthias; Korpershoek, Esther; De Krijger, Ronald; Waldmann, Jens; Bartsch, Detlef K.; Quinkler, Marcus; Haissaguerre, Magalie; Tabarin, Antoine; Chabre, Olivier; Sturm, Nathalie; Luconi, Michaela; Mantero, Franco; Mannelli, Massimo; Cohen, Regis; Kerlan, Veronique; Touraine, Philippe; Barrande, Gaelle; Groussin, Lionel; Bertagna, Xavier; Baudin, Eric; Amar, Laurence; Beuschlein, Felix; Clauser, Eric; Coste, Joel; Bertherat, Jerome

    2017-01-01

    Context: Adrenocortical cancer (ACC) is an aggressive tumor with a heterogeneous outcome. Prognostic stratification is difficult even based on tumor stage and Ki67. Recently integrated genomics studies have demonstrated that CpG islands hypermethylation is correlated with poor survival. Objective:

  11. Adrenocortical neoplasia: Evolving concepts in tumorigenesis with an emphasis on adrenal cortical carcinoma variants

    NARCIS (Netherlands)

    R.R. de Krijger (Ronald); T.G. Papathomas (Thomas)

    2012-01-01

    textabstractAdrenocortical carcinoma (ACC) is a rare, heterogeneous malignancy with a poor prognosis. According to WHO classification 2004, ACC variants include oncocytic ACCs, myxoid ACCs and ACCs with sarcomatous areas. Herein, we provide a comprehensive review of these rare subtypes of

  12. Emotional and Adrenocortical Regulation in Early Adolescence: Prediction by Attachment Security and Disorganization in Infancy

    Science.gov (United States)

    Spangler, Gottfried; Zimmermann, Peter

    2014-01-01

    The aim of the present study was to examine differences in emotion expression and emotion regulation in emotion-eliciting situations in early adolescence from a bio-psycho-social perspective, specifically investigating the influence of early mother-infant attachment and attachment disorganization on behavioural and adrenocortical responses. The…

  13. Maternal-child adrenocortical attunement in early childhood: continuity and change.

    Science.gov (United States)

    Hibel, Leah C; Granger, Douglas A; Blair, Clancy; Finegood, Eric D

    2015-01-01

    This study evaluated continuity and change in maternal-child hypothalamic-pituitary-adrenal axis attunement in early childhood. Participants were drawn from a prospective study of 1,292 mother-child dyads, which were racially diverse, predominantly low-income, and non-urban. Child focused stress tasks designed to elicit anger, fear, and frustration were administered during early infancy, later infancy, and toddlerhood. Mothers' and children's saliva samples (later assayed for cortisol) were collected before and after the tasks. The strength of mother-child adrenocortical attunement was conserved across infancy and toddlerhood. The magnitude of maternal-child adrenocortical attunement decreased in response to the child-focused stress tasks. Maternal sensitivity and the child's task-related emotional reactivity moderated adrenocortical attunement across the task, with greater maternal sensitivity during a free-play, and lower levels of child emotional reactivity during the stress tasks, stabilizing attunement from pre- to post-task levels. The findings advance our understanding of individual differences in the social regulation of adrenocortical activity in early childhood. © 2014 Wiley Periodicals, Inc.

  14. The Relations between Bullying Exposures in Middle Childhood, Anxiety, and Adrenocortical Activity

    Science.gov (United States)

    Carney, JoLynn V.; Hazler, Richard J.; Oh, Insoo; Hibel, Leah C.; Granger, Douglas A.

    2010-01-01

    This exploratory study investigated how exposure to bullying at school in middle childhood is associated with student anxiety levels and adrenocortical activity at a time preceding lunch when anxiety about potential bullying would potentially be higher. Ninety-one sixth-grade students (55 female and 36 male) reported being exposed one or more…

  15. Treatment with docetaxel and cisplatin in advanced adrenocortical carcinoma, a phase II study

    DEFF Research Database (Denmark)

    Urup, Thomas; Pawlak, W Z; Petersen, P M

    2013-01-01

    Adrenocortical carcinoma (ACC) is a rare disease with a poor response to chemotherapy. Cisplatin is the most widely investigated drug in the treatment of ACC and in vitro studies have indicated activity of taxanes. The objectives of this study were to evaluate the efficacy and toxicity of cisplatin...... combined with docetaxel as first-line treatment of advanced ACC....

  16. A Late Onset of Adrenocortical Cancer Assosiated with Beckwith-Wiedemann Syndrome

    Directory of Open Access Journals (Sweden)

    N S Kuznetsov

    2014-06-01

    Full Text Available Beckwith-Wiedemann syndrome (BWS is a genetic overgrowth disorder involving a predisposition to tumor development. The common features of Beckwith-Wiedemann syndrome include omphalocele, macroglos- sia and macrosomia. The increased risk for neoplasia is concentrated in the first eight years of life. However, this case presents a late onset of adrenocortical cancer assosiated with Beckwith-Wiedemann syndrome.

  17. Advanced diagnostic approaches and current medical management of insulinomas and adrenocortical disease in ferrets (Mustela putorius furo).

    Science.gov (United States)

    Chen, Sue

    2010-09-01

    Endocrine neoplasia is the most common tumor type in domestic ferrets, especially in middle-aged to older ferrets. Islet cell tumors and adrenocortical tumors constitute the major types of endocrine neoplasms. Insulinoma is a tumor that produces and releases excessive amounts of insulin. Evaluation of fasted blood glucose levels provides a quick diagnostic assessment for the detection of insulinomas. Use of glucocorticoids, diazoxide, and diet modification are some of the medical treatment options for insulinomas. Adrenocortical neoplasia in ferrets usually overproduces one or more sex hormones. Sex hormones which can result in progressive alopecia, vulvar swelling in females, and prostagomegaly in males. Abdominal ultrasonography and sex hormone assays can be used to diagnose adrenocortical neoplasms. Drugs such as leuprolide acetate, deslorelin acetate, and the hormone melatonin can be used to treat adrenocortical neoplasms in ferrets when surgery is not an option. Copyright 2010 Elsevier Inc. All rights reserved.

  18. A case of low renin hyperaldosteronism considered to be aldosterone-producing adrenocortical adenoma by CT image of adrenal gland

    International Nuclear Information System (INIS)

    Hayashi, Kozo; Tsuchihashi, Yoshihiro; Ito, Kazuro; Ozono, Noboru

    1983-01-01

    A case was reported in which hypertension, hypopotassemia, low plasma renin activity and hyperaldosteronemia were observed. Imaging suggested adrenocortical adenoma, leading to the diagnosis of low renin hyperaldosteronism. (Chiba, N.)

  19. Association of mitotane with chylomicrons and serum lipoproteins: practical implications for treatment of adrenocortical carcinoma.

    Science.gov (United States)

    Kroiss, Matthias; Plonné, Dietmar; Kendl, Sabine; Schirmer, Diana; Ronchi, Cristina L; Schirbel, Andreas; Zink, Martina; Lapa, Constantin; Klinker, Hartwig; Fassnacht, Martin; Heinz, Werner; Sbiera, Silviu

    2016-03-01

    Oral mitotane (o,p'-DDD) is a cornerstone of medical treatment for adrenocortical carcinoma (ACC). Serum mitotane concentrations >14  mg/l are targeted for improved efficacy but not achieved in about half of patients. Here we aimed at a better understanding of intestinal absorption and lipoprotein association of mitotane and metabolites o,p'-dichlorodiphenylacetic acid (o,p'-DDA) and o,p'-dichlorodiphenyldichloroethane (o,p'-DDE). Lipoproteins were isolated by ultracentrifugation from the chyle of a 29-year-old patient and serum from additional 14 ACC patients treated with mitotane. HPLC was applied for quantification of mitotane and metabolites. We assessed NCI-H295 cell viability, cortisol production, and expression of endoplasmic reticulum (ER) stress marker genes to study the functional consequences of mitotane binding to lipoproteins. Chyle of the index patient contained 197  mg/ml mitotane, 53  mg/ml o,p'-DDA, and 51  mg/l o,p'-DDE. Of the total mitotane in serum, lipoprotein fractions contained 21.7±21.4% (VLDL), 1.9±0.8% (IDL), 8.9±5.5% (LDL1), 18.9±9.6% (LDL2), 10.1±4.0% (LDL3), and 26.3±13.0% (HDL2). Only 12.3±5.5% were in the lipoprotein-depleted fraction. Mitotane content of lipoproteins directly correlated with their triglyceride and cholesterol content. O,p'-DDE was similarly distributed, but 87.9±4.2% of o,p'-DDA found in the HDL2 and lipoprotein-depleted fractions. Binding of mitotane to human lipoproteins blunted its anti-proliferative and anti-hormonal effects on NCI-H295 cells and reduced ER stress marker gene expression. Mitotane absorption involves chylomicron binding. High concentrations of o,p'-DDA and o,p'-DDE in chyle suggest intestinal mitotane metabolism. In serum, the majority of mitotane is bound to lipoproteins. In vitro, lipoprotein binding inhibits activity of mitotane suggesting that lipoprotein-free mitotane is the therapeutically active fraction. © 2016 European Society of Endocrinology.

  20. The effect of oxygen on aldosterone release from bovine adrenocortical cells in vitro: PO2 versus steroidogenesis.

    Science.gov (United States)

    Raff, H; Kohandarvish, S

    1990-08-01

    Hypoxia decreases plasma aldosterone in vivo without a decrease in PRA, angiotensin II (ANG II), ACTH, or cortisol. The present study evaluated whether this could be due to a direct, specific inhibitory effect on the zona glomerulosa related to the magnitude of the decrease in oxygen (O2). Bovine adrenocortical cells were dispersed with collagenase and studied in vitro within 48 h. Cells were stimulated for 2 h with ANG II (0.1-1000 nM) or (Bu)2cAMP (0.3-3 mM) under oxygen levels ranging from 0 to 100% O2 (PO2 from 66 +/- 4 to 561 +/- 46 torr) vs. a reference gas mixture (21% O2 PO2 approximately 140 torr). Exposure to 123 +/- 8, 110 +/- 12, 100 +/- 16, and 66 +/- 4 torr led to 27%, 30%, 40% and 70% inhibition, respectively, of 3 nM ANG II-stimulated aldosterone secretion as compared to 140 +/- 16 torr (reference). Exposure to hyperoxia (288 +/- 36 to 561 +/- 46 torr) led to a small (10%) increase in ANG II-stimulated aldosterone secretion which was not statistically significant. The P50 (half-maximal PO2) for aldosteronogenesis was approximately 95 torr. The results for other doses of ANG II and for cAMP were similar. The inhibitory effect of low O2 was reversed by returning the cells to reference conditions (140 +/- 16 torr). Cortisol secretion was not significantly affected by changes in oxygen tension. We conclude that small changes in O2 within the physiological range directly and specifically inhibit aldosteronogenesis in a dose-dependent manner with a P50 of approximately 95 torr. Inhibition of cAMP-stimulated aldosterone secretion suggests a postreceptor site of action. This direct, reversible, and specific effect on the zona glomerulosa of the adrenal cortex may account for the dissociation of renin and aldosterone during hypoxia in vivo.

  1. Adrenocortical carcinoma with extension to the inferior vena cava and right atrium: 20-month-old girl with TP53 mutation

    Directory of Open Access Journals (Sweden)

    Terry L. Levin, MD

    2015-01-01

    Full Text Available A 20-month-old female presented with respiratory distress and a right adrenal mass extending into the inferior vena cava and right atrium. The mass was initially thought to be neuroblastoma. Pathology later revealed adrenocortical carcinoma. Inferior vena cava extension is far more common in adrenocortical carcinoma than neuroblastoma, and its presence should prompt clinical and laboratory evaluation for an adrenocortical tumor. The genetic findings in TP53 associated with this disease are discussed.

  2. Imaging Findings of Pelvic Tumor Thrombosis Extending from Sacral Bone Metastasis of Adrenocortical Carcinoma

    Directory of Open Access Journals (Sweden)

    Kenichiro Ishida

    2012-01-01

    Full Text Available We report the imaging findings of a patient with adrenocortical carcinoma who showed pelvic tumor thrombosis extending from sacral bone metastasis. Contrast-enhanced computed tomography demonstrated extensive intraluminal filling defects in the pelvic veins. A lytic lesion in the sacrum was also noted and continuity between the sacral lesion and the filling defect in the branch of pelvic veins was indicated. The filling defects showed increased uptake on positron emission tomography with 18F-fluorodeoxyglucose and single-photon emission computed tomography with 131I-iodomethylnorcholesterol, and fusion images with computed tomography aided the localization of the increased uptake areas. Multimodality imaging may be beneficial for the characterization and localization of lesions in patients suspected of having metastatic adrenocortical carcinoma.

  3. Adrenocortical function and reserve in children treated for acute lymphoblastic leukemia

    International Nuclear Information System (INIS)

    Pawlaczyk, B.; Malecka, E.H.; Krause, W.

    1993-01-01

    Serum cortisol and 17 OHS, 17 KS and DHA levels in 24-hour urine were determined in 30 children (22 girls and boys) 0.5 to 4 years after completion of therapy (radio- and chemotherapy) for acute lymphoblastic leukemia (ALL). Serum cortisol after Syncthen (adrenocortical reserve) was determined in 15 girls and 4 boys. The results show that therapy for ALL depresses glucocorticosteroid synthesis; however, it does not disturb the adrenal reserve or androgenesis. (author)

  4. Increased adrenocortical response to adrenocorticotropic hormone (ACTH) in sport horses with equine glandular gastric disease (EGGD).

    Science.gov (United States)

    Scheidegger, M D; Gerber, V; Bruckmaier, R M; van der Kolk, J H; Burger, D; Ramseyer, A

    2017-10-01

    This study tested the hypothesis that adrenocortical function would be altered in horses with equine gastric ulcer syndrome (EGUS). Twenty-six sport horses competing at national or international levels in eventing (n=15) or endurance (n=11) were subjected to a gastroscopic examination and an adrenocorticotropic hormone (ACTH) stimulation test. Salivary cortisol concentrations were measured before (baseline) and after (30, 60, 90, 120 and 150min) IV ACTH injection (1μg/kg bodyweight). Within EGUS, two distinct diseases, equine squamous gastric disease (ESGD) and equine glandular gastric disease (EGGD), can be distinguished. ESGD was diagnosed in 8/11 (73%; 95% confidence intervals [95%CI], 43-92%) endurance horses and 5/15 (33%; 95% CI, 14-58%) eventing horses. EGGD was observed in 9/11 (82%; 95% CI, 53-96%) endurance horses and 9/15 (60%; 95% CI, 35-81%) eventing horses. The presence or severity of ESGD was unrelated to the presence or severity of EGGD. ACTH stimulation induced a larger increase in cortisol concentration in horses with moderate EGGD than in horses with mild EGGD. Cortisol concentration during the entire sampling period (total increase in cortisol concentration during the entire sampling period [dAUC], 31.1±6.4ng/mL) and the highest measured concentration at a single time point (maximal increase in cortisol concentration [dMAX], 10.3±2.3ng/mL) were increased (P=0.005 and P=0.038, respectively), indicating that horses with glandular gastric disease exhibited increased adrenocortical responses to ACTH stimulation. These results suggest that EGGD might be associated with an enhanced adrenocortical sensitivity. Further investigations are warranted to confirm the association between adrenocortical sensitivity and EGGD and to elucidate the pathophysiological mechanisms involved. Copyright © 2017 Elsevier Ltd. All rights reserved.

  5. Nationwide analysis of adrenocortical carcinoma reveals higher perioperative morbidity in functional tumors.

    Science.gov (United States)

    Parikh, Punam P; Rubio, Gustavo A; Farra, Josefina C; Lew, John I

    2017-08-25

    Current adrenalectomy outcomes for functional adrenocortical carcinoma (ACC) remain unclear. This study examines nationwide in-hospital post-adrenalectomy outcomes for ACC. A retrospective analysis of the Nationwide Inpatient Sample database (2006-2011) to identify unilateral adrenalectomy patients for functional or nonfunctional ACC was performed. Patient demographics, comorbidities and postoperative outcomes were evaluated by t-test, Chi-square and multivariate regression. Of 2199 patients who underwent adrenalectomy, 87% had nonfunctional and 13% had functional ACC (86% hypercortisolism, 16% hyperaldosteronism, 4% hyperandrogenism). Functional ACC patients had significantly more comorbidities, and experienced certain postoperative complications more frequently including wound issues, adrenocortical insufficiency and acute kidney injury with longer hospital stay compared to nonfunctional ACC (P analysis, functional ACC was an independent prognosticator for wound complications (28.1, 95%CI 4.59-176.6). Patients with functional ACC manifest significant comorbidities with certain in-hospital complications. Such high-risk patients require appropriate preoperative medical optimization prior to adrenalectomy. Patients with functional adrenocortical carcinoma (ACC) have significant preoperative comorbidities and experience higher rates of certain postoperative complications including wound complications, hematoma formation, adrenal insufficiency, pulmonary embolism and acute kidney injury. Functional ACC patients also necessitate longer hospitalizations. These patients should undergo appropriate preoperative counseling in preparation for adrenalectomy. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. Expression of StAR and Key Genes Regulating Cortisol Biosynthesis in Near Term Ovine Fetal Adrenocortical Cells: Effects of Long-Term Hypoxia.

    Science.gov (United States)

    Vargas, Vladimir E; Myers, Dean A; Kaushal, Kanchan M; Ducsay, Charles A

    2018-02-01

    We previously demonstrated decreased expression of key genes regulating cortisol biosynthesis in long-term hypoxic (LTH) sheep fetal adrenals compared to controls. We also showed that inhibition of the extracellular signal-regulated kinases (ERKs) with the mitogen-activated protein kinase (MEK)/ERK inhibitor UO126 limited adrenocorticotropic (ACTH)-induced cortisol production in ovine fetal adrenocortical cells (FACs), suggesting a role for ERKs in cortisol synthesis. This study was designed to determine whether the previously observed decrease in LTH cytochrome P45011A1/cytochrome P450c17 (CYP11A1/CYP17) in adrenal glands was maintained in vitro, and whether ACTH alone with or without UO126 treatment had altered the expression of CYP11A1, CYP17, and steroidogenic acute regulatory protein (StAR) in control versus LTH FACs. Ewes were maintained at high altitude (3820 m) from ∼40 days of gestation (dG). At 138 to 141 dG, fetal adrenal glands were collected from LTH (n = 5) and age-matched normoxic controls (n = 6). Fetal adrenocortical cells were challenged with ACTH (10 -8 M) with or without UO126 (10 µM) for 18 hours. Media samples were collected for cortisol analysis and messenger RNA (mRNA) for CYP11A1, CYP17, and StAR was quantified by quantitative real-time polymerase chain reaction. Cortisol was higher in the LTH versus control ( P StAR mRNA was decreased in LTH versus control ( P StAR expression.

  7. Inhibition and Exuberance in Preschool Classrooms: Associations with Peer Social Experiences and Changes in Cortisol across the Preschool Year

    Science.gov (United States)

    Tarullo, Amanda R.; Mliner, Shanna; Gunnar, Megan R.

    2011-01-01

    Associations between behavioral inhibition and activity of the hypothalamic-pituitary-adrenocortical (HPA) system, a stress-sensitive neuroendocrine system indexed by salivary cortisol, have varied widely across studies. In the current study, we examined the role of peer social experiences in moderating patterns of association between…

  8. High-Throughput Screening of Chemical Effects on Steroidogenesis Using H295R Human Adrenocortical Carcinoma Cells.

    Science.gov (United States)

    Karmaus, Agnes L; Toole, Colleen M; Filer, Dayne L; Lewis, Kenneth C; Martin, Matthew T

    2016-04-01

    Disruption of steroidogenesis by environmental chemicals can result in altered hormone levels causing adverse reproductive and developmental effects. A high-throughput assay using H295R human adrenocortical carcinoma cells was used to evaluate the effect of 2060 chemical samples on steroidogenesis via high-performance liquid chromatography followed by tandem mass spectrometry quantification of 10 steroid hormones, including progestagens, glucocorticoids, androgens, and estrogens. The study employed a 3 stage screening strategy. The first stage established the maximum tolerated concentration (MTC; ≥ 70% viability) per sample. The second stage quantified changes in hormone levels at the MTC whereas the third stage performed concentration-response (CR) on a subset of samples. At all stages, cells were prestimulated with 10 µM forskolin for 48 h to induce steroidogenesis followed by chemical treatment for 48 h. Of the 2060 chemical samples evaluated, 524 samples were selected for 6-point CR screening, based in part on significantly altering at least 4 hormones at the MTC. CR screening identified 232 chemical samples with concentration-dependent effects on 17β-estradiol and/or testosterone, with 411 chemical samples showing an effect on at least one hormone across the steroidogenesis pathway. Clustering of the concentration-dependent chemical-mediated steroid hormone effects grouped chemical samples into 5 distinct profiles generally representing putative mechanisms of action, including CYP17A1 and HSD3B inhibition. A distinct pattern was observed between imidazole and triazole fungicides suggesting potentially distinct mechanisms of action. From a chemical testing and prioritization perspective, this assay platform provides a robust model for high-throughput screening of chemicals for effects on steroidogenesis. © The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology.

  9. PCP4: a regulator of aldosterone synthesis in human adrenocortical tissues

    Science.gov (United States)

    Felizola, Saulo J. A.; Nakamura, Yasuhiro; Ono, Yoshikiyo; Kitamura, Kanako; Kikuchi, Kumi; Onodera, Yoshiaki; Ise, Kazue; Takase, Kei; Sugawara, Akira; Hattangady, Namita; Rainey, William E.; Satoh, Fumitoshi; Sasano, Hironobu

    2014-01-01

    Purkinje cell protein 4 (PCP4) is a calmodulin (CaM) binding protein that accelerates calcium association and dissociation with CaM. It has been previously detected in aldosterone-producing adenomas (APA) but details on its expression and function in adrenocortical tissues have remained unknown. Therefore, we performed the immunohistochemical analysis of PCP4 in the following tissues: normal adrenal (NA; n=15), APA (n=15), cortisol producing adenomas (CPA; n=15) and idiopathic hyperaldosteronism cases (IHA; n=5). APA samples (n=45) were also submitted to quantitative RT-PCR (qPCR) of PCP4, CYP11B1, and CYP11B2, as well as DNA sequencing for KCNJ5 mutations. Transient transfection analysis using PCP4 siRNA was also performed in H295R adrenocortical carcinoma cells, following ELISA analysis, and CYP11B2 luciferase assays were also performed after PCP4 vector transfection in order to study the regulation of PCP4 protein expression. In our findings, PCP4 immunoreactivity was predominantly detected in APA and in the zona glomerulosa (ZG) of NA and IHA. In APA, the mRNA levels of PCP4 were significantly correlated with those of CYP11B2 (P<0.0001) and were significantly higher in cases with KCNJ5 mutation than wild-type (P=0.005). Following PCP4 vector transfection, CYP11B2 luciferase reporter activity was significantly higher than controls in the presence of angiotensin-II. Knockdown of PCP4 resulted in a significant decrease in CYP11B2 mRNA levels (P=0.012) and aldosterone production (P=0.011). Our results indicate that PCP4 is a regulator of aldosterone production in normal, hyperplastic and neoplastic human adrenocortical cells. PMID:24403568

  10. Magnetic resonance imaging of adrenocortical adenomas in childhood: correlation with computed tomography and ultrasound

    International Nuclear Information System (INIS)

    Hanson, J.A.; Weber, A.; Reznek, R.H.; Cotterill, A.M.; Ross, R.J.M.; Harris, R.J.; Armstrong, P.; Savage, M.O.

    1996-01-01

    There are few descriptions of the magnetic resonance (MR) appearance of hyperfunctioning adrenocortical tumours, particularly those occurring in childhood. We studied five patients, two girls and three boys, aged 6-14.3 years, presenting with clinical syndromes of adrenocortical hyperfunction. The diagnoses were Cushing's syndrome (n = 2), virilisation (n = 2), and Conn's syndrome (n = 1). Biochemical features suggested an adrenal lesion in each case. MR and ultrasound were performed in all five cases, with CT in four. Each patient had a functional adrenal tumour secreting either cortisol, androgens or aldosterone alone, or a combination of cortisol, androgens and oestradiol. The histological diagnosis was adenoma in four cases and tumour of indeterminate nature in one case. MR clearly showed the tumours (diameter 1.0-7.5 cm), all the lesions being of high signal intensity relative to liver on T2-weighted sequences. CT revealed an adrenal mass in each of the four patients scanned, three of which enhanced after intravenous contrast medium injection. The multiplanar imaging of MR allowed better distinction from adjacent structures and also demonstrated an unenlarged contralateral adrenal gland. In the patient with a 1-cm Conn's adenoma the lesion was more easily seen on MR than CT. Ultrasound showed the four larger tumours but was unable to visualise the contralateral adrenal or the Conn's adenoma. In conclusion, the MR appearances of four adrenocortical adenomas and one indeterminate tumour in children are described. MR has been found to be at least equal to CT in the detection of these tumours, with some possible advantages. Both techniques are superior to ultrasound. (orig.). With 4 figs

  11. Extension of adrenocortical carcinoma into the right atrium – echocardiographic diagnosis: A case report

    Directory of Open Access Journals (Sweden)

    Rozenman Yoseph

    2003-05-01

    Full Text Available Abstract Background Adrenocortical carcinoma is a rare, highly malignant tumor. Cardiac involvement of the tumor is very rare. Echocardiography facilitates the evaluation of the cardiac involvement of the tumor. Case Presentation We describe a patient with an adrenal tumor. Transthoracic echo showed its extension into the right atrium. Accordingly, a combined abdominal and cardiac operation was performed, monitored by transesophageal echocardiography. Conclusion This case highlights the importance of echocardiography in revealing the cardiac involvement by this tumor and in planning the operative procedure.

  12. Adrenocortical Regulation, Eating in the Absence of Hunger and BMI in Young Children

    OpenAIRE

    Francis, L. A.; Granger, D. A.; Susman, E. J.

    2012-01-01

    The purpose of this study was to examine relations among adrenocortical regulation, eating in the absence of hunger, and body mass index (BMI) in children ages 5 to 9 years (N = 43). Saliva was collected before and after the Trier Social Stress Test for children (TSST-C), and was later assayed for cortisol. Area under the curve with respect to increase (AUCi) was used as a measure of changes in cortisol release from baseline to 60 minutes post-TSST-C. Age- and sex-specific BMI scores were cal...

  13. Environmental enrichment affects adrenocortical stress responses in the endangered black-footed ferret

    Science.gov (United States)

    Poessel, S.A.; Biggins, D.E.; Santymire, R.M.; Livieri, T.M.; Crooks, K.R.; Angeloni, L.

    2011-01-01

    Potential stressors of wildlife living in captivity, such as artificial living conditions and frequent human contact, may lead to a higher occurrence of disease and reduced reproductive function. One successful method used by wildlife managers to improve general well-being is the provision of environmental enrichment, which is the practice of providing animals under managed care with environmental stimuli. The black-footed ferret (Mustela nigripes) is a highly-endangered carnivore species that was rescued from extinction by removal of the last remaining individuals from the wild to begin an ex situ breeding program. Our goal was to examine the effect of environmental enrichment on adrenocortical activity in ferrets by monitoring fecal glucocorticoid metabolites (FGM). Results demonstrated that enrichment lowered FGM in juvenile male ferrets, while increasing it in adult females; enrichment had no effect on FGM in juvenile females and adult males. These results correspond with our findings that juvenile males interacted more with the enrichment items than did adult females. However, we did not detect an impact of FGM on the incidence of disease or on the ability of ferrets to become reproductive during the following breeding season. We conclude that an environmental enrichment program could benefit captive juvenile male ferrets by reducing adrenocortical activity. ?? 2011 Elsevier Inc.

  14. If It Goes up, Must It Come Down? Chronic Stress and the Hypothalamic-Pituitary Adrenocortical Axis in Humans

    Science.gov (United States)

    Miller, Gregory E.; Chen, Edith; Zhou, Eric S.

    2007-01-01

    The notion that chronic stress fosters disease by activating the hypothalamic-pituitary adrenocortical (HPA) axis is featured prominently in many theories. The research linking chronic stress and HPA function is contradictory, however, with some studies reporting increased activation, and others reporting the opposite. This meta-analysis showed…

  15. Association of the M1V PRKAR1A mutation with primary pigmented nodular adrenocortical disease in two large families

    NARCIS (Netherlands)

    Pereira, Alberto M.; Hes, Frederik J.; Horvath, Anelia; Woortman, Sanne; Greene, Elizabeth; Bimpaki, Eirini; Alatsatianos, Anton; Boikos, Sosipatros; Smit, Johannes W.; Romijn, Johannes A.; Nesterova, Maria; Stratakis, Constantine A.

    2010-01-01

    Carney complex (CNC) is a familial multiple neoplasia syndrome frequently associated with primary pigmented nodular adrenocortical disease (PPNAD), a bilateral form of micronodular adrenal hyperplasia that leads to Cushing's syndrome (CS). Germline PRKAR1A mutations cause CNC and only rarely

  16. Cushing's Syndrome caused by pigmented adrenocortical micro nodular dysplasia - A familial case

    Energy Technology Data Exchange (ETDEWEB)

    Gomez-Segovia, I; Gallowitsch, H J; Kresnik, E; Kumnig, G; Mikosch, P; Lind, P [Dept.of Nuclear Medicine and Endocrinology, LKH Klagenfurt (Austria)

    2002-09-01

    Introduction: We present a Case of Cushing's syndrome (CS) in a 16 year old male adolescent. Adrenocortical micro nodular dysplasia is a rare cause of CS. It mostly develops in the first two decades of life. In pathogenesis a stimulatory effect of circulating Immunoglobulins on adrenal steroidogenesis has been postulated. Familial cases have been reported in relation to Carney's Syndrome. We report the clinical case at first diagnosis and preoperative follow up of 1 year prior to treatment. The leading symptoms were severe bilateral (fibrotic) gynaecomastia, weight gain and growth retardation, without hypertension,but osteoporosis, secondary hypogonadism and glucose intolerance. Laboratory findings and the results of functional tests were diagnostic for CS. In addition LDH (I-131 Isotopes), CK, Lipoproteins, GPT, Androstendion, Prolactin were elevated. MRI abdomen revealed a slight enlargement of the adrenals, and suspected a bilateral micro nodular dysplasia. Iodo-cholesterol-scan under dexamethason suppression showed a diffuse bilateral Iodo-cholesterol uptake confirming the autonomous production of cortisol bilateral in the adrenals.Whole body bone scan showed a diffuse reduced diphosphonate uptake in the skeleton and the growth plates. The bone mineral density was significantly reduced.Radiologically osteoporosis was overt. The rapid increase of free urinary cortisol excretion/24h within one year of observation led to a total bilateral adrenalectomy. Postoperative 5 year follow up examinations. Documentation of the outcome and recovery of clinical signs,symptoms and laboratory findings, discussion about the most appropriate long-term substitution therapy. Familial anamnesis:affected family member was the father (micro nodular bilateral adrenocortical dysplasia), the aunt (pararenal incidentaloma, histologically lipoma) and a cousin (micro nodular adrenocortical dysplasia). Sequential analysis of the menin gene from the patient was negative.The detection of

  17. Cushing's Syndrome caused by pigmented adrenocortical micro nodular dysplasia - A familial case

    International Nuclear Information System (INIS)

    Gomez-Segovia, I.; Gallowitsch, H.J.; Kresnik, E.; Kumnig, G.; Mikosch, P.; Lind, P.

    2002-01-01

    Introduction: We present a Case of Cushing's syndrome (CS) in a 16 year old male adolescent. Adrenocortical micro nodular dysplasia is a rare cause of CS. It mostly develops in the first two decades of life. In pathogenesis a stimulatory effect of circulating Immunoglobulins on adrenal steroidogenesis has been postulated. Familial cases have been reported in relation to Carney's Syndrome. We report the clinical case at first diagnosis and preoperative follow up of 1 year prior to treatment. The leading symptoms were severe bilateral (fibrotic) gynaecomastia, weight gain and growth retardation, without hypertension,but osteoporosis, secondary hypogonadism and glucose intolerance. Laboratory findings and the results of functional tests were diagnostic for CS. In addition LDH (I-131 Isotopes), CK, Lipoproteins, GPT, Androstendion, Prolactin were elevated. MRI abdomen revealed a slight enlargement of the adrenals, and suspected a bilateral micro nodular dysplasia. Iodo-cholesterol-scan under dexamethason suppression showed a diffuse bilateral Iodo-cholesterol uptake confirming the autonomous production of cortisol bilateral in the adrenals.Whole body bone scan showed a diffuse reduced diphosphonate uptake in the skeleton and the growth plates. The bone mineral density was significantly reduced.Radiologically osteoporosis was overt. The rapid increase of free urinary cortisol excretion/24h within one year of observation led to a total bilateral adrenalectomy. Postoperative 5 year follow up examinations. Documentation of the outcome and recovery of clinical signs,symptoms and laboratory findings, discussion about the most appropriate long-term substitution therapy. Familial anamnesis:affected family member was the father (micro nodular bilateral adrenocortical dysplasia), the aunt (pararenal incidentaloma, histologically lipoma) and a cousin (micro nodular adrenocortical dysplasia). Sequential analysis of the menin gene from the patient was negative.The detection of

  18. Differentiating pheochromocytoma from lipid-poor adrenocortical adenoma by CT texture analysis: feasibility study.

    Science.gov (United States)

    Zhang, Gu-Mu-Yang; Shi, Bing; Sun, Hao; Jin, Zheng-Yu; Xue, Hua-Dan

    2017-09-01

    To investigate the feasibility of using CT texture analysis (CTTA) to differentiate pheochromocytoma from lipid-poor adrenocortical adenoma (lp-ACA). Ninety-eight pheochromocytomas and 66 lp-ACAs were included in this retrospective study. CTTA was performed on unenhanced and enhanced images. Receiver operating characteristic (ROC) analysis was performed, and the area under the ROC curve (AUC) was calculated for texture parameters that were significantly different for the objective. Diagnostic accuracies were evaluated using the cutoff values of texture parameters with the highest AUCs. Compared to lp-ACAs, pheochromocytomas had significantly higher mean gray-level intensity (Mean), entropy, and mean of positive pixels (MPP), but lower skewness and kurtosis on unenhanced images (P feasible to use CTTA to differentiate pheochromocytoma from lp-ACA.

  19. Adrenocortical Secreting Mass in a Patient with Gardner's Syndrome: A Case Report

    Directory of Open Access Journals (Sweden)

    Nabila Mejdoub Rekik

    2010-01-01

    Full Text Available Gardner's syndrome (GS is a dysplasia characterized by neoformations of the intestine, soft tissue, and osseous tissue. Endocrine neoplasms have occasionally been reported in association with GS. Adrenal masses in GS are rare, and few have displayed clinical manifestations. In the current paper, The authors report a 37-year-old male patient with GS including familial adenomatous polyposis (FAP and mandible osteoma who presented with an incidental adrenal mass. Computerized tomography adrenal scan identified bilateral masses. Functional analyses showed a hormonal secretion pattern consistent with pre-Cushing's syndrome. Other extraintestinal manifestations were hypertrophy of the pigmented layer of the retina and histiocytofibroma in the right leg. This paper describes a rare association of adrenocortical secreting mass in an old male patient with Gardner syndrome.

  20. Adrenocortical carcinoma presenting as varicocele and renal vein thrombosis: a case report

    Directory of Open Access Journals (Sweden)

    Horne John M

    2011-08-01

    Full Text Available Abstract Introduction Adrenocortical carcinomas are rare aggressive tumors. Their annual incidence is approximately one to two per million among the population of the United States of America. Patients with active endocrine tumors often present with Cushing's syndrome accompanied by virilizing features. Conversely, patients with non-functioning tumors may present with symptoms related to a mass-occupying lesion, such as abdominal pain and flank pain. Although varicoceles and acute kidney injuries are common problems in medicine, they are uncommon presentations of these rare tumors and easy to miss. We report a case of a large adrenocortical carcinoma that presented as testicular pain, varicocele, and acute kidney injury secondary to renal vein thrombosis. Case presentation A 54-year-old Caucasian man with a left-sided varicocele presented to our emergency department with lower abdominal pain and a decrease in urination. Four months previously, he had noticed pain and swelling in his left groin and had been diagnosed with left-sided varicocele. For one week, he began developing left-sided abdominal pain and decreased urination frequency, so he came to our emergency department for evaluation. His physical examination revealed a hard mass occupying the entire left side of his abdomen, crossing the midline, and extending to the pelvic brim. His blood tests showed acute kidney injury and mild anemia. Computed tomography of his abdomen showed a large retroperitoneal mass on the left side, displacing the left kidney inferiorly and the spleen superiorly with thoracic epidural compression. Thrombus was also identified in his left renal vein and inferior vena cava. Computed tomography of his chest showed bilateral pulmonary nodules. A computed tomography-guided abdominal mass biopsy was performed, and the diagnosis of adrenocortical carcinoma was made on the basis of pathology and immunohistochemistry. His hormonal evaluations were normal. His kidney

  1. A mathematical model of the hypothalamo-pituitary-adrenocortical system and its stability analysis

    International Nuclear Information System (INIS)

    Savic, Danka; Jelic, Smiljana

    2005-01-01

    It is commonly assumed that the hypothalamo-pituitary-adrenocortical (HPA) axis generates oscillations, because a regular daily rhythm of its component hormones is observed. We offer another plausible explanation of the origin of its circadian oscillations: HPA just responds to an independent external pacemaker (from the suprachiazmatic nucleus, SCN). Five versions (with and without time delay) of a qualitative non-phenomenological mathematical model of the HPA axis as a feedback mechanism are constructed wherein all the terms in the equations are introduced according to the rules of chemical kinetics, i.e. are physicochemically interpretable. The dynamics of the HPA axis model was examined using linear stability analysis. The results show stability of this system, meaning that it does not generate diurnal oscillations. Computer simulation based on this model shows oscillations that are system's response to an external pulsing activator (SCN) implying that the observed time-periodic pattern does not have to be an intrinsic property of the HPA axis

  2. Biosynthesis of Various Steroids in vitro by Isolated Adrenal Cells in Primary Aldosteronism, Cushing's Syndrome, and Adrenogenital Syndrome due to Adrenocortical Adenoma

    OpenAIRE

    MIZUNO, SHIGERU; FUNAHASHI, HIROOMI

    1981-01-01

    To a further understanding of the role of steroid hormones in adrenal disorders, we have prepared free cell system of adrenal cells, using adrenal tissues that had been removed by operation from (i) cases of Cushing's syndrome due to adrenocortical adenoma or adrenocortical hyperplasia, (ii) a case of primary aldosteronism, and (iii) a patient with virilizing adrenal tumor. Twelve important steroid hormones were measured, such as pregnenolone, cortisol and aldosterone, which were produced by ...

  3. Adrenal incidentalomas showing unilateral concordant visualization by adrenocortical scintigraphy. Comparison with adenomas in Cushing's syndrome

    International Nuclear Information System (INIS)

    Tani, Atsushi; Nakajo, Masayuki; Tsuchimochi, Shinsaku; Nakabeppu, Yoshiaki; Umanodan, Tomokazu

    2000-01-01

    An adrenocortical adenoma causing Cushing's syndrome (Cushing's adenoma) produces a unilateral concordant visualization (UCV) imaging pattern in which the adenoma is only visualized on radioiodocholesterol adrenocortical scintigraphy. But because this imaging pattern is also noted in some patients with adrenal incidentalomas, we examined whether the UCV-incidentaloma was essentially identical with Cushing's adenoma and would develop Cushing's syndrome. The subjects were 9 patients with UCV-incidentalomas (mean size, 30 mm; range, 20-45 mm) and 6 patients with Cushing's adenomas (mean size, 28 mm; range, 25-35 mm). Endocrinological evaluations showed several abnormalities including blunted diurnal rhythm of plasma cortisol within the normal range, low plasma ACTH and/or high 24-hr urinary 17-OHCS levels in 8 of 9 patients with UCV-incidentalomas, but these abnormalities did not meet the diagnostic criteria of Cushing's syndrome. Adrenal uptake of the tracer in the patients with UCV-incidentalomas was not statistically different from that in the patients with Cushing's adenomas and had no relationship with hormonal values in either patient group. Tumor size on CT correlated with the levels of 24-hr urinary 17-OHCS (r=0.75, p=0.02) and plasma cortisol at 7:00 (r=0.82, p=0.007) in the patients with UCV-incidentalomas, but not in the patients with Cushing's adenomas. Although 3 UCV-incidentalomas increased slightly in size, none of 9 patients with UCV-incidentalomas has developed Cushing's syndrome for 4 to 52 months. These results suggest that the UCV-incidentaloma may be essentially different from the Cushing's adenoma and unlikely to develop Cushing's syndrome. (author)

  4. A mathematical model of the hypothalamo-pituitary-adrenocortical system and its stability analysis

    Energy Technology Data Exchange (ETDEWEB)

    Savic, Danka [Vinca Institute of Nuclear Sciences, Laboratory for Theoretical and Condensed Matter Physics, P.O. Box 522, Belgrade 11001 (Serbia and Montenegro)] e-mail: dankasav@eunet.yu; Jelic, Smiljana [Vinca Institute of Nuclear Sciences, Laboratory for Theoretical and Condensed Matter Physics, P.O. Box 522, Belgrade 11001 (Serbia and Montenegro)

    2005-10-01

    It is commonly assumed that the hypothalamo-pituitary-adrenocortical (HPA) axis generates oscillations, because a regular daily rhythm of its component hormones is observed. We offer another plausible explanation of the origin of its circadian oscillations: HPA just responds to an independent external pacemaker (from the suprachiazmatic nucleus, SCN). Five versions (with and without time delay) of a qualitative non-phenomenological mathematical model of the HPA axis as a feedback mechanism are constructed wherein all the terms in the equations are introduced according to the rules of chemical kinetics, i.e. are physicochemically interpretable. The dynamics of the HPA axis model was examined using linear stability analysis. The results show stability of this system, meaning that it does not generate diurnal oscillations. Computer simulation based on this model shows oscillations that are system's response to an external pulsing activator (SCN) implying that the observed time-periodic pattern does not have to be an intrinsic property of the HPA axis.

  5. Germline PRKACA amplification leads to Cushing syndrome caused by 3 adrenocortical pathologic phenotypes.

    Science.gov (United States)

    Carney, J Aidan; Lyssikatos, Charalampos; Lodish, Maya B; Stratakis, Constantine A

    2015-01-01

    We describe the pathology of 5 patients with germline PRKACA copy number gain and Cushing syndrome: 4 males and 1 female, aged 2 to 43 years, including a mother and son. Imaging showed normal or slightly enlarged adrenal glands in 4 patients and a unilateral mass in the fifth. Biochemically, the patients had corticotropin-independent hypercortisolism. Four underwent bilateral adrenalectomy; unilateral adrenalectomy was performed in the patient with the adrenal mass. Pathologically, 3 patients, including the 1 with the tumor (adenoma), had primary pigmented nodular adrenocortical disease with extranodular cortical atrophy and mild intracapsular and extracapsular extension of cortical cells. The other 2 patients had cortical hyperplasia and prominent capsular and extracapsular micronodular cortical hyperplasia. Immunoperoxidase staining revealed differences for synaptophysin, inhibin-A, and Ki-67 (nuclei) in the atrophic cortices (patients 1, 2, and 3) and hyperplastic cortices (patients 4 and 5) and for Ki-67 (nuclei) and vimentin in the extracortical nodules in the 2 groups of patients. β-Catenin stained the cell membrane, cytoplasm, and nuclei of the adenoma. The patients were well at follow-up (1-23 years); 24-hour urinary cortisol excretion was elevated in the patient who had unilateral adrenalectomy. Copyright © 2014 Elsevier Inc. All rights reserved.

  6. Polychlorinated biphenyl 126 stimulates basal and inducible aldosterone biosynthesis of human adrenocortical H295R cells

    International Nuclear Information System (INIS)

    Li, L.-A.; Wang, P.-W.; Chang, Louis W.

    2004-01-01

    To understand the effects of polychlorinated biphenyls (PCBs) on adrenal aldosterone biosynthesis, we have performed a systematical study to characterize the corresponding steroidogenic response of human adrenocortical cell line H295R to PCB126 exposure. We found that PCB126 at high concentrations stimulated basal and inducible aldosterone production. The aldosterone induction occurred concomitantly with activation of the CYP11B2 gene. Despite the fact that PCB126 acted in synergy with both potassium and angiotensin II (Ang II) in activation of aldosterone synthesis, PCB126 only modestly increased CYP11B2 mRNA expression in the presence of Ang II contrary to the synergistic transcriptional induction elicited by PCB126 and potassium. This implicated that PCB126 had differential interactions with the potassium and Ang II signaling systems in the regulation of aldosterone biosynthesis. In addition, high concentrations of PCB126 elevated transcriptional expression of the type I Ang II receptor (AT 1 ) and might thus sensitize the cellular Ang II responsiveness in both basal and inducible aldosterone biosynthesis. SF-1 was not involved in the PCB126-induced transcriptional regulation despite its importance in steroidogenic gene activation

  7. Cytodiagnosis of myxoid adrenocortical carcinoma and role of immunocytochemistry to differentiate it from renal cell carcinoma

    Directory of Open Access Journals (Sweden)

    Santosh Kumar Mondal

    2014-01-01

    Full Text Available Adrenocortical carcinoma (ACC is a rare malignancy and cytodiagnosis of this tumor is not routinely encountered by a cytopathologist. Here, we report a case of ACC initially diagnosed by computed tomography (CT-guided fine needle aspiration cytology (FNAC with the help of immunocytochemistry. A 48-year-old lady presented with flank pain and abdominal mass for the last 6 months. A CT scan of her abdomen revealed a large mass arising from the upper part of the left kidney. CT-guided FNAC was performed. Cytologic smears showed pleomorphic large cells arranged discretely and in small aggregates against a myxoid background. The cells had a high nucleocytoplasmic ratio, anisonucleosis and conspicuous nucleoli. Based on cytomorphology, differential diagnoses of ACC and renal cell carcinoma (RCC were made. On immunocytochemistry, the tumor cells were synaptophysin, inhibin, vimentin and Melan-A positive but cytokeratin and epithelial membrane antigen negative. Thus, a cytodiagnosis of myxoid ACC was made and histopathologic examination was suggested. Subsequent histologic examination and immunohistochemistry proved the case to be myxoid ACC.

  8. Human Adrenocortical Remodeling Leading to Aldosterone-Producing Cell Cluster Generation

    Directory of Open Access Journals (Sweden)

    Koshiro Nishimoto

    2016-01-01

    Full Text Available Background. The immunohistochemical detection of aldosterone synthase (CYP11B2 and steroid 11β-hydroxylase (CYP11B1 has enabled the identification of aldosterone-producing cell clusters (APCCs in the subcapsular portion of the human adult adrenal cortex. We hypothesized that adrenals have layered zonation in early postnatal stages and are remodeled to possess APCCs over time. Purposes. To investigate changes in human adrenocortical zonation with age. Methods. We retrospectively analyzed adrenal tissues prepared from 33 autopsied patients aged between 0 and 50 years. They were immunostained for CYP11B2 and CYP11B1. The percentage of APCC areas over the whole adrenal area (AA/WAA, % and the number of APCCs (NOA, APCCs/mm2 were calculated by four examiners. Average values were used in statistical analyses. Results. Adrenals under 11 years old had layered zona glomerulosa (ZG and zona fasciculata (ZF without apparent APCCs. Some adrenals had an unstained (CYP11B2/CYP11B1-negative layer between ZG and ZF, resembling the rat undifferentiated cell zone. Average AA/WAA and NOA correlated with age, suggesting that APCC development is associated with aging. Possible APCC-to-APA transitional lesions were incidentally identified in two adult adrenals. Conclusions. The adrenal cortex with layered zonation remodels to possess APCCs over time. APCC generation may be associated with hypertension in adults.

  9. Adrenocortical regulation, eating in the absence of hunger and BMI in young children.

    Science.gov (United States)

    Francis, L A; Granger, D A; Susman, E J

    2013-05-01

    The purpose of this study was to examine relations among adrenocortical regulation, eating in the absence of hunger, and body mass index (BMI) in children ages 5-9years (N=43). Saliva was collected before and after the Trier Social Stress Test for Children (TSST-C), and was later assayed for cortisol. Area under the curve with respect to increase (AUCi) was used as a measure of changes in cortisol release from baseline to 60min post-TSST-C. Age- and sex-specific BMI scores were calculated from measured height and weight, and eating in the absence of hunger was assessed using weighed food intake during a behavioral procedure. We also included a measure of parents' report of child impulsivity, as well as family demographic information. Participants were stratified by age into younger (5-7years) and older (8-9years) groups. In younger children, parents' reports of child impulsivity were significantly and positively associated with BMI; cortisol AUCi was not associated with BMI or eating in the absence of hunger. In older children, however, greater stress-related cortisol AUCi was related to higher BMI scores and greater energy intake in the absence of hunger. The results suggest that cortisol AUCi in response to psychosocial stress may be linked to problems with energy balance in children, with some variation by age. Published by Elsevier Ltd.

  10. Adrenocortical responses to offspring-directed threats in two open-nesting birds.

    Science.gov (United States)

    Butler, Luke K; Bisson, Isabelle-Anne; Hayden, Timothy J; Wikelski, Martin; Romero, L Michael

    2009-07-01

    Dependent young are often easy targets for predators, so for many parent vertebrates, responding to offspring-directed threats is a fundamental part of reproduction. We tested the parental adrenocortical response of the endangered black-capped vireo (Vireo atricapilla) and the common white-eyed vireo (V. griseus) to acute and chronic threats to their offspring. Like many open-nesting birds, our study species experience high offspring mortality. Parents responded behaviorally to a predator decoy or human 1-2m from their nests, but, in contrast to similar studies of cavity-nesting birds, neither these acute threats nor chronic offspring-directed threats altered plasma corticosterone concentrations of parents. Although parents in this study showed no corticosterone response to offspring-directed threats, they always increased corticosterone concentrations in response to capture. To explain these results, we propose that parents perceive their risk of nest-associated death differently depending on nest type, with cavity-nesting adults perceiving greater risk to themselves than open-nesters that can readily detect and escape from offspring-directed threats. Our results agree with previous studies suggesting that the hypothalamic-pituitary-adrenal axis, a major physiological mechanism for coping with threats to survival, probably plays no role in coping with threats to offspring when risks to parents and offspring are not correlated. We extend that paradigm by demonstrating that nest style may influence how adults perceive the correlation between offspring-directed and self-directed threats.

  11. Adrenocortical carcinoma: the dawn of a new era of genomic and molecular biology analysis.

    Science.gov (United States)

    Armignacco, R; Cantini, G; Canu, L; Poli, G; Ercolino, T; Mannelli, M; Luconi, M

    2018-05-01

    Over the last decade, the development of novel and high penetrance genomic approaches to analyze biological samples has provided very new insights in the comprehension of the molecular biology and genetics of tumors. The use of these techniques, consisting of exome sequencing, transcriptome, miRNome, chromosome alteration, genome, and epigenome analysis, has also been successfully applied to adrenocortical carcinoma (ACC). In fact, the analysis of large cohorts of patients allowed the stratification of ACC with different patterns of molecular alterations, associated with different outcomes, thus providing a novel molecular classification of the malignancy to be associated with the classical pathological analysis. Improving our knowledge about ACC molecular features will result not only in a better diagnostic and prognostic accuracy, but also in the identification of more specific therapeutic targets for the development of more effective pharmacological anti-cancer approaches. In particular, the specific molecular alteration profiles identified in ACC may represent targetable events by the use of already developed or newly designed drugs enabling a better and more efficacious management of the ACC patient in the context of new frontiers of personalized precision medicine.

  12. Kindergarten stressors and cumulative adrenocortical activation: the "first straws" of allostatic load?

    Science.gov (United States)

    Bush, Nicole R; Obradović, Jelena; Adler, Nancy; Boyce, W Thomas

    2011-11-01

    Using an ethnically diverse longitudinal sample of 338 kindergarten children, this study examined the effects of cumulative contextual stressors on children's developing hypothalamic-pituitary-adrenocortical (HPA) axis regulation as an early life indicator of allostatic load. Chronic HPA axis regulation was assessed using cumulative, multiday measures of cortisol in both the fall and spring seasons of the kindergarten year. Hierarchical linear regression analyses revealed that contextual stressors related to ethnic minority status, socioeconomic status, and family adversity each uniquely predicted children's daily HPA activity and that some of those associations were curvilinear in conformation. Results showed that the quadratic, U-shaped influences of family socioeconomic status and family adversity operate in different directions to predict children's HPA axis regulation. Results further suggested that these associations differ for White and ethnic minority children. In total, this study revealed that early childhood experiences contribute to shifts in one of the principal neurobiological systems thought to generate allostatic load, confirming the importance of early prevention and intervention efforts. Moreover, findings suggested that analyses of allostatic load and developmental theories accounting for its accrual would benefit from an inclusion of curvilinear associations in tested predictive models.

  13. Rapid and Complete Remission of Metastatic Adrenocortical Carcinoma Persisting 10 Years After Treatment With Mitotane Monotherapy

    Science.gov (United States)

    Ghorayeb, Nada El; Rondeau, Geneviève; Latour, Mathieu; Cohade, Christian; Olney, Harold; Lacroix, André; Perrotte, Paul; Sabourin, Alexis; Mazzuco, Tania L; Bourdeau, Isabelle

    2016-01-01

    Abstract Mitotane has been used for more than 5 decades as therapy for adrenocortical carcinoma (ACC). However its mechanism of action and the extent of tumor response remain incompletely understood. To date no cases of rapid and complete remission of metastatic ACC with mitotane monotherapy has been reported. A 52-year-old French Canadian man presented with metastatic disease 2 years following a right adrenalectomy for stage III nonsecreting ACC. He was started on mitotane which was well tolerated despite rapid escalation of the dose. The patient course was exceptional as he responded to mitotane monotherapy after only few months of treatment. Initiation of chemotherapy was not needed and he remained disease-free with good quality of life on low maintenance dose of mitotane during the following 10 years. A germline heterozygous TP53 exon 4 polymorphism c.215C>G (p. Pro72Arg) was found. Immunohistochemical stainings for IGF-2 and cytoplasmic β-catenin were positive. Advanced ACC is an aggressive disease with poor prognosis and the current therapeutic options remain limited. These findings suggest that mitotane is a good option for the treatment of metastatic ACC and might result in rapid complete remission in selected patients. PMID:27043680

  14. Agonist-induced desensitization of adenylyl cyclase in Y1 adrenocortical tumor cells

    International Nuclear Information System (INIS)

    Olson, M.F.; Tsao, J.; Pon, D.J.; Schimmer, B.P.

    1991-01-01

    Y1 adrenocortical tumor cells (Y1DS) and Y1 mutants resistant to ACTH-induced desensitization of adenylyl cyclase (Y1DR) were transfected with a gene encoding the mouse beta 2-adrenergic receptor (beta 2-AR). Transfectants expressed beta 2-ARs that were able to stimulate adenylyl cyclase activity and steroid biosynthesis. These transfectants were used to explore the basis for the DR mutation in Y1 cells. The authors demonstrate that beta-adrenergic agonists desensitize the adenylyl cyclase system in transfected Y1DS cells whereas transfected Y1DR cells are resistant to desensitization by beta-adrenergic agonists. The fate of the beta 2-ARs during desensitization was evaluated by photoaffinity labelling with [125I]iodocyanopindolol diazerine. Desensitization of Y1DS transfectants was accompanied by a modest loss in receptor density that was insufficient to account for the complete loss of responsiveness to beta-adrenergic agonists. The extent of receptor loss induced by beta-adrenergic agonists in Y1DR transfectants exceeded that in the Y1DS transfectants indicating that the mutation which protects Y1DR cells from agonist-induced desensitization is prior to receptor down-regulation in the desensitization pathway. From these results we infer that ACTH and isoproterenol desensitize adenylyl cyclase by a common pathway and that receptor loss is not a major component of the desensitization process in these cells

  15. Adrenocortical carcinoma, an unusual extracolonic tumor associated with Lynch II syndrome.

    Science.gov (United States)

    Medina-Arana, V; Delgado, L; González, L; Bravo, A; Díaz, H; Salido, E; Riverol, D; González-Aguilera, J J; Fernández-Peralta, A M

    2011-06-01

    Lynch syndrome (LS) is an autosomal dominant condition that predisposes to colorectal cancer and specific other tumors. Extracolonic tumors occur mainly in the endometrium, stomach, ovary, small intestine and urinary tract. The presence of rare tumors in patients belonging to families who have Lynch syndrome is always interesting, because the question arises whether these tumors should be considered as a coincidence or are related with the syndrome. In this last case, they are also the result of the defect in the mismatch repair system, opening the possibility of extending the tumor spectrum associated with the syndrome. Here we describe a patient from a Lynch syndrome family with a germline mutation c.2063T>G (p.M688R) in the MSH2 gene, who developed an adrenal cortical carcinoma, a tumor not usually associated with LS. We analyzed the adrenocortical tumour for microsatellite instability (MSI), LOH and the presence of the germline c.2063T>G (M688R) mutation. The adrenal cortical carcinoma showed the MSH2 mutation, loss of heterozygosity of the normal allele in the MSH2 gene and loss of immunohistochemical expression for MSH2 protein, but no microsatellite instability. Additionally, the adrenal cortical carcinoma did not harbour a TP53 mutation. The molecular study indicates that this adrenal cortical cancer is probably due to the mismatch repair defect.

  16. Determination by R/A of plasma cortisol levels as a parameter of adrenocortical function before and after radiotherapy of gynaecological genital carcinoma

    International Nuclear Information System (INIS)

    Freischem, C.W.

    1980-01-01

    rn 20 female patients with carcinoma of the genitals, day profiles of cortisol were established and ACTH stimulation tests carried out directly after radiotherapy and 6 months later. Plasma concentrations of cortisol were determined in a RIA as parameters of the adrenocortical function. The assumption of a change in adrenocortical activity after radiotherapy of gynaecological genital carcinoma could not be validated. Instead, there was a typical diurnal rhythm of plasma cortisol, with a peak in the early morning hours and a decrease until midnight. The same applies to the ACTH stimulation tests: In all cases, plasma cortisol levels were elevated after intravenous application of ACTH. This means that the 1976 findings of Samundzham and Butsan could not be proved. Since adrenal functions were absolutely normal in the observed cases, the adynamic clinical picture of patients after radiotherapy, which is rather infrequent, cannot be explained as being due to an impaired adrenocortical function. (orig./MG) [de

  17. Differential expression of microRNA-675, microRNA-139-3p and microRNA-335 in benign and malignant adrenocortical tumours

    Science.gov (United States)

    Helwig, J; Bertram, S; Sheu, S Y; Suttorp, A C; Seggewiß, J; Willscher, E; Walz, M K; Worm, K; Schmid, K W

    2011-01-01

    Background For the clinical management of adrenocortical neoplasms it is crucial to correctly distinguish between benign and malignant tumours. Even histomorphologically based scoring systems do not allow precise separation in single lesions, thus novel parameters are desired which offer a more accurate differentiation. The tremendous potential of microRNAs (miRNAs) as diagnostic biomarkers in surgical pathology has recently been shown in a broad variety of tumours. Methods In order to elucidate the diagnostic impact of miRNA expression in adrenocortical neoplasms, a cohort of 20 adrenocortical specimens including normal adrenal tissue (n=4), adrenocortical adenomas (ACAs) (n=9), adrenocortical carcinomas (ACCs) (n=4) and metastases (n=3) was analysed using TaqMan low density arrays to identify specific miRNA profiles in order to distinguish between benign and malignant adrenocortical lesions. Results were validated in a validation cohort (n=16). Results Concerning the differential diagnosis of ACAs and ACCs, 159 out of 667 miRNAs were up- and 89 were down-regulated in ACAs. Using real-time PCR analysis of three of the most significantly expressed single key miRNAs allowed separation of ACAs from ACCs. ACCs exhibited significantly lower levels of miR-139-3p (up to 8.49-fold, p<0.001), miR-675 (up to 23.25-fold, p<0.001) and miR-335 (up to 5.25-fold, p<0.001). A validation cohort of 16 specimen with known Weiss score showed up-regulation of miR-335 and miR-675 in the majority of cases with probable malignant course, although overlapping values exist. Conclusion miRNA profiling of miR-675 and miR-335 helps in discriminating ACCs from ACAs. miRNA analysis may indicate malignant behaviour in cases with indeterminate malignant potential. PMID:21471143

  18. Assessment of survey radiography and comparison with x-ray computed tomography for detection of hyperfunctioning adrenocortical tumors in dogs

    International Nuclear Information System (INIS)

    Voorhout, G.; Stolp, R.; Rijnberk, A.; Waes, P.F.G.M. van

    1990-01-01

    Results of abdominal survey radiography and x-ray computed tomography (CT) were compared in 13 dogs with hyperadrenocorticism histologically attributed to adrenocortical tumors. X-ray computed tomography enabled accurate localization of the tumor in all 13 dogs. Apart from 2 poorly demarcated irregular-shaped and mineralized carcinomas, there were no differences between adenoma (n = 3) and carcinoma (n = 10) on CT images. In 1 dog, invasion of the caudal vena cava by the tumor was suggested on CT images and was confirmed during surgery. Suspicion of adhesions between tumors of the right adrenal gland and the caudal vena cava on the basis of CT images was confirmed during surgery in only 2 of 6 dogs. Survey radiography allowed accurate localization of the tumor in 7 dogs (4 on the right side and 3 on the left). In 6 of these dogs, the tumor was visible as a well-demarcated soft tissue mass and, in the other dog, as a poorly demarcated mineralized mass. The smallest tumor visualized on survey radiographs had a diameter of 20 mm on CT images. Six tumors with diameter less than or equal to 20 mm were not visualized on survey radiographs. In 1 of these dogs, a mineralized nodule was found in the left adrenal region, without evidence of a mass. In a considerable number of cases, survey radiography can provide presurgical localization of adrenocortical tumors in dogs with hyperadrenocorticism; CT is redundant in these instances. In the absence of positive radiographic findings, CT is valuable for localization of adrenocortical tumors

  19. The Contingency of Cocaine Administration Accounts for Structural and Functional Medial Prefrontal Deficits and Increased Adrenocortical Activation

    Science.gov (United States)

    Anderson, Rachel M.; Cosme, Caitlin V.; Glanz, Ryan M.; Miller, Mary C.; Romig-Martin, Sara A.; LaLumiere, Ryan T.

    2015-01-01

    The prelimbic region (PL) of the medial prefrontal cortex (mPFC) is implicated in the relapse of drug-seeking behavior. Optimal mPFC functioning relies on synaptic connections involving dendritic spines in pyramidal neurons, whereas prefrontal dysfunction resulting from elevated glucocorticoids, stress, aging, and mental illness are each linked to decreased apical dendritic branching and spine density in pyramidal neurons in these cortical fields. The fact that cocaine use induces activation of the stress-responsive hypothalamo-pituitary-adrenal axis raises the possibility that cocaine-related impairments in mPFC functioning may be manifested by similar changes in neuronal architecture in mPFC. Nevertheless, previous studies have generally identified increases, rather than decreases, in structural plasticity in mPFC after cocaine self-administration. Here, we use 3D imaging and analysis of dendritic spine morphometry to show that chronic cocaine self-administration leads to mild decreases of apical dendritic branching, prominent dendritic spine attrition in PL pyramidal neurons, and working memory deficits. Importantly, these impairments were largely accounted for in groups of rats that self-administered cocaine compared with yoked-cocaine- and saline-matched counterparts. Follow-up experiments failed to demonstrate any effects of either experimenter-administered cocaine or food self-administration on structural alterations in PL neurons. Finally, we verified that the cocaine self-administration group was distinguished by more protracted increases in adrenocortical activity compared with yoked-cocaine- and saline-matched controls. These studies suggest a mechanism whereby increased adrenocortical activity resulting from chronic cocaine self-administration may contribute to regressive prefrontal structural and functional plasticity. SIGNIFICANCE STATEMENT Stress, aging, and mental illness are each linked to decreased prefrontal plasticity. Here, we show that chronic

  20. Familial isolated primary pigmented nodular adrenocortical disease associated with a novel low penetrance PRKAR1A gene splice site mutation

    DEFF Research Database (Denmark)

    Storr, Helen L; Metherell, Louise A; Dias, Renuka

    2010-01-01

    Primary pigmented nodular adrenocortical disease (PPNAD) is associated with inactivating germline protein kinase A regulatory subunit type 1-alpha (PRKAR1A) mutations and loss of heterozygosity at the 17q22-24 locus in approximately 50% patients. PRKAR1A mutations are observed in both isolated PP...... PPNAD (iPPNAD) and Carney complex (CNC). Most mutations result in a functionally null-allele and exhibit high penetrance. We genotyped members of an extended family for a novel PRKAR1A mutation and undertook detailed phenotyping for CNC in the affected individuals....

  1. Detection of adrenocortical autoantibodies in Addison's disease with a peroxidase-labelled protein A technique

    Directory of Open Access Journals (Sweden)

    R.C. Silva

    1998-09-01

    Full Text Available Adrenocortical autoantibodies (ACA, present in 60-80% of patients with idiopathic Addison's disease, are conventionally detected by indirect immunofluorescence (IIF on frozen sections of adrenal glands. The large-scale use of IIF is limited in part by the need for a fluorescence microscope and the fact that histological sections cannot be stored for long periods of time. To circumvent these restrictions we developed a novel peroxidase-labelled protein A (PLPA technique for the detection of ACA in patients with Addison's disease and compared the results with those obtained with the classical IIF assay. We studied serum samples from 90 healthy control subjects and 22 patients with Addison's disease, who had been clinically classified into two groups: idiopathic (N = 13 and granulomatous (N = 9. ACA-PLPA were detected in 10/22 (45% patients: 9/13 (69% with the idiopathic form and 1/9 (11% with the granulomatous form, whereas ACA-IIF were detected in 11/22 patients (50%: 10/13 (77% with the idiopathic form and 1/9 (11% with the granulomatous form. Twelve of the 13 idiopathic addisonians (92% were positive for either ACA-PLPA or ACA-IIF, but only 7 were positive by both methods. In contrast, none of 90 healthy subjects was found to be positive for ACA. Thus, our study shows that the PLPA-based technique is useful, has technical advantages over the IIF method (by not requiring the use of a fluorescence microscope and by permitting section storage for long periods of time. However, since it is only 60% concordant with the ACA-IIF method, it should be considered complementary instead of an alternative method to IIF for the detection of ACA in human sera.

  2. Molecular Profiling of Refractory Adrenocortical Cancers and Predictive Biomarkers to Therapy

    Directory of Open Access Journals (Sweden)

    Sherri Z. Millis

    2015-01-01

    Full Text Available Purpose Current first-line chemotherapy for patients with metastatic adrenocortical cancer (ACC includes doxorubicin, etoposide, cisplatin, and mitotane with a reported response rate of only 23.2%. New therapeutic leads for patients with refractory tumors are needed; there is no standard second-line treatment. Methods Samples from 135 ACC tumors were analyzed by immunohistochemistry, in situ hybridization (FISH or CISH, and/or gene sequencing at a single commercial reference laboratory (Caris Life Sciences to identify markers associated with drug sensitivity and resistance. Results Overexpression of proteins related to demonstrated chemotherapy sensitivity or resistance included topoisomerase 1, progesterone receptor, and topoisomerase 2-alpha in 46%, 63%, and 42% of cases, respectively. Loss of excision repair cross-complementary group 1 (ERCC1, phosophatase and tensin homolog, O(6-methylguanine-methyltransferase, and ribonucleotide reductase M1 (RRM1 was identified in 56%, 59%, 71%, and 58% of cases, respectively. Other aberrations included overexpression of programmed death-ligand 1 or programmed cell death protein 1 tumor-infiltrating lymphocytes in >40% of cases. In all, 35% of cases had a mutation in the canonical Wnt signaling pathway (either CTNNB1 or APC and 48% had a mutation in TP53. No other genomic alterations were identified. Conclusion Biomarker alterations in ACC may be used to direct therapies, including recommendations for and potential resistance of some patients to traditional chemotherapies, which may explain the low response rate in the unselected population. Limited outcomes data support the use of mitotane and platinum therapies for patients with low levels of the proteins RRM1 and ERCC1.

  3. Effects of Insufficient Sleep on Pituitary-Adrenocortical Response to CRH Stimulation in Healthy Men.

    Science.gov (United States)

    Guyon, Aurore; Morselli, Lisa L; Balbo, Marcella L; Tasali, Esra; Leproult, Rachel; L'Hermite-Balériaux, Mireille; Van Cauter, Eve; Spiegel, Karine

    2017-06-01

    Severe sleep restriction results in elevated evening cortisol levels. We examined whether this relative hypercortisolism is associated with alterations in the pituitary-adrenocortical response to evening corticotropin-releasing hormone (CRH) stimulation. Eleven subjects participated in 2 sessions (2 nights of 10 hours vs. 4 hours in bed) in randomized order. Sleep was polygraphically recorded. After the second night of each session, blood was sampled at 20-minute intervals from 09:00 to 24:00 for adrenocorticotropic hormone (ACTH) and cortisol measurements, and perceived stress was assessed hourly. Ovine CRH was injected at 18:00 (1 µg/kg body weight). Prior to CRH injection, baseline ACTH, but not cortisol, levels were elevated after sleep restriction. Relative to the well-rested condition, sleep restriction resulted in a 27% decrease in overall ACTH response to CRH (estimated by the incremental area under the curve from 18:00 to 24:00; p = .002) while the cortisol response was decreased by 21% (p = .083). Further, the magnitude of these decreases was correlated with the individual amount of sleep loss (ACTH: rSp = -0.65, p = .032; cortisol: rSp = -0.71, p = .015). The acute post-CRH increment of cortisol was reduced (p = .002) without changes in ACTH reactivity, suggesting decreased adrenal sensitivity. The rate of decline from peak post-injection levels was reduced for cortisol (p = .032), but not for ACTH. Scores of perceived stress were unaffected by CRH injection and were low and similar under both sleep conditions. Sleep restriction is associated with a reduction of the overall ACTH and cortisol responses to evening CRH stimulation, and a reduced reactivity and slower recovery of the cortisol response. © Sleep Research Society 2017. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.

  4. Effect of KCNJ5 Mutations on Gene Expression in Aldosterone-Producing Adenomas and Adrenocortical Cells

    Science.gov (United States)

    Monticone, Silvia; Hattangady, Namita G.; Nishimoto, Koshiro; Mantero, Franco; Rubin, Beatrice; Cicala, Maria Verena; Pezzani, Raffaele; Auchus, Richard J.; Ghayee, Hans K.; Shibata, Hirotaka; Kurihara, Isao; Williams, Tracy A.; Giri, Judith G.; Bollag, Roni J.; Edwards, Michael A.; Isales, Carlos M.

    2012-01-01

    Context: Primary aldosteronism is a heterogeneous disease that includes both sporadic and familial forms. A point mutation in the KCNJ5 gene is responsible for familial hyperaldosteronism type III. Somatic mutations in KCNJ5 also occur in sporadic aldosterone producing adenomas (APA). Objective: The objective of the study was to define the effect of the KCNJ5 mutations on gene expression and aldosterone production using APA tissue and human adrenocortical cells. Methods: A microarray analysis was used to compare the transcriptome profiles of female-derived APA samples with and without KCNJ5 mutations and HAC15 adrenal cells overexpressing either mutated or wild-type KCNJ5. Real-time PCR validated a set of differentially expressed genes. Immunohistochemical staining localized the KCNJ5 expression in normal adrenals and APA. Results: We report a 38% (18 of 47) prevalence of KCNJ5 mutations in APA. KCNJ5 immunostaining was highest in the zona glomerulosa of NA and heterogeneous in APA tissue, and KCNJ5 mRNA was 4-fold higher in APA compared with normal adrenals (P APA with and without KCNJ5 mutations displayed slightly different gene expression patterns, notably the aldosterone synthase gene (CYP11B2) was more highly expressed in APA with KCNJ5 mutations. Overexpression of KCNJ5 mutations in HAC15 increased aldosterone production and altered expression of 36 genes by greater than 2.5-fold (P APA, and our data suggest that these mutations increase expression of CYP11B2 and NR4A2, thus increasing aldosterone production. PMID:22628608

  5. Vincristine, cisplatin, teniposide, and cyclophosphamide combination in the treatment of recurrent or metastatic adrenocortical cancer.

    Science.gov (United States)

    Khan, Tanweera S; Sundin, Anders; Juhlin, Claes; Wilander, Erik; Oberg, Kjell; Eriksson, Barbro

    2004-01-01

    The efficacy and tolerability of a combination of vincristine, cisplatin, teniposide, and cyclophosphamide (OPEC) in 11 patients (median age, 45 yr) with recurrent and/or metastatic adrenocortical cancer (ACC) (seven functional and four nonfunctional) were evaluated. All patients received this regimen after the failure of streptozocin and o,p'-DDD (SO) combination therapy. The regimen comprised cyclophosphamide, 600 mg/m2, and vincristine, 1.5 mg/m2, maximum dose 2.0 mg (d 1); cisplatin, 100 mg/m2 (d 2) and teniposide, 150 mg/m2 (d 4). Cycles were repeated every 4 wk. One to eight cycles (median, six cycles) of OPEC were administered to each patient. The median duration of treatment was 6 mo. The overall 2-yr survival rate was 82% and the median survival since diagnosis was 44 mo while it was 21 mo since start of OPEC therapy. Responses were obtained in nine patients: partial response in two patients, and stable disease in seven patients. The median duration of response was 6.75 mo. A total of 60 cycles of chemotherapy were given to all patients; grade 1-2 toxicity occurred in 57 cycles, while grade 3 toxicity was observed only in two cycles, according to NCI's Common Toxicity Criteria. We conclude that the OPEC regimen may be considered in recurrent or metastatic ACC as a second-line medical treatment. However, the combination is accompanied by considerable side effects and dose modifications are necessary in order to be able to recommend the treatment. This regimen needs further evaluation compared with SO therapy preferably in a randomized multicenter trial.

  6. Novelty-induced emotional arousal modulates cannabinoid effects on recognition memory and adrenocortical activity.

    Science.gov (United States)

    Campolongo, Patrizia; Morena, Maria; Scaccianoce, Sergio; Trezza, Viviana; Chiarotti, Flavia; Schelling, Gustav; Cuomo, Vincenzo; Roozendaal, Benno

    2013-06-01

    Although it is well established that cannabinoid drugs can influence cognitive performance, the findings-describing both enhancing and impairing effects-have been ambiguous. Here, we investigated the effects of posttraining systemic administration of the synthetic cannabinoid agonist WIN55,212-2 (0.1, 0.3, or 1.0 mg/kg) on short- and long-term retention of object recognition memory under two conditions that differed in their training-associated arousal level. In male Sprague-Dawley rats that were not previously habituated to the experimental context, WIN55,212-2 administered immediately after a 3-min training trial, biphasically impaired retention performance at a 1-h interval. In contrast, WIN55,212-2 enhanced 1-h retention of rats that had received extensive prior habituation to the experimental context. Interestingly, immediate posttraining administration of WIN55,212-2 to non-habituated rats, in doses that impaired 1-h retention, enhanced object recognition performance at a 24-h interval. Posttraining WIN55,212-2 administration to habituated rats did not significantly affect 24-h retention. In light of intimate interactions between cannabinoids and the hypothalamic-pituitary-adrenal axis, we further investigated whether cannabinoid administration might differently influence training-induced glucocorticoid activity in rats in these two habituation conditions. WIN55,212-2 administered after object recognition training elevated plasma corticosterone levels in non-habituated rats whereas it decreased corticosterone levels in habituated rats. Most importantly, following pretreatment with the corticosterone-synthesis inhibitor metyrapone, WIN55,212-2 effects on 1- and 24-h retention of non-habituated rats became similar to those seen in the low-aroused habituated animals, indicating that cannabinoid-induced regulation of adrenocortical activity contributes to the environmentally sensitive effects of systemically administered cannabinoids on short- and long

  7. Salivary cortisol as an indicator of adrenocortical function in healthy infants, using massage therapy

    Directory of Open Access Journals (Sweden)

    Monalisa de Cássia Fogaça

    Full Text Available CONTEXT AND OBJECTIVE: The evaluation of adrenocortical function with the use of therapeutic massage has been little studied in Brazil. The purpose of this study was to evaluate the salivary cortisol levels before and after Shantala massage therapy on healthy infants. DESIGN AND SETTING: Prospective case series, in a public nursery, in São Paulo. METHODS: Saliva was obtained from 11 infants at the times of 8:00-9:00 a.m. and 4:00-5:00 p.m. in a nursery and 9:00-10:00 p.m. at home. They received a 15-minute therapeutic massage on two consecutive days, and saliva was collected before and after the massage. The procedure was repeated after a one-week interval. Cortisol values (intra-assay < 5%; inter-assay < 10% at different times of the day were compared by ANOVA. RESULTS: The mean cortisol values (nmol/l ± SD on the first day were: morning (M = 14.1 ± 5.7, afternoon (A = 8.3 ± 2.7, night (N = 3.3 ± 1.1; after two consecutive days of therapeutic massage: M = 22.3 ± 13.5, A = 13.4 ± 6.0, N = 5.8 ± 3.5; after a one-week interval: M = 15.8 ± 7.7, A = 14.3 ± 7.7, N = 3.4 ± 2.0. CONCLUSION: There was a modification in the salivary cortisol values following massage, thus reflecting possible adaptation of the hypothalamic-pituitary-adrenal axis.

  8. The Many Faces of Primary Aldosteronism and Cushing Syndrome: A Reflection of Adrenocortical Tumor Heterogeneity.

    Science.gov (United States)

    Mete, Ozgur; Duan, Kai

    2018-01-01

    Adrenal cortical tumors constitute a heterogeneous group of neoplasms with distinct clinical, morphological, and molecular features. Recent discoveries of specific genotype-phenotype correlations in adrenal cortical adenomas have transformed our understanding of their respective endocrine syndromes. Indeed, a proportion of patients with primary aldosteronism are now known to harbor adrenal cortical adenomas with heterogeneous molecular alterations ( KCNJ5, ATP1A1, ATP2B3 , and CACNA1D ) involving the calcium/calmodulin kinase signaling pathway. Several lines of evidence suggest that KCNJ5 -mutant aldosterone-producing adenomas have distinct clinicopathological phenotype compared to those harboring ATP1A1, ATP2B3 , and CACNA1D mutations. Benign adrenal cortical tumors presenting with Cushing syndrome often have diverse mutations ( PRKACA, PRKAR1A, GNAS, PDE11A , and PDE8B ) involving the cyclic AMP signaling pathway. In addition to cortisol-producing adenomas, bilateral micronodular adrenocortical disease and primary bilateral macronodular adrenal hyperplasia (PBMAH) have also expanded the spectrum of benign neoplasms causing adrenal Cushing disease. The recent discovery of inactivating ARMC5 germline mutations in PBMAH has challenged the old belief that this disorder is mainly a sporadic disease. Emerging evidence suggests that PBMAH harbors multiple distinct clonal proliferations, reflecting the heterogeneous genomic landscape of this disease. Although most solitary adrenal cortical tumors are sporadic, there is an increasing recognition that inherited susceptibility syndromes may also play a role in their pathogenesis. This review highlights the molecular and morphological heterogeneity of benign adrenal cortical neoplasms, reflected in the diverse presentations of primary aldosteronism and adrenal Cushing syndrome.

  9. The Many Faces of Primary Aldosteronism and Cushing Syndrome: A Reflection of Adrenocortical Tumor Heterogeneity

    Directory of Open Access Journals (Sweden)

    Ozgur Mete

    2018-03-01

    Full Text Available Adrenal cortical tumors constitute a heterogeneous group of neoplasms with distinct clinical, morphological, and molecular features. Recent discoveries of specific genotype–phenotype correlations in adrenal cortical adenomas have transformed our understanding of their respective endocrine syndromes. Indeed, a proportion of patients with primary aldosteronism are now known to harbor adrenal cortical adenomas with heterogeneous molecular alterations (KCNJ5, ATP1A1, ATP2B3, and CACNA1D involving the calcium/calmodulin kinase signaling pathway. Several lines of evidence suggest that KCNJ5-mutant aldosterone-producing adenomas have distinct clinicopathological phenotype compared to those harboring ATP1A1, ATP2B3, and CACNA1D mutations. Benign adrenal cortical tumors presenting with Cushing syndrome often have diverse mutations (PRKACA, PRKAR1A, GNAS, PDE11A, and PDE8B involving the cyclic AMP signaling pathway. In addition to cortisol-producing adenomas, bilateral micronodular adrenocortical disease and primary bilateral macronodular adrenal hyperplasia (PBMAH have also expanded the spectrum of benign neoplasms causing adrenal Cushing disease. The recent discovery of inactivating ARMC5 germline mutations in PBMAH has challenged the old belief that this disorder is mainly a sporadic disease. Emerging evidence suggests that PBMAH harbors multiple distinct clonal proliferations, reflecting the heterogeneous genomic landscape of this disease. Although most solitary adrenal cortical tumors are sporadic, there is an increasing recognition that inherited susceptibility syndromes may also play a role in their pathogenesis. This review highlights the molecular and morphological heterogeneity of benign adrenal cortical neoplasms, reflected in the diverse presentations of primary aldosteronism and adrenal Cushing syndrome.

  10. Gemcitabine-Based Chemotherapy in Adrenocortical Carcinoma: A Multicenter Study of Efficacy and Predictive Factors.

    Science.gov (United States)

    Henning, Judith E K; Deutschbein, Timo; Altieri, Barbara; Steinhauer, Sonja; Kircher, Stefan; Sbiera, Silviu; Wild, Vanessa; Schlötelburg, Wiebke; Kroiss, Matthias; Perotti, Paola; Rosenwald, Andreas; Berruti, Alfredo; Fassnacht, Martin; Ronchi, Cristina L

    2017-11-01

    Adrenocortical carcinoma (ACC) is rare and confers an unfavorable prognosis in advanced stages. Other than combination chemotherapy with cisplatin, etoposide, doxorubicin, and mitotane, the second- and third-line regimens are not well-established. Gemcitabine (GEM)-based chemotherapy was suggested in a phase 2 clinical trial with 28 patients. In other solid tumors, human equilibrative nucleoside transporter type 1 (hENT1) and/or ribonucleotide reductase catalytic subunit M1 (RRM1) expression have been associated with resistance to GEM. To assess the efficacy of GEM-based chemotherapy in ACC in a real-world setting and the predictive role of molecular parameters. Retrospective multicenter study. Referral centers of university hospitals. A total of 145 patients with advanced ACC were treated with GEM-based chemotherapy (132 with concomitant capecitabine). Formalin-fixed paraffin-embedded tumor material was available for 70 patients for immunohistochemistry. The main outcome measures were progression-free survival (PFS) and an objective response to GEM-based chemotherapy. The secondary objective was the predictive role of hENT1 and RRM1. The median PFS for the patient population was 12 weeks (range, 1 to 94). A partial response or stable disease was achieved in 4.9% and 25.0% of cases, with a median duration of 26.8 weeks. Treatment was generally well tolerated, with adverse events of grade 3 or 4 occurring in 11.0% of cases. No substantial effect of hENT1 and/or RRM1 expression was observed in response to GEM-based chemotherapy. GEM-based chemotherapy is a well-tolerated, but modestly active, regimen against advanced ACC. No reliable molecular predictive factors could be identified. Owing to the scarce alternative therapeutic options, GEM-based chemotherapy remains an important option for salvage treatment for advanced ACC. Copyright © 2017 Endocrine Society

  11. Adrenocortical and adrenomedullary homologs in eight species of adult and developing teleosts: morphology, histology, and immunohistochemistry.

    Science.gov (United States)

    Grassi Milano, E; Basari, F; Chimenti, C

    1997-12-01

    Morphology, histology, and immunohistochemistry of the adrenocortical and adrenomedullary homologs (adrenal glands) of the following developing and adult teleosts were examined: Salmoniformes-Oncorhynchus mykiss (rainbow trout), Salmo trutta fario (brown trout), Coregonus lavaretus (white fish); Cyprinodontiformes-Gambusia affinis (mosquito fish). Perciformes-Dicentrarchus labrax (sea bass), Sparus aurata (sea bream), Diplodus sargus (white bream), Oblada melanura (saddled bream). The anatomical relationships of the gland with the renal system and venous vessels were also noted. In adults of all species steroidogenic and catecholaminergic chromaffin cells were found in the head kidney, which is pronephric in origin and subsequently transformed into a hematopoietic lymphatic organ. In Perciformes, chromaffin cells are distributed around the anterior and posterior cardinal veins and ducts of Cuvier; in Salmoniformes, around the posterior cardinal veins and in the hematopoietic tissue; and in G. affinis, around the ducts of Cuvier and posterior cardinal veins, while a few are visible also around the sinus venosus. In Perciformes and Salmoniformes, numerous chromaffin cells are also present in the posterior kidney, derived from the opisthonephros, in contact with the caudal vein. Steroidogenic cells are always confined to the head kidney. During development chromaffin and steroidogenic cells appear early after hatching in the pronephric kidney, at the level of the ducts of Cuvier and of the cephalic part of the posterior cardinal veins. Later, chromaffin cells in Perciformes reach the anterior cardinal veins, and subsequently, in both Perciformes and Salmoniformes, they reach the developing posterior kidney. Their localization along the posterior kidney is still in progress about 4 months after hatching and is completed about a year after hatching. These findings support the concept that the structure of the adrenal gland in teleosts is intermediate between that of the

  12. Role of changes in functional status of hypothalamic-pituitary-adrenocortical axis in immunoenhancement after low dose radiation

    International Nuclear Information System (INIS)

    Liu Shuzheng; Zhao Yong; Han Zhenbo

    1994-01-01

    Whole-body irradiation (WBI) of mice with 75 mGy X-rays caused increase in 5-hydroxytryptamine (5HT) content of hypothalamus and decrease in serum adrenocorticotropic hormone (ACTH) and corticosterone (CS) level, accompanied with potentiation of immune functions, expressed as increased spontaneous incorporation of 3 H-TdR into thymocytes, augmented proliferative reaction of the splenocytes to Con A and increased production of interleukin-2 by the splenocytes. After intra hypothalamic injection of 5HT there occurred a lowering of serum ACTH level and enhancement of immune reactivity of the splenic and thymic lymphocytes. It is assumed that low dose radiation could influence the central 5-hydroxytryptaminergic neurons causing increase in hypothalamic 5HT content and this, in turn, decreases pituitary secretion of ACTH with a down-regulation of the adrenocortical function. This would partially release the tonic suppression normally exerted on the immune organs by the hypothalamic-pituitary-adrenocortical axis, thus leading to potentiation of immune functions. These neuroendocrine changes should be considered as an important factor in the analysis of the mechanism of immunoenhancement after WBI with low doses

  13. The effect of a maternal history of childhood abuse on adrenocortical attunement in mothers and their toddlers.

    Science.gov (United States)

    Fuchs, Anna; Moehler, Eva; Resch, Franz; Kaess, Michael

    2017-07-01

    We investigated circadian mother-child adrenocortical attunement in the context of a maternal history of childhood abuse (HoA). Mothers were screened after birth using the Childhood Trauma Questionnaire. Women reporting moderate or severe abuse formed the HoA group (n = 37; HoAG) and were compared with a non-maltreated comparison group (n = 45; CG). Three years later, cortisol awakening response (CAR) and diurnal slope (DSL) were assessed. Mother-child interaction was coded using the Emotional Availability Scales at 12 months of age. For the CAR, we found adrenocortical attunement only in the HoAG (2-way interaction: p = .004), particularly if mothers scored low on structuring (3-way interaction: p = .042) and children scored low on responsiveness (3-way interaction: p = .044). DSL-attunement was dependent on maternal sensitivity (3-way interaction: p = .012) and child involvement (3-way interaction: p = .012). In the context of a maternal HoA, it seems possible for mother-child-dyads to show less optimal interactional quality but be stronger attuned to each other biologically. © 2017 Wiley Periodicals, Inc.

  14. The effect of types I and III interferons on adrenocortical cells and its possible implications for autoimmune Addison's disease.

    Science.gov (United States)

    Hellesen, A; Edvardsen, K; Breivik, L; Husebye, E S; Bratland, E

    2014-06-01

    Autoimmune Addison's disease (AAD) is caused by selective destruction of the hormone-producing cells of the adrenal cortex. As yet, little is known about the potential role played by environmental factors in this process. Type I and/or type III interferons (IFNs) are signature responses to virus infections, and have also been implicated in the pathogenesis of autoimmune endocrine disorders such as type 1 diabetes and autoimmune thyroiditis. Transient development of AAD and exacerbation of established or subclinical disease, as well as the induction of autoantibodies associated with AAD, have been reported following therapeutic administration of type I IFNs. We therefore hypothesize that exposure to such IFNs could render the adrenal cortex susceptible to autoimmune attack in genetically predisposed individuals. In this study, we investigated possible immunopathological effects of type I and type III IFNs on adrenocortical cells in relation to AAD. Both types I and III IFNs exerted significant cytotoxicity on NCI-H295R adrenocortical carcinoma cells and potentiated IFN-γ- and polyinosine-polycytidylic acid [poly (I : C)]-induced chemokine secretion. Furthermore, we observed increased expression of human leucocyte antigen (HLA) class I molecules and up-regulation of 21-hydroxylase, the primary antigenic target in AAD. We propose that these combined effects could serve to initiate or aggravate an ongoing autoimmune response against the adrenal cortex in AAD. © 2014 British Society for Immunology.

  15. Oncocytic adrenocortical neoplasms--a clinicopathologic study of 13 new cases emphasizing the importance of their recognition.

    Science.gov (United States)

    Wong, Daniel D; Spagnolo, Dominic V; Bisceglia, Michele; Havlat, Marek; McCallum, Dugald; Platten, Michael A

    2011-04-01

    Oncocytic adrenocortical neoplasms (OANs) are a rare but important subtype of adrenal tumors with unique clinical and morphological features. We present 13 previously unpublished cases, of which 3 were classified as benign, 2 as having borderline malignant potential, and 8 as malignant according to the Lin-Weiss-Bisceglia criteria. Seven tumors (54%) showed evidence of endocrine activity. All were composed of more than 90% oncocytes confirmed immunohistochemically using the antimitochondrial antibody mES-13 and ultrastructurally in 4 cases. Small oncocytes were a frequent finding that challenges the conventional notion of oncocytes as necessarily having abundant cytoplasm. Most cases were immunoreactive for vimentin, synaptophysin, inhibin-α, melan A, and calretinin, the latter being a novel finding in this group of neoplasms. Cytokeratin positivity with AE1/AE3 and CAM5.2 was variable. The literature was comprehensively reviewed to identify all cases of OANs reported to date. Hormone production is not as uncommon as previously believed, occurring in 30%. The Lin-Weiss-Bisceglia criteria were retrospectively applied to all published cases with sufficient information and were shown to effectively separate tumors according to their future risk of recurrence and survival using Kaplan-Meier survival curves (log-rank test, P interval = 27.5-88.5 months), providing the first preliminary evidence that the prognosis of malignant OANs is likely to be more favorable than conventional adrenocortical carcinomas, in which the reported median survival is between 14 and 32 months. Copyright © 2011 Elsevier Inc. All rights reserved.

  16. Prenatal Maternal Stress Predicts Methylation of Genes Regulating the Hypothalamic-Pituitary-Adrenocortical System in Mothers and Newborns in the Democratic Republic of Congo

    Science.gov (United States)

    Kertes, Darlene A.; Kamin, Hayley S.; Hughes, David A.; Rodney, Nicole C.; Bhatt, Samarth; Mulligan, Connie J.

    2016-01-01

    Exposure to stress early in life permanently shapes activity of the hypothalamic-pituitary-adrenocortical (HPA) axis and the brain. Prenatally, glucocorticoids pass through the placenta to the fetus with postnatal impacts on brain development, birth weight (BW), and HPA axis functioning. Little is known about the biological mechanisms by which…

  17. The Role of the Pituitary-Adrenocortical Axis System in the Regulation of Secretion of Digestive Glands of Wrestlers during Sports and Postsports Ontogenesis

    Science.gov (United States)

    Panov, Sergei F.; Panova, Irina P.; Volunskaya, Elena V.; Chebotarev, Andrei V.

    2016-01-01

    According to many researchers its necessary to research a hormonal profile in order to determine mechanisms of regulation of functions of the digestive conveyor during sports activities. In the paper the results of the carried out research on studying of a role of pituitary-adrenocortical axis system of adaptive reactions in activities of the…

  18. {sup 18}F-Labelled metomidate analogues as adrenocortical imaging agents

    Energy Technology Data Exchange (ETDEWEB)

    Erlandsson, Maria; Karimi, Farhad [Department of Biochemistry and Organic Chemistry, Uppsala University, Box 576, S-751 23 Uppsala (Sweden); Lindhe, Orjan [Uppsala Imanet, GE Healthcare, Box 967, S-751 09 Uppsala (Sweden); Langstroem, Bengt [Department of Biochemistry and Organic Chemistry, Uppsala University, Box 576, S-751 23 Uppsala (Sweden)], E-mail: bengt.langstrom@biorg.uu.se

    2009-05-15

    Introduction: Two- and one-step syntheses of {sup 18}F-labelled analogues of metomidate, such as 2-[{sup 18}F]fluoroethyl 1-[(1R)-1-phenylethyl]-1H-imidazole-5-carboxylate (1), 2-[{sup 18}F]fluoroethyl 1-[(1R)-1-(4-chlorophenyl)ethyl]-1H-imidazole-5-carboxylate (2), 2-[{sup 18}F]fluoroethyl 1-[(1R)-1-(4-bromophenyl)ethyl]-1H-imidazole-5-carboxylate (3), 3-[{sup 18}F]fluoropropyl 1-[(1R)-1-(4-bromophenyl)ethyl]-1H-imidazole-5-carboxylate (4) and 3-[{sup 18}F]fluoropropyl 1-[(1R)-1-phenylethyl]-1H-imidazole-5-carboxylate (5) are presented. Methods: Analogues 1-5 were prepared by a two-step reaction sequence that started with the synthesis of either 2-[{sup 18}F]fluoroethyl 4-methylbenzenesulfonate or 3-[{sup 18}F]fluoropropyl 4-methylbenzenesulfonate. These were used as {sup 18}F-alkylating agents in the second step, in which they reacted with the ammonium salt of a 1-[(1R)-1-phenylethyl]-1H-imidazole-5-carboxylic acid. One-step-labelling syntheses of 1, 2 and 5 were also explored. Analogues 1-4 were biologically validated by frozen-section autoradiography and organ distribution. Metabolite analysis was performed for 2 and 3. Results: The radiochemical yield of the two-step synthesis was in the range of 10-29% and that of the one-step synthesis was 25-37%. Using microwave irradiation in the one-step synthesis of 1 and 2 increased the radiochemical yield to 46{+-}3% and 79{+-}30%, respectively. Conclusion: Both the frozen-section autoradiography and organ distribution results indicated that analogue 2 has a potential as an adrenocortical imaging agent, having the highest degree of specific adrenal binding and best ratio of adrenal to organ uptake among the compounds studied.

  19. Cyclic estrous-like behavior in a spayed cat associated with excessive sex-hormone production by an adrenocortical carcinoma.

    Science.gov (United States)

    Meler, Erika N; Scott-Moncrieff, J Catharine; Peter, Augustine T; Bennett, Sara; Ramos-Vara, Jose; Salisbury, S Kathleen; Naughton, James F

    2011-06-01

    A 15-year-old, spayed female domestic shorthair cat was evaluated for 1-year duration of cyclic intermittent estrous behavior. Diagnostic testing performed before referral, including baseline progesterone concentration, human chorionic gonadotropin (hCG) hormone stimulation test and surgical exploratory laparotomy, had remained inconclusive for a remnant ovary. Evaluation of sex hormones before and after adrenocorticotropic hormone (ACTH) administration revealed increased basal concentrations of androstenedione, estradiol, progesterone, and 17α-hydroxyprogesterone and normal ACTH-stimulated hormone concentrations. Enlargement of the right adrenal gland was identified by abdominal ultrasound. The cat underwent an adrenalectomy and histopathology of the excised adrenal gland was consistent with an adrenocortical carcinoma. Clinical signs resolved immediately following surgery, and most hormone concentrations declined to within or below the reference interval (RI) by 2 months after surgery. Copyright © 2011 ISFM and AAFP. Published by Elsevier Ltd. All rights reserved.

  20. Adrenal incidentalomas showing unilateral concordant visualization by adrenocortical scintigraphy. Comparison with adenomas in Cushing's syndrome

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    Tani, Atsushi; Nakajo, Masayuki; Tsuchimochi, Shinsaku; Nakabeppu, Yoshiaki; Umanodan, Tomokazu [Kagoshima Univ. (Japan). Faculty of Medicine

    2000-06-01

    An adrenocortical adenoma causing Cushing's syndrome (Cushing's adenoma) produces a unilateral concordant visualization (UCV) imaging pattern in which the adenoma is only visualized on radioiodocholesterol adrenocortical scintigraphy. But because this imaging pattern is also noted in some patients with adrenal incidentalomas, we examined whether the UCV-incidentaloma was essentially identical with Cushing's adenoma and would develop Cushing's syndrome. The subjects were 9 patients with UCV-incidentalomas (mean size, 30 mm; range, 20-45 mm) and 6 patients with Cushing's adenomas (mean size, 28 mm; range, 25-35 mm). Endocrinological evaluations showed several abnormalities including blunted diurnal rhythm of plasma cortisol within the normal range, low plasma ACTH and/or high 24-hr urinary 17-OHCS levels in 8 of 9 patients with UCV-incidentalomas, but these abnormalities did not meet the diagnostic criteria of Cushing's syndrome. Adrenal uptake of the tracer in the patients with UCV-incidentalomas was not statistically different from that in the patients with Cushing's adenomas and had no relationship with hormonal values in either patient group. Tumor size on CT correlated with the levels of 24-hr urinary 17-OHCS (r=0.75, p=0.02) and plasma cortisol at 7:00 (r=0.82, p=0.007) in the patients with UCV-incidentalomas, but not in the patients with Cushing's adenomas. Although 3 UCV-incidentalomas increased slightly in size, none of 9 patients with UCV-incidentalomas has developed Cushing's syndrome for 4 to 52 months. These results suggest that the UCV-incidentaloma may be essentially different from the Cushing's adenoma and unlikely to develop Cushing's syndrome. (author)

  1. Comparisons among serum, egg albumin and yolk concentrations of corticosterone as biomarkers of basal and stimulated adrenocortical activity of laying hens.

    Science.gov (United States)

    Cook, N J; Renema, R; Wilkinson, C; Schaefer, A L

    2009-09-01

    1. Serial blood samples from individual birds were analysed for corticosterone concentrations under basal and stimulated conditions, and matched to eggs from the same birds for comparison to albumin and yolk concentrations of corticosterone. 2. Serum corticosterone exhibited increases in response to stimulation by ACTH and Handling stress. There were no significant increases in egg albumin or yolk concentrations of corticosterone following stimulation. 3. Several significant correlations were observed between the mean and area under the curve (AUC) measurements of serum corticosterone concentrations with albumin and yolk corticosterone concentrations in eggs laid from 1 to 2 d later. 4. The results demonstrated a relationship between endogenous concentrations of serum corticosterone that reflected daily adrenocortical output with albumin and yolk corticosterone concentrations in eggs laid the following day. 5. The results do not support the concept of albumin and yolk concentrations of corticosterone as biomarkers of acute adrenocortical responses to stimulation.

  2. Assessment of the role of transcript for GATA-4 as a marker of unfavorable outcome in human adrenocortical neoplasms

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    Martin Regina M

    2004-07-01

    Full Text Available Abstract Background Malignant neoplasia of the adrenal cortex is usually associated with very poor prognosis. When adrenocortical neoplasms are diagnosed in the early stages, distinction between carcinoma and adenoma can be very difficult to accomplish, since there is yet no reliable marker to predict tumor recurrence or dissemination. GATA transcription factors play an essential role in the developmental control of cell fate, cell proliferation and differentiation, organ morphogenesis, and tissue-specific gene expression. Normal mouse adrenal cortex expresses GATA-6 while its malignant counterpart only expresses GATA-4. The goal of the present study was to assess whether this reciprocal change in the expression of GATA factors might be relevant for predicting the prognosis of human adrenocortical neoplasms. Since human adrenal cortices express luteinizing hormone (LH/hCG receptor and the gonadotropins are known to up-regulate GATA-4 in gonadal tumor cell lines, we also studied the expression of LH/hCG receptor. Methods We conducted a study on 13 non-metastasizing (NM and 10 metastasizing/recurrent (MR tumors obtained from a group of twenty-two adult and pediatric patients. The expression of GATA-4, GATA-6, and LH/hCG receptor (LHR in normal and tumoral human adrenal cortices was analysed using reverse transcriptase-polymerase chain reaction (RT-PCR complemented by dot blot hybridization. Results Messenger RNA for GATA-6 was detected in normal adrenal tissue, as well as in the totality of NM and MR tumors. GATA-4, by its turn, was detected in normal adrenal tissue, in 11 out of 13 NM tumors, and in 9 of the 10 MR tumors, with larger amounts of mRNA found among those presenting aggressive clinical behavior. Transcripts for LH receptor were observed both in normal tissue and neoplasms. A more intense LHR transcript accumulation was observed on those tumors with better clinical outcome. Conclusion Our data suggest that the expression of GATA-6 in

  3. Role of Endocrine Gland-Derived Vascular Endothelial Growth Factor (EG-VEGF) and Its Receptors in Adrenocortical Tumors.

    Science.gov (United States)

    Heck, Dorothee; Wortmann, Sebastian; Kraus, Luitgard; Ronchi, Cristina L; Sinnott, Richard O; Fassnacht, Martin; Sbiera, Silviu

    2015-12-01

    Angiogenesis is essential for tumor growth and metastasis. Endocrine gland-derived vascular endothelial growth factor (EG-VEGF) is an angiogenic factor predominantly expressed in steroidogenic organs like the adrenal gland, ovary, testes, and placenta. EG-VEGF has antiapoptotic, mitogenic, and chemoattractive properties mediated via the two G protein-coupled receptors prokineticin receptor 1 (PKR1) and prokineticin receptor 2 (PKR2). We investigated the expression of EG-VEGF and its receptors in a large number of normal adrenal glands (NAG), adrenocortical adenomas (ACA), and carcinomas (ACC) using real-time PCR (NAG, n = 12; ACA, n = 24; and ACC, n = 30) and immunohistochemistry (NAG, n = 9; ACA, n = 23; and ACC, n = 163) and evaluated its impact on patients' survival. EG-VEGF, PKR1, and PKR2 mRNA and protein are expressed in NAG and the vast majority of ACA and ACC samples. The mean EG-VEGF mRNA expression was significantly lower in ACC (606.5 ± 77.1 copies) compared to NAG (4,043 ± 1,111) and cortisol-producing adenomas (CPA) (4,433 ± 2,378) (p < 0.01 and p < 0.05, respectively). However, cytoplasmic and nuclear EG-VEGF protein expression was either significantly higher or similar in ACC (H score 2.4 ± 0.05, p < 0.05 and 1.7 ± 0.08, n.s., respectively) compared to NAG (1.8 ± 0.14 and 1.7 ± 0.2). Nuclear protein expression of either EG-VEGF or PKR1 or both is predictive for a higher mortality compared to patients without nuclear expression (hazard ratio (HR) = 5.15; 95% confidence interval (CI) = 1.24-21.36, n = 100, p = 0.02 independent of age, sex, and tumor stage). These findings suggest that EG-VEGF and its receptor PKR1 might play a role in the pathogenesis of adrenocortical tumors and could serve as prognostic markers for this rare malignant disease.

  4. Masked volume wise principal component analysis of small adrenocortical tumours in dynamic [11C]-metomidate positron emission tomography

    International Nuclear Information System (INIS)

    Razifar, Pasha; Hennings, Joakim; Monazzam, Azita; Hellman, Per; Långström, Bengt; Sundin, Anders

    2009-01-01

    In previous clinical Positron Emission Tomography (PET) studies novel approaches for application of Principal Component Analysis (PCA) on dynamic PET images such as Masked Volume Wise PCA (MVW-PCA) have been introduced. MVW-PCA was shown to be a feasible multivariate analysis technique, which, without modeling assumptions, could extract and separate organs and tissues with different kinetic behaviors into different principal components (MVW-PCs) and improve the image quality. In this study, MVW-PCA was applied to 14 dynamic 11C-metomidate-PET (MTO-PET) examinations of 7 patients with small adrenocortical tumours. MTO-PET was performed before and 3 days after starting per oral cortisone treatment. The whole dataset, reconstructed by filtered back projection (FBP) 0–45 minutes after the tracer injection, was used to study the tracer pharmacokinetics. Early, intermediate and late pharmacokinetic phases could be isolated in this manner. The MVW-PC1 images correlated well to the conventionally summed image data (15–45 minutes) but the image noise in the former was considerably lower. PET measurements performed by defining 'hot spot' regions of interest (ROIs) comprising 4 contiguous pixels with the highest radioactivity concentration showed a trend towards higher SUVs when the ROIs were outlined in the MVW-PC1 component than in the summed images. Time activity curves derived from '50% cut-off' ROIs based on an isocontour function whereby the pixels with SUVs between 50 to 100% of the highest radioactivity concentration were delineated, showed a significant decrease of the SUVs in normal adrenal glands and in adrenocortical adenomas after cortisone treatment. In addition to the clear decrease in image noise and the improved contrast between different structures with MVW-PCA, the results indicate that the definition of ROIs may be more accurate and precise in MVW-PC1 images than in conventional summed images. This might improve the precision of PET

  5. A Novel PRKAR1A Mutation Identified in a Patient with Isolated Primary Pigmented Nodular Adrenocortical Disease

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    Sira Korpaisarn

    2017-08-01

    Full Text Available Primary pigmented nodular adrenocortical disease (PPNAD is a rare cause of Cushing syndrome, especially the isolated form without Carney complex, associated with germline mutations in PRKAR1A, the protein kinase A regulatory subunit type 1 alpha gene. We report a 31-year-old female who presented with secondary amenorrhea, cushingoid appearance, and hypertension without Carney complex. Biochemical laboratory examinations confirmed the ACTH-independent adrenal Cushing syndrome with negative Liddle test. A small right adrenal adenoma of 0.8 cm was shown on computed tomography while magnetic resonance imaging revealed nodularity of both adrenal glands. The histological report confirmed PPNAD using laparoscopic right adrenalectomy, and subsequent left adrenalectomy was performed 6 months later. She had inherited heterozygosity of a novel germline mutation of the PRKAR1A gene (g.114213T>G or c.709-5T>G. This splice site mutation results in exon 8 skipping. Her father carrying the same mutation had no clinical features of either PPNAD or Carney complex. This novel PRKAR1A gene mutation, c.709-5T>G, is reported here for the first time manifesting as an incomplete clinical expression of the isolated form of PPNAD and being inherited with low penetrance unlike other inherited mutations of the Carney complex which have a penetrance of almost 100%.

  6. Adrenocortical and Adipose Responses to High-Altitude-Induced, Long-Term Hypoxia in the Ovine Fetus

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    Dean A. Myers

    2012-01-01

    Full Text Available By late gestation, the maturing hypothalamo-pituitary-adrenal (HPA axis aids the fetus in responding to stress. Hypoxia represents a significant threat to the fetus accompanying situations such as preeclampsia, smoking, high altitude, and preterm labor. We developed a model of high-altitude (3,820 m, long-term hypoxia (LTH in pregnant sheep. We describe the impact of LTH on the fetal HPA axis at the level of the hypothalamic paraventricular nucleus (PVN, anterior pituitary corticotrope, and adrenal cortex. At the PVN and anterior pituitary, the responses to LTH are consistent with hypoxia being a potent activator of the HPA axis and potentially maladaptive, while the adrenocortical response to LTH appears to be primarily adaptive. We discuss mechanisms involved in the delicate balance between these seemingly opposing responses that preserve the normal ontogenic rise in fetal plasma cortisol essential for organ maturation and in this species, birth. Further, we examine the response to, and ramifications of, an acute secondary stressor in the LTH fetus. We provide an integrative model on the potential role of adipose in modulating these responses to LTH. Integration of these adaptive responses to LTH plays a key role in promoting normal fetal growth and development under conditions of a chronic stress.

  7. Adrenocortical Production Is Associated with Higher Levels of Luteinizing Hormone in Nonobese Women with Polycystic Ovary Syndrome

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    Luciana Tock

    2014-01-01

    Full Text Available Objective. Insulin resistance (IR and ovarian and adrenal hyperandrogenism are a common finding in women with polycystic ovary syndrome (PCOS. The aim of the present study was to access possible differences in insulin resistance, gonadotropins, and androgens production in obese and nonobese PCOS women. Study Design. We studied 37 PCOS women (16 nonobese and 21 obese and 18 nonobese controls. Fasting glucose, insulin, androgens, and gonadotropins levels were determined. Salivary cortisol was measured basal and in the morning after dexamethasone (DEX 0.25 mg. Results. Nonobese PCOS women showed higher basal salivary cortisol and serum dehydroepiandrosterone sulfate and luteinizing hormone (LH levels than controls and obese PCOS. These hormones levels did not differ between the obese and control groups. After DEX administration no differences were found between the three groups. In PCOS women, salivary cortisol levels showed negative correlation with BMI (r=-0.52; P=0.001 and insulin (r=-0.47; P=0.003 and positive correlation with LH (r=0.40; P=0.016. Conclusion. Our results show an increased adrenocortical production in nonobese PCOS women, not related to IR and associated with a normal hypothalamic-pituitary-adrenal suppression. Higher LH levels might be involved in this event.

  8. Amplification of 9q34 in childhood adrenocortical tumors: a specific feature unrelated to ethnic origin or living conditions

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    Figueiredo B.C.

    2000-01-01

    Full Text Available Adrenocortical tumors (ACT in children under 15 years of age exhibit some clinical and biological features distinct from ACT in adults. Cell proliferation, hypertrophy and cell death in adrenal cortex during the last months of gestation and the immediate postnatal period seem to be critical for the origin of ACT in children. Studies with large numbers of patients with childhood ACT have indicated a median age at diagnosis of about 4 years. In our institution, the median age was 3 years and 5 months, while the median age for first signs and symptoms was 2 years and 5 months (N = 72. Using the comparative genomic hybridization technique, we have reported a high frequency of 9q34 amplification in adenomas and carcinomas. This finding has been confirmed more recently by investigators in England. The lower socioeconomic status, the distinctive ethnic groups and all the regional differences in Southern Brazil in relation to patients in England indicate that these differences are not important to determine 9q34 amplification. Candidate amplified genes mapped to this locus are currently being investigated and Southern blot results obtained so far have discarded amplification of the abl oncogene. Amplification of 9q34 has not been found to be related to tumor size, staging, or malignant histopathological features, nor does it seem to be responsible for the higher incidence of ACT observed in Southern Brazil, but could be related to an ACT from embryonic origin.

  9. State of the art knowledge in adrenocortical and behavioral responses to environmental challenges in a threatened South American ratite: Implications to in situ and ex-situ conservation.

    Science.gov (United States)

    Luis, Navarro Joaquín; Lèche, Alvina; Costa, Natalia S Della; Cortez, Marilina Vera; Marin, Raúl H; Martella, Mónica B

    2018-04-12

    The Greater Rhea (Rhea americana) is an endemic ratite to South America, whose wild populations have undergone a remarkable decrease due to habitat degradation and fragmentation by the expansion of the agricultural frontier, poaching and predation by dogs. Anthropogenic perturbations in wild environments, as well as the management in captivity, can generate different stress responses in this species, thus, the monitoring of adrenocortical and behavioral activities are considered primary assessment tools with both conservation and welfare implications. In this review we analyze and integrate the different measurements of glucocorticoids (in plasma, feces, and yolk) carried out in different captive and wild populations, taking into account the diverse predictable and unpredictable conditions to which the Greater Rhea responds in each of those environments. In addition, the translocation of this bird is presented as an application of stress physiology in field ecology for conservation purposes, in which we evaluated how this species responds when it is released into a novel environment. Our results indicate that this ratite has a striking high sensitivity of the hypothalamic-pituitary-adrenal (HPA) axis compared to that of other bird species and shows a wide variety of adrenocortical responses depending on the environment in which it lives. This suggests that its HPA axis has a phenotypic plasticity that enables the rhea to cope with the environmental challenges. In this sense, we propose that one of the routes of this plasticity could be mediated by the maternal transfer of steroid hormones to the egg. Finally, we discuss the importance of integrating the monitoring of the adrenocortical response along with the environmental variables that define the life history of the species, in management and conservation programs ex-situ and in situ. Copyright © 2018. Published by Elsevier Inc.

  10. Role of glutathione redox cycle and catalase in defense against oxidative stress induced by endosulfan in adrenocortical cells of rainbow trout (Oncorhynchus mykiss)

    International Nuclear Information System (INIS)

    Dorval, J.; Hontela, A.

    2003-01-01

    The role of antioxidants in maintaining the functional integrity of adrenocortical cells during in vitro exposure to endosulfan, an organochlorine pesticide, was investigated in rainbow trout (Oncorhynchus mykiss). Aminotriazole (ATA), an inhibitor of catalase (CAT), L-buthionine sulfoximine (L-BSO), an inhibitor of glutathione (GSH) synthesis, and N-acetyl cysteine (NAC), a glutathione precursor, were used to investigate the role of CAT and GSH redox cycle in protection against the adrenal toxicity of endosulfan, a pesticide that impairs cell viability (LC 50 366 μM) and cortisol secretion (EC 50 19 μM) in a concentration-related manner. Pretreatment with ATA and L-BSO enhanced the toxicity of endosulfan (LC 50 and EC 50 , respectively, 302 and 2.6 μM with ATA, 346 and 3.1 μM with L-BSO), while pretreatment with NAC had no significant effect on cell viability and increased the EC 50 of endosulfan to 51 μM. CAT activity was significantly reduced following exposure to endosulfan when cells were pretreated with ATA. Pretreatment with L-BSO significantly decreased glutathione peroxidase (GPx) activity and reduced glutathione (GSH) levels in a concentration-related manner following exposure to endosulfan, while GSH levels were significantly higher in NAC pretreated cells compared to untreated cells. Finally, pretreatment with ATA and L-BSO increased, while pretreatment with NAC decreased, lipid hydroperoxides (LOOH) levels. CAT, GPx, and GSH were identified as important antioxidants in maintaining the function and integrity of rainbow trout adrenocortical cells and ATA, L-BSO, and NAC were identified as effective modulators of CAT and GSH redox cycle. Moreover, this study suggests that the glutathione redox cycle may be more efficient than catalase in protecting adrenocortical cells against endosulfan-induced oxidative stress

  11. Biology is Destiny: A Case of Adrenocortical Carcinoma Diagnosed and Resected at Inception in a Patient Under Close Surveillance for Lung Cancer.

    Science.gov (United States)

    Miron, Benjamin; Ristau, Benjamin T; Tomaszewski, Jeffrey J; Jones, Josh; Milestone, Bart; Wong, Yu-Ning; Uzzo, Robert G; Edmondson, Donna; Scott, Walter; Kutikov, Alexander

    2016-11-01

    Adrenocortical carcinoma (ACC) is a rare malignancy that is generally associated with a poor prognosis whose existence dictates the management of incidental renal masses. We report a case of ACC diagnosed and treated at its apparent inception in a patient undergoing close surveillance imaging of a prior malignancy. Despite timely detection and resection of a localized ACC this patient rapidly progressed to systemic disease. This case highlights the rapid growth kinetics of ACC and puts into perspective the challenges associated with the established treatment paradigm for patients diagnosed with an adrenal mass.

  12. Biology is Destiny: A Case of Adrenocortical Carcinoma Diagnosed and Resected at Inception in a Patient Under Close Surveillance for Lung Cancer

    Directory of Open Access Journals (Sweden)

    Benjamin Miron

    2016-11-01

    Full Text Available Adrenocortical carcinoma (ACC is a rare malignancy that is generally associated with a poor prognosis whose existence dictates the management of incidental renal masses. We report a case of ACC diagnosed and treated at its apparent inception in a patient undergoing close surveillance imaging of a prior malignancy. Despite timely detection and resection of a localized ACC this patient rapidly progressed to systemic disease. This case highlights the rapid growth kinetics of ACC and puts into perspective the challenges associated with the established treatment paradigm for patients diagnosed with an adrenal mass.

  13. Effects of bisphenol A-related diphenylalkanes on vitellogenin production in male carp (Cyprinus carpio) hepatocytes and aromatase (CYP19) activity in human H295r adrenocortical carcinoma cells

    International Nuclear Information System (INIS)

    Letcher, Robert J.; Sanderson, J. Thomas; Bokkers, Abraham; Giesy, John P.; Berg, Martin van den

    2005-01-01

    The present study investigated the effects of the known xenoestrogen bisphenol A (BPA) relative to eight BPA-related diphenylalkanes on estrogen receptor (ER)-mediated vitellogenin (vtg) production in hepatocytes from male carp (Cyprinus carpio), and on aromatase (CYP19) activity in the human adrenocortical H295R carcinoma cell line. Of the eight diphenylalkanes, only 4,4'-(hexafluoropropylidene)diphenol (BHF) and 2,2'-bis(4-hydroxy-3-methylphenyl)propane (BPRO) induced vtg, i.e., to a maximum of 3% to 4% (at 100 μM) compared with 8% for BPA relative to the maximum induction by 17β-estradiol (E2, 1 μM). Bisphenol A diglycidyl ether (BADGE) was a potent antagonist of vtg production with an IC50 of 5.5 μM, virtually 100% inhibition of vtg at 20 μM, and an inhibitive (IC50) potency about one-tenth that of the known ER antagonist tamoxifen (IC50, 0.6 μM). 2,2'-Diallyl bisphenol A, 4,4'-(1,4-phenylene-diisopropylidene)bisphenol, BPRO, and BHF were much less inhibitory with IC50 concentrations of 20-70 μM, and relative potencies of 0.03 and 0.009 with tamoxifen. Bisphenol ethoxylate showed no anti-estrogenicity (up to 100 μM), and 4,4'-isopropylidene-diphenol diacetate was only antagonistic at 100 μM. When comparing the (anti)estrogenic potencies of these bisphenol A analogues/diphenylalkanes, anti-estrogenicity occurred at lower concentrations than estrogenicity. 4,4'-Isopropylidenebis(2,6-dimethylphenol) (IC50, 2.0 μM) reduced E2-induced (EC50, 100 nM) vtg production due to concentration-dependent cytotoxicity as indicated by a parallel decrease in MTT activity and vtg, whereas the remaining diphenylalkanes did not cause any cytotoxicity relative to controls. None of the diphenylalkanes (up to 100 μM) induced EROD activity indicating that concentration-dependent, CYP1A enzyme-mediated metabolism of E2, or any Ah-receptor-mediated interaction with the ER, was not a likely explanation for the observed anti-estrogenic effects. At concentrations as great as 100

  14. Adjuvant Radiation Therapy Improves Local Control After Surgical Resection in Patients With Localized Adrenocortical Carcinoma

    International Nuclear Information System (INIS)

    Sabolch, Aaron; Else, Tobias; Griffith, Kent A.; Ben-Josef, Edgar; Williams, Andrew; Miller, Barbra S.; Worden, Francis; Hammer, Gary D.; Jolly, Shruti

    2015-01-01

    Purpose: Adrenocortical carcinoma (ACC) is a rare malignancy known for high rates of local recurrence, though the benefit of postoperative radiation therapy (RT) has not been established. In this study of grossly resected ACC, we compare local control of patients treated with surgery followed by adjuvant RT to a matched cohort treated with surgery alone. Methods and Materials: We retrospectively identified patients with localized disease who underwent R0 or R1 resection followed by adjuvant RT. Only patients treated with RT at our institution were included. Matching to surgical controls was on the basis of stage, surgical margin status, tumor grade, and adjuvant mitotane. Results: From 1991 to 2011, 360 ACC patients were evaluated for ACC at the University of Michigan (Ann Arbor, MI). Twenty patients with localized disease received postoperative adjuvant RT. These were matched to 20 controls. There were no statistically significant differences between the groups with regard to stage, margins, grade, or mitotane. Median RT dose was 55 Gy (range, 45-60 Gy). Median follow-up was 34 months. Local recurrence occurred in 1 patient treated with RT, compared with 12 patients not treated with RT (P=.0005; hazard ratio [HR] 12.59; 95% confidence interval [CI] 1.62-97.88). However, recurrence-free survival was no different between the groups (P=.17; HR 1.52; 95% CI 0.67-3.45). Overall survival was also not significantly different (P=.13; HR 1.97; 95% CI 0.57-6.77), with 4 deaths in the RT group compared with 9 in the control group. Conclusions: Postoperative RT significantly improved local control compared with the use of surgery alone in this case-matched cohort analysis of grossly resected ACC patients. Although this retrospective series represents the largest study to date on adjuvant RT for ACC, its findings need to be prospectively confirmed

  15. The stress of being contaminated? Adrenocortical function and reproduction in relation to persistent organic pollutants in female black legged kittiwakes.

    Science.gov (United States)

    Tartu, Sabrina; Angelier, Frédéric; Herzke, Dorte; Moe, Børge; Bech, Claus; Gabrielsen, Geir W; Bustnes, Jan Ove; Chastel, Olivier

    2014-04-01

    High levels of environmental pollutants such as persistent organic pollutants (POPs) including PCB and DDT have been found in the Arctic and many of those pollutants may impair reproduction through endocrine disruption. Nevertheless, their effects on stress hormones remain poorly understood, especially in free-ranging birds. Corticosterone, the principal glucocorticoid in birds, can indirectly impair reproduction. The aim of the present study was to examine the relationships between POPs and reproduction through their potential consequences on different reproductive traits (breeding decision, egg-laying date, breeding success) and corticosterone secretion (baseline and stress-induced levels). We addressed those questions in an Arctic population of female black-legged kittiwakes during the pre-breeding stage and measured several legacy POPs (PCBs and pesticides: HCB, p,p'-DDE, CHL) in whole blood. POP levels were not related to breeding decision neither to breeding success, whereas females with high levels of pesticides laid their eggs earlier in the season. We found a negative relationship between POP levels and body condition index in non-breeding females. Black-legged kittiwakes with higher levels of PCB showed stronger adrenocortical response when subjected to a capture-handling stress protocol. We suggest that PCBs may disrupt corticosterone secretion whereas the positive relationship between pesticides and egg-laying date could either originate from a direct effect of pesticides or may be related to other confounding factors such as age or individual's quality. Although no direct negative reproduction output of POPs was found in this study, it is possible that the most contaminated individuals would be more sensitive to environmental stress and would be less able to maintain parental investment than less polluted individuals. Copyright © 2014 Elsevier B.V. All rights reserved.

  16. Activation in the hypothalamic-pituitary-adrenocortical axis and sympathetic nervous system in women with carpal tunnel syndrome.

    Science.gov (United States)

    Fernández-de-Las-Peñas, César; Díaz-Rodríguez, Lourdes; Salom-Moreno, Jaime; Galiano-Castillo, Noelia; Valverde-Herreros, Lis; Martínez-Martín, Javier; Pareja, Juan A

    2014-08-01

    The aim of this study is to investigate the differences in salivary cortisol (hypothalamic-pituitary-adrenocortical [HPA] axis), α-amylase activity (sympathetic nervous system [SNS]), and immunoglobulin A (IgA; immune system) concentrations between women with carpal tunnel syndrome (CTS) and healthy women. A cross-sectional study. Activation of HPA, SNS, and immune system in CTS has not been clearly determined. One hundred two women (age: 45 ± 7 years) with electrodiagnostic and clinical diagnosis of CTS and 102 matched healthy women. The intensity of the pain was assessed with a Numerical Pain Rating Scale (0-10), and disability was determined with Boston Carpal Tunnel Questionnaire. Salivary cortisol concentration, α-amylase activity, salivary flow rate, and IgA concentration were collected from nonstimulated saliva. Women with CTS exhibited lower salivary flow rate (P  0.2) were found between groups as a total. Women with severe CTS exhibited lower salivary flow rate (P < 0.001), higher α-amylase activity (P = 0.002), and higher cortisol concentration (P = 0.03) than healthy women and than those with minimal/moderate CTS (P < 0.05). Within women with CTS, significant positive associations between α-amylase activity and the intensity of pain were found: the highest the level of pain, the higher the α-amylase activity, i.e., higher SNS activation. These results suggest that women with severe CTS exhibit changes in activation in the HPA axis and SNS but not in the humoral immune system. Activation of the SNS was associated with the intensity of pain. Future studies are needed to elucidate the direction of this relationship. Wiley Periodicals, Inc.

  17. No effect of pinealectomy on the parallel shift in circadain rhythms of adrenocortical activity and food intake in blinded rats.

    Science.gov (United States)

    Takahashi, K; Inoue, K; Takahashi, Y

    1976-10-01

    Twenty-four-hr patterns of plasma corticosterone levels were determined at 4-hr intervals every 3-4 weeks in sighted and blinded pinealectomized rats of adult age. Through the whole period of the experiment, 24-hr patterns of food intake were also measured weekly. The sighted rats manifested the same 24-hr patterns of plasma corticosterone levels and food intake for 15 weeks after pinealectomy as those observed in the intact control rats. The magnitude of peak levels of plasma corticosterone and the amount of food intake did not differ between the two groups. A phase shift in circadian rhythms of plasma corticosterone levels and food intake was observed in both groups of blinded rats, with and without pinealectomy. Between the two groups, the patterns of phase shift were essentially similar for 10 weeks examined after optic enucleation. The peak elevation of plasma levels took place at 11 p.m. at the end of the 4th week after optic enucleation. Thereafter, 4- to 8-hr delay of peak appearance was observed every 3 weeks. No significant differences were found in peak values between the two groups of blinded rats. Furthermore, the circadian rhythm of food intake shifted in parallel with that of plasma corticosterone levels. A phase reversal of these two activities was observed between the 8th and 10th week after the operation. These results indicate that the pineal gland does not play any important role either in the maintenance of normal circadian periodicities of adrenocortical activity and food intake or in the shift in circadian rhythms of the two activities in the blinded rats.

  18. Adjuvant Radiation Therapy Improves Local Control After Surgical Resection in Patients With Localized Adrenocortical Carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Sabolch, Aaron [Department of Radiation Oncology, University of Michigan Hospital and Health Systems, Ann Arbor, Mchigan (United States); Else, Tobias [Division of Metabolism, Endocrinology, and Diabetes, Department of Internal Medicine, University of Michigan Hospital and Health Systems, Ann Arbor, Mchigan (United States); Griffith, Kent A. [Center for Cancer Biostatistics, School of Public Health, University of Michigan, Ann Arbor, Mchigan (United States); Ben-Josef, Edgar [Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania (United States); Williams, Andrew [University of Michigan Medical School, Ann Arbor, Mchigan (United States); Miller, Barbra S. [Division of Endocrine Surgery, Department of General Surgery, University of Michigan Hospital and Health Systems, Ann Arbor, Mchigan (United States); Worden, Francis [Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan Hospital and Health Systems, Ann Arbor, Mchigan (United States); Hammer, Gary D. [Division of Metabolism, Endocrinology, and Diabetes, Department of Internal Medicine, University of Michigan Hospital and Health Systems, Ann Arbor, Mchigan (United States); Jolly, Shruti, E-mail: shrutij@med.umich.edu [Department of Radiation Oncology, University of Michigan Hospital and Health Systems, Ann Arbor, Mchigan (United States)

    2015-06-01

    Purpose: Adrenocortical carcinoma (ACC) is a rare malignancy known for high rates of local recurrence, though the benefit of postoperative radiation therapy (RT) has not been established. In this study of grossly resected ACC, we compare local control of patients treated with surgery followed by adjuvant RT to a matched cohort treated with surgery alone. Methods and Materials: We retrospectively identified patients with localized disease who underwent R0 or R1 resection followed by adjuvant RT. Only patients treated with RT at our institution were included. Matching to surgical controls was on the basis of stage, surgical margin status, tumor grade, and adjuvant mitotane. Results: From 1991 to 2011, 360 ACC patients were evaluated for ACC at the University of Michigan (Ann Arbor, MI). Twenty patients with localized disease received postoperative adjuvant RT. These were matched to 20 controls. There were no statistically significant differences between the groups with regard to stage, margins, grade, or mitotane. Median RT dose was 55 Gy (range, 45-60 Gy). Median follow-up was 34 months. Local recurrence occurred in 1 patient treated with RT, compared with 12 patients not treated with RT (P=.0005; hazard ratio [HR] 12.59; 95% confidence interval [CI] 1.62-97.88). However, recurrence-free survival was no different between the groups (P=.17; HR 1.52; 95% CI 0.67-3.45). Overall survival was also not significantly different (P=.13; HR 1.97; 95% CI 0.57-6.77), with 4 deaths in the RT group compared with 9 in the control group. Conclusions: Postoperative RT significantly improved local control compared with the use of surgery alone in this case-matched cohort analysis of grossly resected ACC patients. Although this retrospective series represents the largest study to date on adjuvant RT for ACC, its findings need to be prospectively confirmed.

  19. Tumor-specific loss of 11p15.5 alleles in del11p13 Wilms tumor and in familial adrenocortical carcinoma

    International Nuclear Information System (INIS)

    Henry, I.; Grandjouan, S.; Couillin, P.

    1989-01-01

    The authors have compared constitutional and tumor genotypes in nine cases of hereditary Wilms tumor (WT) and in three unrelated cases of familial adrenocortical carcinoma (ADCC). Since susceptibility to these tumors can be observed in malformation syndromes associated with a constitutional deletion of band 11p13 (WT) and with a constitutional duplication of band 11p15.5 (WT, ADCC), they investigated these two candidate regions by using 11p polymorphic markers. As expected, somatic chromosomal events, resulting in a loss of heterozygosity limited to region 11p15.5, were observed in the tumor of two familial cases of adrenocortical carcinoma. Surprisingly, however, analysis of the WT of two patients with a constitutional deletion of band 11p13, associated with aniridia, genitourinary abnormalities, and mental retardation (WAGR syndrome), revealed a loss of heterozygosity limited to region 11p15.5. These data therefore suggest that observation of a specific loss of heterozygosity may not necessarily point to the site of the initial germinal mutation. Together with previous similar observations of a loss of heterozygosity limited to 11p15.5 in breast cancer and in rhabdomyosarcoma, the data suggest that region 11p15.5 may carry a non-tissue-specific gene that could be involved in genetic predisposition, in tumor progression, or in both

  20. Non-invasive monitoring of adrenocortical activity in captive African Penguin (Spheniscus demersus) by measuring faecal glucocorticoid metabolites.

    Science.gov (United States)

    Ozella, L; Anfossi, L; Di Nardo, F; Pessani, D

    2015-12-01

    Measurement of faecal glucocorticoid metabolites (FGMs) has become a useful and widely-accepted method for the non-invasive evaluation of stress in vertebrates. In this study we assessed the adrenocortical activity of five captive African Penguins (Spheniscus demersus) by means of FGM evaluation following a biological stressor, i.e. capture and immobilization. In addition, we detected individual differences in secretion of FGMs during a stage of the normal biological cycle of penguins, namely the breeding period, without any external or induced causes of stress. Our results showed that FGM concentrations peaked 5.5-8h after the induced stress in all birds, and significantly decreased within 30 h. As predictable, the highest peak of FGMs (6591 ng/g) was reached by the youngest penguin, which was at its first experience with the stressor. This peak was 1.8-2.7-fold higher compared to those of the other animals habituated to the stimulus. For the breeding period, our results revealed that the increase in FGMs compared to ordinary levels, and the peaks of FGMs, varied widely depending on the age and mainly on the reproductive state of the animal. The bird which showed the lowest peak (2518 ng/g) was an old male that was not in a reproductive state at the time of the study. Higher FGM increases and peaks were reached by the two birds which were brooding (male: 5552%, 96,631 ng/g; female: 1438%, 22,846 ng/g) and by the youngest bird (1582%, 39,700 ng/g). The impact of the reproductive state on FGM levels was unexpected compared to that produced by the induced stress. The EIA used in this study to measure FGM levels proved to be a reliable tool for assessing individual and biologically-relevant changes in FGM concentrations in African Penguin. Moreover, this method allowed detection of physiological stress during the breeding period, and identification of individual differences in relation to the reproductive status. The increase in FGM levels as a response to capture and

  1. Impact of {sup 18}F-FDG PET/CT on the management of adrenocortical carcinoma: analysis of 106 patients

    Energy Technology Data Exchange (ETDEWEB)

    Takeuchi, Satoshi; Macapinlac, Homer A.; Chuang, Hubert H. [The University of Texas MD Anderson Cancer Center, Department of Nuclear Medicine, Houston, TX (United States); Balachandran, Aparna [The University of Texas MD Anderson Cancer Center, Department of Diagnostic Radiology, Houston, TX (United States); Habra, Mouhammed Amir [The University of Texas MD Anderson Cancer Center, Department of Endocrine Neoplasia and Hormonal Disorders, Houston, TX (United States); Phan, Alexandria T. [The University of Texas MD Anderson Cancer Center, Department of Gastrointestinal Medical Oncology, Houston, TX (United States); Bassett, Roland L. [The University of Texas MD Anderson Cancer Center, Department of Biostatistics, Houston, TX (United States)

    2014-11-15

    Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy. Limited data are available about on value of {sup 18}F-FDG PET/CT in ACC. We evaluated the impact of PET/CT on the management of ACC. We performed a retrospective review in patients with ACC who had undergone PET/CT. The impact of PET/CT on the management plan was evaluated by comparing the findings on PET/CT to the findings on contrast-enhanced CT. The sensitivity, specificity, and accuracy of each form of imaging were calculated. The correlations between PET/CT parameters, including maximum standardized uptake value (SUV{sub max}), total lesion glycolysis, and decline in SUV{sub max} after chemotherapy, and clinical outcome were evaluated. Included in the analysis were 106 patients with 180 PET/CT scans. Of the 106 patients, 7 underwent PET/CT only for initial staging, 84 underwent PET/CT only for restaging, and 15 underwent PET/CT for both initial staging and restaging. PET/CT changed the management plan in 1 of 22 patients (5 %) at initial staging and 9 of 99 patients (9 %) at restaging. In 5 of the patients in whom PET/CT changed the management plan, PET/CT showed response to chemotherapy but contrast-enhanced CT showed stable disease. Sensitivity, specificity, and accuracy were 100 %, 100 %, and 100 % for PET/CT at initial staging; 92.6 %, 100 %, and 96.4 % for CT at initial staging; 98.4 %, 100 %, and 99.5 % for PET/CT at restaging; and 96.8 %, 98.6 %, and 98.0 % for CT at restaging, respectively. No PET/CT parameters were associated with survival at either initial diagnosis or recurrence. PET/CT findings could substantially change the management plan in a small proportion of patients with ACC. Although lesion detection was similar between PET/CT and CT, PET/CT may be preferred for chemotherapeutic response assessment because it may predict response before anatomic changes are detected on CT. (orig.)

  2. In vivo and in vitro evaluation of [18F]FETO with respect to the adrenocortical and GABAergic system in rats

    International Nuclear Information System (INIS)

    Mitterhauser, Markus; Wadsak, Wolfgang; Wabnegger, Leila; Sieghart, Werner; Viernstein, Helmut; Kletter, Kurt; Dudczak, Robert

    2003-01-01

    11β-Hydroxylase (CYP11B1, P450 11β ) plays an important role in the biosynthesis of cortisol and aldosterone and has been shown to be a good target for the in vivo imaging of adrenocortical incidentalomas in nuclear medicine. [ 11 C]Metomidate (MTO), a potent inhibitor of this enzyme, is used for positron emission tomography (PET) imaging of adrenocortical pathology. The synthesis of (R)-1-(1-phenylethyl)-1H-imidazole-5-carboxylic acid 2-[ 18 F]fluoroethylester (FETO), a close analogue to MTO and etomidate (ETO), has been presented recently, and the present investigation aimed to characterise the in vivo distribution of FETO. Since ETO is a well-known anaesthetic drug acting via the GABAergic system, the interaction of FETO with GABA A receptors was also evaluated. Eighteen male Sprague-Dawley rats were injected with 1.73-3.06 MBq of FETO into a tail vein after venodilatation in a 40 C water bath. Rats were sacrificed by exsanguination from the abdominal aorta under deep ether anaesthesia after 10 (n=6), 30 (n=6) or 60 min (n=6); organs were removed, weighed and counted. For binding experiments, rat cerebellar membranes were incubated for 90 min at 4 C in TC-50 buffer, 150 mM NaCl and 2 nM of [ 3 H]flunitrazepam in the absence or presence of 10 μM diazepam or various concentrations of ETO, MTO and FETO. In vivo evaluation evinced very high uptake in the adrenal glands (7.52%±1.19% ID/g at 30 min), followed by lung (1.18%±0.19% ID/g, 10 min), liver (0.59%±0.13% ID/g, 10 min) and duodenum (0.7%±0.29% ID/g, 60 min). No defluorination nor fluoroethyl-ester cleavage was observed. When brain regions were compared with the thalamus (the reference region), highest relative uptake was seen in the cortex (2.34), followed by ''rest brain'' (2.13) and cerebellum (1.96). FETO and ETO were able to increase the binding of [ 3 H]flunitrazepam with similar potencies and to a comparable extent. It is concluded that FETO shows characteristics suitable for the imaging of

  3. In vivo and in vitro evaluation of [{sup 18}F]FETO with respect to the adrenocortical and GABAergic system in rats

    Energy Technology Data Exchange (ETDEWEB)

    Mitterhauser, Markus [Department of Nuclear Medicine, AKH Wien, University of Vienna, Waehringer Guertel 18-20, 1090, Vienna (Austria); Department of Pharmaceutic Technology and Biopharmaceutics, University of Vienna (Austria); Hospital Pharmacy of the General Hospital of Vienna (Austria); Wadsak, Wolfgang [Department of Nuclear Medicine, AKH Wien, University of Vienna, Waehringer Guertel 18-20, 1090, Vienna (Austria); Department of Inorganic Chemistry, University of Vienna (Austria); Ludwig-Boltzmann-Institute for Nuclear Medicine, Vienna (Austria); Wabnegger, Leila; Sieghart, Werner [Institute for Brain Research, University of Vienna (Austria); Viernstein, Helmut [Department of Pharmaceutic Technology and Biopharmaceutics, University of Vienna (Austria); Kletter, Kurt [Department of Nuclear Medicine, AKH Wien, University of Vienna, Waehringer Guertel 18-20, 1090, Vienna (Austria); Dudczak, Robert [Department of Nuclear Medicine, AKH Wien, University of Vienna, Waehringer Guertel 18-20, 1090, Vienna (Austria)

    2003-10-01

    11{beta}-Hydroxylase (CYP11B1, P450{sub 11{beta}}) plays an important role in the biosynthesis of cortisol and aldosterone and has been shown to be a good target for the in vivo imaging of adrenocortical incidentalomas in nuclear medicine. [{sup 11}C]Metomidate (MTO), a potent inhibitor of this enzyme, is used for positron emission tomography (PET) imaging of adrenocortical pathology. The synthesis of (R)-1-(1-phenylethyl)-1H-imidazole-5-carboxylic acid 2-[{sup 18}F]fluoroethylester (FETO), a close analogue to MTO and etomidate (ETO), has been presented recently, and the present investigation aimed to characterise the in vivo distribution of FETO. Since ETO is a well-known anaesthetic drug acting via the GABAergic system, the interaction of FETO with GABA{sub A} receptors was also evaluated. Eighteen male Sprague-Dawley rats were injected with 1.73-3.06 MBq of FETO into a tail vein after venodilatation in a 40 C water bath. Rats were sacrificed by exsanguination from the abdominal aorta under deep ether anaesthesia after 10 (n=6), 30 (n=6) or 60 min (n=6); organs were removed, weighed and counted. For binding experiments, rat cerebellar membranes were incubated for 90 min at 4 C in TC-50 buffer, 150 mM NaCl and 2 nM of [{sup 3}H]flunitrazepam in the absence or presence of 10 {mu}M diazepam or various concentrations of ETO, MTO and FETO. In vivo evaluation evinced very high uptake in the adrenal glands (7.52%{+-}1.19% ID/g at 30 min), followed by lung (1.18%{+-}0.19% ID/g, 10 min), liver (0.59%{+-}0.13% ID/g, 10 min) and duodenum (0.7%{+-}0.29% ID/g, 60 min). No defluorination nor fluoroethyl-ester cleavage was observed. When brain regions were compared with the thalamus (the reference region), highest relative uptake was seen in the cortex (2.34), followed by ''rest brain'' (2.13) and cerebellum (1.96). FETO and ETO were able to increase the binding of [{sup 3}H]flunitrazepam with similar potencies and to a comparable extent. It is concluded

  4. Efficacy of dexamethasone suppression test during the diagnosis of primary pigmented nodular adrenocortical disease in Chinese adrenocorticotropic hormone-independent Cushing syndrome.

    Science.gov (United States)

    Chen, Shi; Li, Ran; Lu, Lin; Duan, Lian; Zhang, Xuebin; Tong, Anli; Pan, Hui; Zhu, Huijuan; Lu, Zhaolin

    2018-01-01

    To evaluate the cut-off value of the ratio of 24 h urinary free cortisol (24 h UFC) levels post-dexamethasone to prior-dexamethasone in dexamethasone suppression test (DST) during the diagnosis of primary pigmented nodular adrenocortical disease in Chinese adrenocorticotropic hormone-independent Cushing syndrome. Retrospective study. The patients diagnosed with primary pigmented nodular adrenocortical disease (PPNAD, n = 25), bilateral macronodular adrenal hyperplasia (BMAH, n = 27), and adrenocortical adenoma (ADA, n = 84) were admitted to the Peking Union Medical College Hospital from 2001 to 2016. Serum cortisol, adrenocorticotropic hormone (ACTH), and 24 h UFC were measured before and after low-dose dexamethasone suppression test (LDDST) and high-dose dexamethasone suppression test (HDDST). After LDDST and HDDST, 24 h UFC elevated in patients with PPNAD (paired t-test, P = 0.007 and P = 0.001), while it remained unchanged in the BMAH group (paired t-test, P = 0.471 and P = 0.414) and decreased in the ADA group (paired t-test, P = 0.002 and P = 0.004). The 24 h UFC level after LDDST was higher in PPNAD and BMAH as compared to ADA (P < 0.017), while no significant difference was observed between PPNAD and BMAH. After HDDST, 24 h UFC was higher in patients with PPNAD as compared to that of ADA and BMAH (P < 0.017). The cut-off value of 24 h UFC (Post-L-Dex)/(Pre-L-Dex) was 1.16 with 64.0% sensitivity and 77.9% specificity, and the cut-off value of 24 h UFC (Post-H-Dex)/(Pre-H-Dex) was 1.08 with 84.0% sensitivity and 75.6% specificity. The ratio of post-dexamethasone to prior-dexamethasone had a unique advantage in distinguishing PPNAD from BMAH and ADA.

  5. Stages of Adrenocortical Carcinoma

    Science.gov (United States)

    ... the adrenal gland is the adrenal medulla . Enlarge Anatomy of the adrenal gland. There are two adrenal ... spleen , or liver ) or to large blood vessels ( renal vein or vena cava ) and may have spread ...

  6. Corrosion inhibition

    Energy Technology Data Exchange (ETDEWEB)

    Fisher, A O

    1965-12-29

    An acid corrosion-inhibiting composition consists essentially of a sugar, and an alkali metal salt selected from the group consisting of iodides and bromides. The weight ratio of the sugar to the alkali metal salt is between 2:1 and about 20,000:1. Also, a corrosion- inhibited phosphoric acid composition comprising at least about 20 wt% of phosphoric acid and between about 0.1 wt% and about 10 wt% of molasses, and between about 0.0005 wt% and about 1 wt% of potassium iodide. The weight ratio of molasses to iodide is greater than about 2:1. (11 claims)

  7. Chronic inhibition of nitric oxide synthase augments the ACTH response to exercise.

    Science.gov (United States)

    Jankord, Ryan; McAllister, Richard M; Ganjam, Venkataseshu K; Laughlin, M Harold

    2009-03-01

    Exercise can activate the hypothalamo-pituitary-adrenocortical (HPA) axis, and regular exercise training can impact how the HPA axis responds to stress. The mechanism by which acute exercise induces HPA activity is unclear. Therefore, the purpose of this study was to test the hypothesis that nitric oxide modulates the neuroendocrine component of the HPA axis during exercise. Female Yucatan miniature swine were treated with N-nitro-l-arginine methyl ester (l-NAME) to test the effect of chronic nitric oxide synthase (NOS) inhibition on the ACTH response to exercise. In addition, we tested the effect of NOS inhibition on blood flow to tissues of the HPA axis and report the effects of handling and treadmill exercise on the plasma concentrations of ACTH and cortisol. Chronic NOS inhibition decreased plasma NO(x) levels by 44%, increased mean arterial blood pressure by 46%, and increased expression of neuronal NOS in carotid arteries. Vascular conductance was decreased in the frontal cortex, the hypothalamus, and the adrenal gland. Chronic NOS inhibition exaggerated the ACTH response to exercise. In contrast, chronic NOS inhibition decreased the ACTH response to restraint, suggesting that the role of NO in modulating HPA activity is stressor dependent. These results demonstrate that NOS activity modulates the response of the neuroendocrine component of the HPA axis during exercise stress.

  8. Naturally Occurring Adrenocortical Insufficiency--An Epidemiological Study Based on a Swedish-Insured Dog Population of 525,028 Dogs.

    Science.gov (United States)

    Hanson, J M; Tengvall, K; Bonnett, B N; Hedhammar, Å

    2016-01-01

    Naturally occurring adrenocortical insufficiency (NOAI) in dogs is considered an uncommon disease with good prognosis with hormonal replacement treatment. However, there are no epidemiological studies with estimates for the general dog population. To investigate the epidemiological characteristics of NOAI in a large population of insured dogs. Data were derived from 525,028 client-owned dogs insured by a Swedish insurance company representing 2,364,652 dog-years at risk (DYAR) during the period between 1995-2006. Retrospective cohort study. Incidence rates, prevalences, and relative risks for dogs with NOAI (AI with no previous claim for hypercortisolism), were calculated for the whole dog population, and for subgroups divided by breed and sex. Mortality rates were calculated and compared in dogs with NOAI and the remaining dogs overall. In total 534 dogs were identified with NOAI. The overall incidence was 2.3 cases per 10,000 DYAR. The relative risk of disease was significantly higher in the Portuguese Water Dog, Standard Poodle, Bearded Collie, Cairn Terrier, and Cocker Spaniel compared with other breeds combined. Female dogs overall were at higher risk of developing AI than male dogs (RR 1.85; 95% CI, 1.55-2.22; P dogs with NOAI than in dogs overall. The data supports the existence of breed-specific differences in incidence rates of NOAI in dogs. Copyright © 2015 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.

  9. The involvement of the hypothalamopituitary-adrenocortical axis in stress physiology and its significance in the assessment of animal welfare in cattle

    Directory of Open Access Journals (Sweden)

    Emma J. Brown

    2017-04-01

    Full Text Available The intensification of cattle production has raised concern for animal welfare due to the stress that is associated with farming practices. The welfare of an animal is determined by the animal’s ability to cope with or adapt to its continuously changing environment and the biological cost that is associated with this adaptation and maintenance. Stressors arise from various psychological, physiological and physical aspects of farming practices due to management and human–cattle interactions. Measuring the activity of the hypothalamopituitary-adrenocortical (HPA axis with plasma cortisol levels is a useful method for determining the effects of stress on animals as it is stimulated at the onset of a perceived stress. The activation of the HPA axis affects various target tissues or systems and can result in suppression of the immune system, increased susceptibility to disease and adverse effects on reproductive success in prenatal and neonatal calves. Although some levels of stress associated with farming practices are unavoidable, improvements in farming methods need to be implemented in order to maintain or increase the efficiency of cattle production in a way that does not compromise the welfare of the animal.

  10. DAX-1 Inhibits Hepatocellular Carcinoma Proliferation by Inhibiting β-Catenin Transcriptional Activity

    Directory of Open Access Journals (Sweden)

    Hong-Lei Jiang

    2014-08-01

    Full Text Available Background/Aims: Hepatocellular carcinoma (HCC represents the most common type of liver cancer. DAX1 (dosage-sensitive sex reversal adrenal hypoplasia congenital critical region on X chromosome, gene 1, an atypical member of the nuclear receptor family due to lack of classical DNA-binding domains, has been known for its fundamental roles in the development, especially in the sex determination and steroidogenesis. Previous studies also showed that DAX-1 played a critical role in endocrine and sex steroid-dependent neoplasms such as adrenocortical, pituitary, endometrial, and ovarian tumors. However, its biological roles in the development of HCC remain largely unexplored. Methods: Real-time PCR and Western blot were used to detect the expression of DAX-1 in HCC tissues and cell lines. Immunoprecipitation (IP assay was used to show the interaction between DAX-1 and β-Catenin. Small interfering RNA (siRNA was used to silence the expression of DAX-1. BrdU incorporation and Cell-cycle assays were used to detect the role of DAX-1 in HCC cells proliferation. Migration and invasion assays were carried out to test the metastasis ability of DAX-1 in HCC cells. Results: In the present study, we found that mRNA and protein levels of DAX-1 were down-regulated in HCC tissues and cell lines. Furthermore, overexpression of DAX-1 could inhibit while its knockdown using small interfering RNA promoted cell proliferation in several HCC cell lines. At the molecular level, we demonstrated that DAX-1 could interact with β-Catenin and attenuate its transcriptional activity. Conclusion: Therefore, our results suggest a previously unknown DAX-1/β-Catenin molecular network controlling HCC development.

  11. Visualizing the effect of dynamin inhibition on annular gap vesicle formation and fission.

    Science.gov (United States)

    Nickel, Beth; Boller, Marie; Schneider, Kimberly; Shakespeare, Teresa; Gay, Vernon; Murray, Sandra A

    2013-06-15

    Although gap junction plaque assembly has been extensively studied, mechanisms involved in plaque disassembly are not well understood. Disassembly involves an internalization process in which annular gap junction vesicles are formed. These vesicles undergo fission, but the molecular machinery needed for these fissions has not been described. The mechanoenzyme dynamin has been previously demonstrated to play a role in gap junction plaque internalization. To investigate the role of dynamin in annular gap junction vesicle fission, immunocytochemical, time-lapse and transmission electron microscopy were used to analyze SW-13 adrenocortical cells in culture. Dynamin was demonstrated to colocalize with gap junction plaques and vesicles. Dynamin inhibition, by siRNA knockdown or treatment with the dynamin GTPase inhibitor dynasore, increased the number and size of gap junction 'buds' suspended from the gap junction plaques. Buds, in control populations, were frequently released to form annular gap junction vesicles. In dynamin-inhibited populations, the buds were larger and infrequently released and thus fewer annular gap junction vesicles were formed. In addition, the number of annular gap junction vesicle fissions per hour was reduced in the dynamin-inhibited populations. We believe this to be the first report addressing the details of annular gap junction vesicle fissions and demonstrating a role of dynamin in this process. This information is crucial for elucidating the relationship between gap junctions, membrane regulation and cell behavior.

  12. Functional morphology of pituitary -thyroid and -adrenocortical axes in middle-aged male rats treated with Vitex agnus castus essential oil.

    Science.gov (United States)

    Šošić-Jurjević, Branka; Ajdžanović, Vladimir; Filipović, Branko; Trifunović, Svetlana; Jarić, Ivana; Ristić, Nataša; Milošević, Verica

    2016-09-01

    We previously reported that Vitex agnus-castus L. essential oil (VACEO), when administered to middle-aged males, exerts a bone-protective effect, induces silencing of locomotor activities and decreases pituitary prolactin immunopositivity. To further assess the putative endocrine effects of VACEO, we examined the pituitary-thyroid and -adrenocortical axes in our model. Sixteen-month-old Wistar rats were subcutaneously administered 60mg/kg of VACEO dissolved in sterile olive oil, while the control group received the same amount of vehicle alone for three weeks. Pituitaries, thyroids and adrenals were analyzed by qualitative and quantitative histological approaches. Concentration of thyroid stimulating hormone (TSH), total thyroxine and triiodothyronine (TH), adrenocorticotrophic hormone (ACTH), corticosterone in serum and in adrenal tissue were measured. In VACEO-treated rats, the relative volume density of pituitary thyrotrophs increased (p<0.001), while intensity of cytoplasmic TSHβ immunostaining decreased (p<0.001), consistent with elevated TSH in serum (p<0.01). The thyroid tissue was characterized by a micro-follicular structure, increased relative volume of follicular epithelium (p<0.05), decreased volume of luminal colloid (p<0.001) and increased basolateral expression of sodium-iodide symporter-immunopositivity (p<0.05). Serum TH also increased (p<0.01). The relative volume density of pituitary corticotrophs decreased (p<0.05), compatible with decline in circulating ACTH (p<0.05). Neither tissue nor serum corticosterone levels were affected by VACEO treatment. In conclusion, the observed changes in TSH and ACTH strongly indicate central endocrine effects of prolonged VACEO treatment. In this respect, production of ACTH decreased without impact on corticosterone production. Increase in serum concentration of both TH and TSH are not compatible with a negative feedback loop and suggest a major change in set-point regulation of the hypothalamic

  13. Activation of the baboon fetal hypothalamic-pituitary-adrenocortical axis at midgestation by estrogen-induced changes in placental corticosteroid metabolism

    International Nuclear Information System (INIS)

    Pepe, G.J.; Waddell, B.J.; Albrecht, E.D.

    1990-01-01

    We have hypothesized that the change in placental cortisol (F)-cortisone (E) metabolism induced by estrogen late in gestation is important to activation of the baboon fetal hypothalamic-pituitary-adrenocortical axis, culminating in the ontogenesis of de novo F secretion by the fetal adrenal. The present study tested this hypothesis in vivo by comparing the proportion of F in the fetus derived via maternal and fetal production on day 100 (n = 7; term = day 184) and day 165 (n = 4) in untreated baboons and on day 100 in baboons (n = 9) in which 50-mg pellets of androstenedione were implanted sc in the mother in increasing numbers (i.e. two on day 70, four on day 78, six on day 86, and eight on day 94) to increase placental estrogen production. Maternal, uterine, and umbilical venous samples were collected during constant maternal infusion (120 min) of [3H]F/[14C]E, endogenous and radiolabeled F/E content was determined, and corticosteroid dynamics were quantified. The MCR and peripheral interconversion of F and E as well as the production rate of F were unaltered in the mother. However, at midgestation, androstenedione increased (P less than 0.05) estrogen by 62% and altered transuterofeto placental F-E metabolism from preferential reduction of E to preferential oxidation of F, a pattern similar to that at term. In untreated baboons, on day 100 none of the F in the fetus was due to fetal production, whereas by day 165, 49 +/- 6% was of fetal origin. In animals treated with androstenedione at midgestation, 22 +/- 4% of fetal F was derived de novo within the fetus. Thus, production of F by the fetus was negligible on day 100, increased near term in association with an increase in transplacental oxidation of F to E, and was induced at midgestation in baboons in which placental F-E metabolism was altered by an increase in estrogen production

  14. Contribution of the TP53 R337H mutation to the cancer burden in southern Brazil: Insights from the study of 55 families of children with adrenocortical tumors.

    Science.gov (United States)

    Mastellaro, Maria J; Seidinger, Ana L; Kang, Guolian; Abrahão, Renata; Miranda, Eliana C M; Pounds, Stanley B; Cardinalli, Izilda A; Aguiar, Simone S; Figueiredo, Bonald C; Rodriguez-Galindo, Carlos; Brandalise, Silvia R; Yunes, José A; Barros-Filho, Antônio de A; Ribeiro, Raul C

    2017-08-15

    The tumor protein p53 (TP53) arginine-to-histidine mutation at codon 337 (R337H) predisposes children to adrenocortical tumors (ACTs) and, rarely, to other childhood tumors, but its impact on adult cancer remains undetermined. The objective of this study was to investigate the frequency and types of cancer in relatives of children with ACT who carry the TP53 R337H mutation. TP53 R337H testing was offered to relatives of probands with ACT. The parental lineage segregating the R337H mutation was identified in all families. The frequency and distribution of cancer types were compared according to R337H status. The authors' data also were compared with those publicly available for children with TP53 mutations other than R337H. The mean and median follow-up times for the probands with ACT were 11.2 years and 9.7 years (range, 3-32 years), respectively. During this time, cancer was diagnosed in 12 of 81 first-degree relatives (14.8%) carrying the R337H mutation but in only 1 of 94 noncarriers (1.1%; P = .0022). At age 45 years, the cumulative risk of cancer was 21% (95% confidence interval, 5%-33%) in carriers and 2% (95% confidence interval, 0%-4%) in noncarriers (P = .008). The frequency of cancer was higher in the R337H segregating lineages than in the nonsegregating lineages (249 of 1410 vs 66 of 984 individuals; P cancer were the most common types. TP53 R337H carriers have a lifelong predisposition to cancer with a bimodal age distribution: 1 peak, represented by ACT, occurs in the first decade of life, and another peak of diverse cancer types occurs in the fifth decade. The current findings have implications for genetic counseling and surveillance of R337H carriers. Cancer 2017;123:3150-58. © 2017 American Cancer Society. © 2017 American Cancer Society.

  15. CYP2W1 is highly expressed in adrenal glands and is positively associated with the response to mitotane in adrenocortical carcinoma.

    Directory of Open Access Journals (Sweden)

    Cristina L Ronchi

    Full Text Available Adrenocortical tumors comprise frequent adenomas (ACA and rare carcinomas (ACC. Human cytochrome P450 2W1 (CYP2W1 is highly expressed in some cancers holding the potential to activate certain drugs into tumor cytotoxins.To investigate the CYP2W1 expression in adrenal samples and its relationship with clinical outcome in ACC.CYP2W1 expression was investigated by qRT-PCR in 13 normal adrenal glands, 32 ACA, 25 ACC, and 9 different non-adrenal normal tissue samples and by immunohistochemistry in 352 specimens (23 normal adrenal glands, 33 ACA, 239 ACC, 67 non-adrenal normal or neoplastic samples.CYP2W1 mRNA expression was absent/low in normal non-adrenal tissues, but high in normal and neoplastic adrenal glands (all P<0.01 vs non-adrenal normal tissues. Accordingly, CYP2W1 immunoreactivity was absent/low (H-score 0-1 in 72% of non-adrenal normal tissues, but high (H-score 2-3 in 44% of non-adrenal cancers, in 65% of normal adrenal glands, in 62% of ACAs and in 50% of ACCs (all P<0.001 vs non-adrenal normal tissues, being significantly increased in steroid-secreting compared to non-secreting tumors. In ACC patients treated with mitotane only, high CYP2W1 immunoreactivity adjusted for ENSAT stage was associated with longer overall survival and time to progression (P<0.05 and P<0.01, respectively, and with a better response to therapy both as palliative (response/stable disease in 42% vs 6%, P<0.01 or adjuvant option (absence of disease recurrence in 69% vs 45%, P<0.01.CYP2W1 is highly expressed in both normal and neoplastic adrenal glands making it a promising tool for targeted therapy in ACC. Furthermore, CYP2W1 may represent a new predictive marker for the response to mitotane treatment.

  16. INHIBITION IN SPEAKING PERFORMANCE

    OpenAIRE

    Humaera, Isna

    2015-01-01

    The most common problem encountered by the learner in the languageacquisition process is learner inhibition. Inhibition refers to a temperamentaltendency to display wariness, fearfulness, or restrain in response tounfamiliar people, objects, and situations. There are some factors that causeinhibition, such as lack of motivation, shyness, self-confidence, self-esteem,and language ego. There are also levels of inhibition, it refers to kinds ofinhibition and caused of inhibition itself. Teacher ...

  17. Treatment Option Overview (Adrenocortical Carcinoma)

    Science.gov (United States)

    ... affect the prognosis (chance of recovery) and treatment options. The prognosis (chance of recovery ) and treatment options ... or in other parts of the body. Treatment Option Overview Key Points There are different types of ...

  18. General Information about Adrenocortical Carcinoma

    Science.gov (United States)

    ... the adrenal gland is the adrenal medulla . Enlarge Anatomy of the adrenal gland. There are two adrenal ... spleen , or liver ) or to large blood vessels ( renal vein or vena cava ) and may have spread ...

  19. Inhibition of lactation.

    Science.gov (United States)

    Llewellyn-Jones, D

    1975-01-01

    The mechanism and hormonal regulation of lactation is explained and illustrated with a schematic representation. Circulating estrogen above a critical amount seems to be the inhibitory factor controlling lactation during pregnancy. Once delivery occurs, the level of estrogen falls, that of prolactin rises, and lactation begins. Nonsuckling can be used to inhibit lactation. Estrogens can also be used to inhibit lactation more quickly and with less pain. The reported association between estrogens and puerperal thromboembolism cannot be considered conclusive due to defects in the reporting studies. There is no reason not to use estrogens in lactation inhibition except for women over 35 who experienced a surgical delivery. Alternative therapy is available for these women. The recently-developed drug, brom-ergocryptine, may replace other methods of lactation inhibition.

  20. Enzyme inhibition by iminosugars

    DEFF Research Database (Denmark)

    López, Óscar; Qing, Feng-Ling; Pedersen, Christian Marcus

    2013-01-01

    Imino- and azasugar glycosidase inhibitors display pH dependant inhibition reflecting that both the inhibitor and the enzyme active site have groups that change protonation state with pH. With the enzyme having two acidic groups and the inhibitor one basic group, enzyme-inhibitor complexes...

  1. Quorum sensing inhibition

    DEFF Research Database (Denmark)

    Persson, T.; Givskov, Michael Christian; Nielsen, J.

    2005-01-01

    /receptor transcriptional regulator in some clinically relevant Gram-negative bacteria. The present review contains all reported compound types that are currently known to inhibit the QS transcriptional regulator in Gram-negative bacteria. These compounds are sub-divided into two main groups, one comprising structural...

  2. Cooperation for Better Inhibiting.

    Science.gov (United States)

    Novoa, Eva Maria; Ribas de Pouplana, Lluís

    2015-06-18

    Cladosporin is an antimalarial drug that acts as an ATP-mimetic to selectively inhibit Plasmodium lysyl-tRNA synthetase. Using multiple crystal structures, Fang et al. (2015) reveal in this issue of Chemistry & Biology the fascinating mechanism responsible for cladosporin selectivity. Copyright © 2015 Elsevier Ltd. All rights reserved.

  3. Plastics for corrosion inhibition

    CERN Document Server

    Goldade, Victor A; Makarevich, Anna V; Kestelman, Vladimir N

    2005-01-01

    The development of polymer composites containing inhibitors of metal corrosion is an important endeavour in modern materials science and technology. Corrosion inhibitors can be located in a polymer matrix in the solid, liquid or gaseous phase. This book details the thermodynamic principles for selecting these components, their compatibility and their effectiveness. The various mechanisms of metal protection – barrier, inhibiting and electromechanical – are considered, as are the conflicting requirements placed on the structure of the combined material. Two main classes of inhibited materials (structural and films/coatings) are described in detail. Examples are given of structural plastics used in friction units subjected to mechano-chemical wear and of polymer films/coatings for protecting metal objects against corrosion.

  4. Inhibiting the inevitable

    DEFF Research Database (Denmark)

    Shashoua, Yvonne

    2006-01-01

    conservation is to ‘buy time’ for the object. Inhibitive conservation of plastics involves the removal or reduction of factors causing or accelerating degradation including light, oxygen, acids, relative humidity and acidic breakdown products. Specific approaches to conservation have been developed......Once plastics objects are registered in museum collections, the institution becomes responsible for their long term preservation, until the end of their useful lifetime. Plastics appear to deteriorate faster than other materials in museum collections and have a useful lifetime between 5 and 25...... years. Preventive or inhibitive conservation involves controlling the environments in which objects are placed during storage and display, with the aim of slowing the major deterioration reactions. Once in progress, degradation of plastics cannot be stopped or reversed, so the aim of preventive...

  5. Nitrophenols isolated from diesel exhaust particles regulate steroidogenic gene expression and steroid synthesis in the human H295R adrenocortical cell line

    International Nuclear Information System (INIS)

    Furuta, Chie; Noda, Shiho; Li Chunmei; Suzuki, Akira K; Taneda, Shinji; Watanabe, Gen; Taya, Kazuyoshi

    2008-01-01

    Studies of nitrophenols isolated from diesel exhaust particles (DEPs), 3-methyl-4-nitrophenol (PNMC) and 4-nitro-3-phenylphenol (PNMPP) have revealed that these chemicals possess estrogenic and anti-androgenic activity in vitro and in vivo and that PNMC accumulate in adrenal glands in vivo. However, the impacts of exposure to these compounds on adrenal endocrine disruption and steroidogenesis have not been investigated. To elucidate the non-receptor mediated effects of PNMC and PNMPP, we investigated the production of the steroid hormones progesterone, cortisol, testosterone, and estradiol-17β and modulation of nine major enzyme genes involved in the synthesis of steroid hormones (CYP11A, CYP11B1, CYP17, CYP19, 17βHSD1, 17βHSD4, CYP21, 3βHSD2, StAR) in human adrenal H295R cells supplied with cAMP. Exposure to 10 -7 to 10 -5 M PNMC and 1 mM 8-Br-cAMP for 48 h decreased testosterone, cortisol, and estradiol-17β levels and increased progesterone secretion. At 10 -5 M, PNMC with 1 mM 8-Br-cAMP significantly stimulated expression of the 17βHSD4 and significantly suppressed expression of 3βHSD2. In comparison, 10 -7 to 2 x 10 -5 M PNMPP with 1 mM 8-Br-cAMP for 48 h decreased concentrations of estradiol-17β, increased progesterone levels, but did not affect testosterone and cortisol secretion due to the significant suppression of CYP17 and the non-significant but obvious suppression of CYP19. Our results clarified steroidogenic enzymes as candidates responsible for the inhibition or stimulation for the production of steroid hormones in the steroidogenic pathway, thus providing the first experimental evidence for multiple mechanisms of disruption of endocrine pathways by these nitrophenols

  6. Inhibition of human placental aromatase activity by hydroxylated polybrominated diphenyl ethers (OH-PBDEs).

    Science.gov (United States)

    Cantón, Rocío F; Scholten, Deborah E A; Marsh, Göran; de Jong, Paul C; van den Berg, Martin

    2008-02-15

    Polybrominated diphenyl ethers (PBDEs) are widely used as flame retardants in many different polymers, resins and substrates. Due to their widespread production and use, their high binding affinity to particles, and their lipophilic properties, several PBDE congeners can bioaccumulate in the environment. As a result, PBDEs and their hydroxylated metabolites (OH-PBDEs) have been detected in humans and various wildlife samples, such as birds, seals, and whales. Furthermore, certain OH-PBDEs and their methoxylated derivatives (MeO-PBDEs) are natural products in the marine environment. Recently, our laboratory focused on the possible effects on steroidogenesis of PBDEs and OH-PBDEs, e.g. in the human adrenocortical carcinoma (H295R) cell line indicating that some OH-PBDEs can significantly influence steroidogenic enzymes like CYP19 (aromatase) and CYP17. In the present study, human placental microsomes have been used to study the possible interaction of twenty two OH-PBDEs and MeO-PBDEs with aromatase, the enzyme that mediates the conversion of androgens into estrogens. All OH-PBDE derivates showed significant inhibition of placental aromatase activity with IC(50) values in the low micromolar range, while the MeO-PBDEs did not have any effect on this enzyme activity. Enzyme kinetics studies indicated that two OH-PBDEs, 5-hydroxy-2,2',4,4'-tetrabromodiphenyl ether (5-OH-BDE47) and 6-hydroxy-2,2',4,4'-tetrabromodiphenyl ether (6-OH-BDE47), had a mixed-type inhibition of aromatase activity with apparent K(i)/K(i)' of 7.68/0,02 microM and 5.01/0.04 microM respectively. For comparison, some structurally related compounds, a dihydroxylated polybrominated biphenyl, which is a natural product (2,2'-dihyroxy-3,3',5,5'-tetrabromobiphenyl (2,2'-diOH-BB80)) and its non-bromo derivative were also included in the study. Again inhibition of aromatase activity could be measured, but their potency was significantly less than those observed for the OH-PBDEs. These results show that a

  7. Inhibition of human placental aromatase activity by hydroxylated polybrominated diphenyl ethers (OH-PBDEs)

    International Nuclear Information System (INIS)

    Canton, Rocio F.; Scholten, Deborah E.A.; Marsh, Goeran; Jong, Paul C. de; Berg, Martin van den

    2008-01-01

    Polybrominated diphenyl ethers (PBDEs) are widely used as flame retardants in many different polymers, resins and substrates. Due to their widespread production and use, their high binding affinity to particles, and their lipophilic properties, several PBDE congeners can bioaccumulate in the environment. As a result, PBDEs and their hydroxylated metabolites (OH-PBDEs) have been detected in humans and various wildlife samples, such as birds, seals, and whales. Furthermore, certain OH-PBDEs and their methoxylated derivatives (MeO-PBDEs) are natural products in the marine environment. Recently, our laboratory focused on the possible effects on steroidogenesis of PBDEs and OH-PBDEs, e.g. in the human adrenocortical carcinoma (H295R) cell line indicating that some OH-PBDEs can significantly influence steroidogenic enzymes like CYP19 (aromatase) and CYP17. In the present study, human placental microsomes have been used to study the possible interaction of twenty two OH-PBDEs and MeO-PBDEs with aromatase, the enzyme that mediates the conversion of androgens into estrogens. All OH-PBDE derivates showed significant inhibition of placental aromatase activity with IC 50 values in the low micromolar range, while the MeO-PBDEs did not have any effect on this enzyme activity. Enzyme kinetics studies indicated that two OH-PBDEs, 5-hydroxy-2,2',4,4'-tetrabromodiphenyl ether (5-OH-BDE47) and 6-hydroxy-2,2',4,4'-tetrabromodiphenyl ether (6-OH-BDE47), had a mixed-type inhibition of aromatase activity with apparent K i /K i ' of 7.68/0,02 μM and 5.01/0.04 μM respectively. For comparison, some structurally related compounds, a dihydroxylated polybrominated biphenyl, which is a natural product (2,2'-dihyroxy-3,3',5,5'-tetrabromobiphenyl (2,2'-diOH-BB80)) and its non-bromo derivative were also included in the study. Again inhibition of aromatase activity could be measured, but their potency was significantly less than those observed for the OH-PBDEs. These results show that a wide

  8. Anxiety and retrieval inhibition: support for an enhanced inhibition account.

    Science.gov (United States)

    Nuñez, Mia; Gregory, Josh; Zinbarg, Richard E

    2017-02-01

    Retrieval inhibition of negative associations is important for exposure therapy for anxiety, but the relationship between memory inhibition and anxiety is not well understood-anxiety could either be associated with enhanced or deficient inhibition. The present study tested these two competing hypotheses by measuring retrieval inhibition of negative stimuli by related neutral stimuli. Non-clinically anxious undergraduates completed measures of trait and state anxiety and completed a retrieval induced forgetting task. Adaptive forgetting varied with state anxiety. Low levels of state anxiety were associated with no evidence for retrieval inhibition for either threatening or non-threatening categories. Participants in the middle tertile of state anxiety scores exhibited retrieval inhibition for non-threatening categories but not for threatening categories. Participants in the highest tertile of state anxiety, however, exhibited retrieval inhibition for both threatening and non-threatening categories with the magnitude of retrieval inhibition being greater for threatening than non-threatening categories. The data are in line with the avoidance aspect of the vigilance-avoidance theory of anxiety and inhibition. Implications for cognitive behavioural therapy practices are discussed.

  9. Inhibition of polyphenoloxidase by sulfite

    International Nuclear Information System (INIS)

    Sayavedra-Soto, L.A.; Montgomery, M.W.

    1986-01-01

    When polyphenoloxidase (PPO) was exposed to sulfite prior to substrate addition, inhibition was irreversible. Trials to regenerate PPO activity, using extensive dialysis, column chromatography, and addition of copper salts were not successful. Increased concentrations of sulfite and pH levels less than 5 enhanced the inhibition of PPO by sulfite. At pH 4, concentrations greater than 0.04 mg/mL completely inhibited 1000 units of PPO activity almost instantaneously. This suggested that the HSO 3 - molecule was the main component in the sulfite system inhibiting PPO. Column chromatography, extensive dialysis, and gel electrophoresis did not demonstrate 35 SO 2 bound to purified pear PPO protein. Formation of extra protein bands of sulfite inhibited purified pear PPO fractions on gel electrophoresis was demonstrated. This and other evidence suggested that the major mode of direct irreversible inhibition of PPO was modification of the protein structure, with retention of its molecular unity

  10. Modeling intentional inhibition of actions

    NARCIS (Netherlands)

    Thilakarathne, D.J.; Treur, J.

    2015-01-01

    Inspired by cognitive and neurological literature on action ownership and action awareness, in this paper a computational cognitive model for intentional inhibition (i.e.; the capacity to voluntarily suspend or inhibit an action) is introduced. The interplay between (positive) potential selection of

  11. Can Arousal Modulate Response Inhibition?

    Science.gov (United States)

    Weinbach, Noam; Kalanthroff, Eyal; Avnit, Amir; Henik, Avishai

    2015-01-01

    The goal of the present study was to examine if and how arousal can modulate response inhibition. Two competing hypotheses can be drawn from previous literature. One holds that alerting cues that elevate arousal should result in an impulsive response and therefore impair response inhibition. The other suggests that alerting enhances processing of…

  12. Assessment of the relationship between melatonin, hormones of the pituitary-ovarian, -thyroid and -adrenocortical axes, and osteoprotegerin and its ligand sRANKL in girls with anorexia nervosa

    Directory of Open Access Journals (Sweden)

    Zofia Ostrowska

    2013-05-01

    Full Text Available Background: It has been suggested that disturbances in melatonin (MEL secretion might play a role in osteoporosis development in females with anorexia nervosa (AN. It might be hypothesized that changes in the levels of hormones of the pituitary-ovarian, -thyroid and -adrenocortical axes might mediate the potential relationship between MEL and bone tissue.Aim: We investigated whether a relationship existed between MEL and LH, FSH-E2, TSH-FT3, FT4 and ACTH-cortisol axes in girls with AN. We also aimed to establish whether such a relationship might adversely affect the balance of the OPG/sRANKL system.Material/Methods: Eighty-six girls with AN and 21 healthy subjects aged 12.6 to 18.2 years participated in the study. The serum levels of hormones as well as OPG and sRANKL were determined by radioimmunoassay (RIA, immunoradiometric assay (IRMA or enzyme-linked immunosorbent assay (ELISA methods.Discussion: Our study participants with AN showed a significant reduction in body mass and body mass index (BMI, a decrease in LH, E2 and FT3 concentrations, increased MEL concentration at 02.00 hours and increased amplitude between its nocturnal and morning levels (Δ MEL2.00/9.00 as well as an increase in cortisol concentration. These changes were associated with a significant increase of OPG and sRANKL levels and a decrease in the OPG/sRANKL ratio. BMI values correlated positively with LH, FSH, E2, FT3 and the OPG/sRANKL ratio while the correlation between BMI and cortisol was negative. Δ MEL2.00/9.00 correlated positively with cortisol and negatively with LH, FSH, E2, FT3 concentrations and the OPG/sRANKL ratio. A positive correlation was observed between LH, E2 and the OPG/sRANKL ratio as well as between cortisol and sRANKL while the correlation between LH and OPG as well as between cortisol and the OPG/sRANKL ratio was negative. E2 and LH were shown to be significant and independent predictors of Δ MEL2.00/9.00. LH turned out to be a

  13. Treatment Options by Stage (Adrenocortical Carcinoma)

    Science.gov (United States)

    ... affect the prognosis (chance of recovery) and treatment options. The prognosis (chance of recovery ) and treatment options ... or in other parts of the body. Treatment Option Overview Key Points There are different types of ...

  14. Late recurrent adrenocortical carcinoma presenting radiologically as ...

    African Journals Online (AJOL)

    A. Beltagy

    2016-07-01

    Jul 1, 2016 ... malignancy with an estimated incidence of 1–2 per million peo- ple [2]. There are 3 .... scopic features of a tumour composed of solid sheets of eosinophilic cells with vesicular .... World J Surg 2001;25:891–7. [14] Hermsen GC ...

  15. Selective inhibition of distracting input.

    Science.gov (United States)

    Noonan, MaryAnn P; Crittenden, Ben M; Jensen, Ole; Stokes, Mark G

    2017-10-16

    We review a series of studies exploring distractor suppression. It is often assumed that preparatory distractor suppression is controlled via top-down mechanisms of attention akin to those that prepare brain areas for target enhancement. Here, we consider two alternative mechanisms: secondary inhibition and expectation suppression within a predictive coding framework. We draw on behavioural studies, evidence from neuroimaging and some animal studies. We conclude that there is very limited evidence for selective top-down control of preparatory inhibition. By contrast, we argue that distractor suppression often relies secondary inhibition of non-target items (relatively non-selective inhibition) and on statistical regularities of the environment, learned through direct experience. Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.

  16. [Concepts of inhibition in psychiatry].

    Science.gov (United States)

    Auroux, Y; Bourrat, M M; Brun, J P

    1978-01-01

    Following a historical approach, the authors first describe the original development of the concept of inhibition in neurophysiology and then analyze the subsequent adaptations made in psychiatry around such concept including those of: -- Pavlov, Hull, Watson and the behaviorists, -- Freud and the Freudian School, -- clinicians and psychopharmacologists. The concept of inhibition has thus various meanings in psychiatry. Although some unity is achieved on the semiological level, this aspect cannot explain the extent of the process.

  17. Inhibition of MMPs by alcohols

    Science.gov (United States)

    Tezvergil-Mutluay, Arzu; Agee, Kelli A.; Hoshika, Tomohiro; Uchiyama, Toshikazu; Tjäderhane, Leo; Breschi, Lorenzo; Mazzoni, Annalisa; Thompson, Jeremy M.; McCracken, Courtney E.; Looney, Stephen W.; Tay, Franklin R.; Pashley, David H.

    2011-01-01

    Objectives While screening the activity of potential inhibitors of matrix metalloproteinases (MMPs), due to the limited water solubility of some of the compounds, they had to be solubilized in ethanol. When ethanol solvent controls were run, they were found to partially inhibit MMPs. Thus, the purpose of this study was to compare the MMP-inhibitory activity of a series of alcohols. Methods The possible inhibitory activity of a series of alcohols was measured against soluble rhMMP-9 and insoluble matrix-bound endogenous MMPs of dentin in completely demineralized dentin. Increasing concentrations (0.17, 0.86, 1.71 and 4.28 moles/L) of a homologous series of alcohols (i.e. methanol, ethanol, propanols, butanols, pentanols, hexanols, the ethanol ester of methacrylic acid, heptanols and octanol) were compared to ethanediol, and propanediol by regression analysis to calculate the molar concentration required to inhibit MMPs by 50% (i.e. the IC50). Results Using two different MMP models, alcohols were shown to inhibit rhMMP-9 and the endogenous proteases of dentin matrix in a dose-dependent manner. The degree of MMP inhibition by alcohols increased with chain length up to 4 methylene groups. Based on the molar concentration required to inhibit rhMMP-9 fifty percent, 2-hydroxyethylmethacrylate (HEMA), 3-hexanol, 3-heptanol and 1-octanol gave the strongest inhibition. Significance The results indicate that alcohols with 4 methylene groups inhibit MMPs more effectively than methanol or ethanol. MMP inhibition was inversely related to the Hoy's solubility parameter for hydrogen bonding forces of the alcohols (i.e. to their hydrophilicity). PMID:21676453

  18. Methanol Extract of Myelophycus caespitosus Inhibits the ...

    African Journals Online (AJOL)

    Methanol Extract of Myelophycus caespitosus Inhibits the Inflammatory Response in Lipopolysaccharidestimulated BV2 Microglial Cells by Downregulating NF-kB via Inhibition of the Akt Signaling Pathway.

  19. Homo economicus belief inhibits trust.

    Directory of Open Access Journals (Sweden)

    Ziqiang Xin

    Full Text Available As a foundational concept in economics, the homo economicus assumption regards humans as rational and self-interested actors. In contrast, trust requires individuals to believe partners' benevolence and unselfishness. Thus, the homo economicus belief may inhibit trust. The present three experiments demonstrated that the direct exposure to homo economicus belief can weaken trust. And economic situations like profit calculation can also activate individuals' homo economicus belief and inhibit their trust. It seems that people's increasing homo economicus belief may serve as one cause of the worldwide decline of trust.

  20. Homo Economicus Belief Inhibits Trust

    Science.gov (United States)

    Xin, Ziqiang; Liu, Guofang

    2013-01-01

    As a foundational concept in economics, the homo economicus assumption regards humans as rational and self-interested actors. In contrast, trust requires individuals to believe partners’ benevolence and unselfishness. Thus, the homo economicus belief may inhibit trust. The present three experiments demonstrated that the direct exposure to homo economicus belief can weaken trust. And economic situations like profit calculation can also activate individuals’ homo economicus belief and inhibit their trust. It seems that people’s increasing homo economicus belief may serve as one cause of the worldwide decline of trust. PMID:24146907

  1. Inhibition of Retinoblastoma Protein Inactivation

    Science.gov (United States)

    2017-11-01

    CONTRACT NUMBER Inhibition of Retinoblastoma Protein Inactivation 5b. GRANT NUMBER W81XWH-14-1-0329 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Seth M...confirmed 108 compounds as giving a dose-response curve with at least 30% inhibition at 10 µM. The flowchart of hit progression is shown on the...Cancer Research Program under Award No. W81XWH-14-1-0329 to S.M.R. Opinions, interpretations, conclusions, and recommendations are those of the author

  2. Is forgetting caused by inhibition?

    NARCIS (Netherlands)

    Raaijmakers, J.G.W.; Jakab, E.

    2013-01-01

    A well-known finding in memory research is the forgetting effect that occurs because of practicing some Item A on the recall of a related Item B. The traditional explanation for such interference effects is based on the notion of competition. According to the inhibition theory of forgetting,

  3. Testing of Biologically Inhibiting Surface

    DEFF Research Database (Denmark)

    Bill Madsen, Thomas; Larsen, Erup

    2003-01-01

    The main purpose of this course is to examine a newly developed biologically inhibiting material with regards to galvanic corrosion and electrochemical properties. More in detail, the concern was how the material would react when exposed to cleaning agents, here under CIP cleaning (Cleaning...

  4. Resveratrol, piceatannol and analogs inhibit activation of both wild-type and T877A mutant androgen receptor.

    Science.gov (United States)

    Lundqvist, Johan; Tringali, Corrado; Oskarsson, Agneta

    2017-11-01

    Prostate cancer growth and progression are mainly dependent on androgens and many current prostate cancer treatment options target the synthesis or function of androgens. We have previously reported that resveratrol and synthetic analogs of resveratrol with a higher bioavailability inhibit the synthesis of androgens in human adrenocortical H295R cells. Now we have studied the antiandrogenic properties of resveratrol, piceatannol and analogs in two different prostate cell lines; LNCaP and RWPE. LNCaP carry a T877A mutation in the androgen receptor while RWPE has a wild-type androgen receptor. We found that resveratrol, piceatannol and all studied analogs were able to inhibit a dihydrotestosterone-induced activation of the androgen receptor, showing that they act as antiandrogens. In LNCaP cells, all studied compounds were able to statistically significantly decrease the androgenic signaling in concentrations ≥1μM and the synthetic analogs trimethylresveratrol (RSVTM) and tetramethylpiceatannol (PICTM) were the most potent compounds. RWPE cells were not as responsive to the studied compounds as the LNCaP cells. A statistically significant decrease in the androgenic signaling was observed at concentrations ≤5μM for most compounds and RSVTM was found to be the most potent compound. Further, we studied the effects of resveratrol, piceatannol and analogs on the levels of prostate-specific antigen (PSA) in LNCaP cells and found that all studied compounds decreased the level of PSA and that the synthetic analogs diacetylresveratrol (RSVDA), triacetylresveratrol (RSVTA) and RSVTM were the most potent compounds, decreasing the PSA level by approx. 50% at concentrations ≥10μM. In a cell-free receptor binding assay we were unable to show binding of resveratrol or analogs to the ligand binding domain of the androgen receptor, indicating that the observed effects are mediated via other mechanisms than direct ligand competition. We conclude that the resveratrol

  5. Inhibiting cancer cell hallmark features through nuclear export inhibition.

    Science.gov (United States)

    Sun, Qingxiang; Chen, Xueqin; Zhou, Qiao; Burstein, Ezra; Yang, Shengyong; Jia, Da

    2016-01-01

    Treating cancer through inhibition of nuclear export is one of the best examples of basic research translation into clinical application. Nuclear export factor chromosomal region maintenance 1 (CRM1; Xpo1 and exportin-1) controls cellular localization and function of numerous proteins that are critical for the development of many cancer hallmarks. The diverse actions of CRM1 are likely to explain the broad ranging anti-cancer potency of CRM1 inhibitors observed in pre-clinical studies and/or clinical trials (phase I-III) on both advanced-stage solid and hematological tumors. In this review, we compare and contrast the mechanisms of action of different CRM1 inhibitors, and discuss the potential benefit of unexplored non-covalent CRM1 inhibitors. This emerging field has uncovered that nuclear export inhibition is well poised as an attractive target towards low-toxicity broad-spectrum potent anti-cancer therapy.

  6. On inhibition of dental erosion.

    Science.gov (United States)

    Rölla, Gunnar; Jonski, Grazyna; Saxegaard, Erik

    2013-11-01

    To examine the erosion-inhibiting effect of different concentrations of hydrofluoric acid. Thirty-six human molars were individually treated with 10 ml of 0.1 M citric acid for 30 min (Etch 1), acid was collected and stored until analysis. The teeth were randomly divided into six groups and then individually treated with 10 ml of one of six dilutions (from 0.1-1%) of hydrofluoric acid. The teeth were then again treated with citric acid (Etch 2). The individual acid samples from Etch 1 and 2 were analyzed for calcium by flame atomic absorption spectroscopy and difference in calcium loss was calculated. The highest erosion inhibiting effect was obtained in groups with the highest concentrations of hydrofluoric acid, where the pH was lowest, below pKa of 3.17, thus the hydrofluoric acids being mainly in an undissociated state. Diluted hydrofluoric acid is present in aqueous solution of SnF2 and TiF4 (which are known to inhibit dental erosion): SnF2 + 3H2O = Sn(OH)2 + 2HF + H2O and TiF4 + 5H2O = Ti(OH)4 + 4HF + H2O. It is also known that pure, diluted hydrofluoric acid can inhibit dental erosion. Teeth treated with hydrofluoric acid are covered by a layer of CaF2-like mineral. This mineral is acid resistant at pH acid resistant mineral, initiated by tooth enamel treatment with hydrofluoric acid. Hydrofluoric acid is different in having fluoride as a conjugated base, which provides this acid with unique properties.

  7. Entanglement and inhibited quantum evolution

    International Nuclear Information System (INIS)

    Toschek, P E; Balzer, Chr; Hannemann, Th; Wunderlich, Ch; Neuhauser, W

    2003-01-01

    The evolution of a quantum system is impeded by the system's state being observed. A test on an ensemble neither proves the causal nexus nor discloses the nature of the inhibition. Two recent experiments that make use of sequential optical or microwave-optical double resonance on an individual trapped ion disprove a dynamical effect of back action by meter or environment. They rather indicate the ionic states involved in the evolution being entangled with the potentially recorded bivalued scattered-light signal

  8. Inhibition Performance in Children with Math Disabilities

    OpenAIRE

    Winegar, Kathryn Lileth

    2013-01-01

    This study examined the inhibition deficit hypothesis in children with math disabilities (MD). Children with and without MD were compared on two inhibition tasks that included the random generation of numbers and letters. The results addressed three hypotheses. Weak support was found for the first hypothesis which stated difficulties related to inhibition are significantly related to math performance. I found partial support for this hypothesis in that inhibition was related to math problem s...

  9. Entanglement and inhibited quantum evolution

    Energy Technology Data Exchange (ETDEWEB)

    Toschek, P E; Balzer, Chr; Hannemann, Th; Wunderlich, Ch; Neuhauser, W [Universitaet Hamburg, Institut fuer Laser-Physik, Jungiusstrasse 9, D-20355 Hamburg (Germany)

    2003-03-14

    The evolution of a quantum system is impeded by the system's state being observed. A test on an ensemble neither proves the causal nexus nor discloses the nature of the inhibition. Two recent experiments that make use of sequential optical or microwave-optical double resonance on an individual trapped ion disprove a dynamical effect of back action by meter or environment. They rather indicate the ionic states involved in the evolution being entangled with the potentially recorded bivalued scattered-light signal.

  10. Behavioral inhibition and obsessive-compulsive disorder.

    Science.gov (United States)

    Coles, Meredith E; Schofield, Casey A; Pietrefesa, Ashley S

    2006-01-01

    Behavioral inhibition is frequently cited as a vulnerability factor for development of anxiety. However, few studies have examined the unique relationship between behavioral inhibition and obsessive-compulsive disorder (OCD). Therefore, the current study addressed the relationship between behavioral inhibition and OCD in a number of ways. In a large unselected student sample, frequency of current OC symptoms was significantly correlated with retrospective self-reports of total levels of childhood behavioral inhibition. In addition, frequency of current OC symptoms was also significantly correlated with both social and nonsocial components of behavioral inhibition. Further, there was evidence for a unique relationship between behavioral inhibition and OC symptoms beyond the relationship of behavioral inhibition and social anxiety. In addition, results showed that reports of childhood levels of behavioral inhibition significantly predicted levels of OCD symptoms in adulthood. Finally, preliminary evidence suggested that behavioral inhibition may be more strongly associated with some types of OC symptoms than others, and that overprotective parenting may moderate the impact of behavioral inhibition on OC symptoms. The current findings suggest the utility of additional research examining the role of behavioral inhibition in the etiology of OCD.

  11. Self-regulation, ego depletion, and inhibition.

    Science.gov (United States)

    Baumeister, Roy F

    2014-12-01

    Inhibition is a major form of self-regulation. As such, it depends on self-awareness and comparing oneself to standards and is also susceptible to fluctuations in willpower resources. Ego depletion is the state of reduced willpower caused by prior exertion of self-control. Ego depletion undermines inhibition both because restraints are weaker and because urges are felt more intensely than usual. Conscious inhibition of desires is a pervasive feature of everyday life and may be a requirement of life in civilized, cultural society, and in that sense it goes to the evolved core of human nature. Intentional inhibition not only restrains antisocial impulses but can also facilitate optimal performance, such as during test taking. Self-regulation and ego depletion- may also affect less intentional forms of inhibition, even chronic tendencies to inhibit. Broadly stated, inhibition is necessary for human social life and nearly all societies encourage and enforce it. Copyright © 2014 Elsevier Ltd. All rights reserved.

  12. Graphene: corrosion-inhibiting coating.

    Science.gov (United States)

    Prasai, Dhiraj; Tuberquia, Juan Carlos; Harl, Robert R; Jennings, G Kane; Rogers, Bridget R; Bolotin, Kirill I

    2012-02-28

    We report the use of atomically thin layers of graphene as a protective coating that inhibits corrosion of underlying metals. Here, we employ electrochemical methods to study the corrosion inhibition of copper and nickel by either growing graphene on these metals, or by mechanically transferring multilayer graphene onto them. Cyclic voltammetry measurements reveal that the graphene coating effectively suppresses metal oxidation and oxygen reduction. Electrochemical impedance spectroscopy measurements suggest that while graphene itself is not damaged, the metal under it is corroded at cracks in the graphene film. Finally, we use Tafel analysis to quantify the corrosion rates of samples with and without graphene coatings. These results indicate that copper films coated with graphene grown via chemical vapor deposition are corroded 7 times slower in an aerated Na(2)SO(4) solution as compared to the corrosion rate of bare copper. Tafel analysis reveals that nickel with a multilayer graphene film grown on it corrodes 20 times slower while nickel surfaces coated with four layers of mechanically transferred graphene corrode 4 times slower than bare nickel. These findings establish graphene as the thinnest known corrosion-protecting coating.

  13. Action inhibition in Tourette syndrome.

    Science.gov (United States)

    Ganos, Christos; Kühn, Simone; Kahl, Ursula; Schunke, Odette; Feldheim, Jan; Gerloff, Christian; Roessner, Veit; Bäumer, Tobias; Thomalla, Götz; Haggard, Patrick; Münchau, Alexander

    2014-10-01

    Tourette syndrome is a neuropsychiatric disorder characterized by tics. Tic generation is often linked to dysfunction of inhibitory brain networks. Some previous behavioral studies found deficiencies in inhibitory motor control in Tourette syndrome, but others suggested normal or even better-than-normal performance. Furthermore, neural correlates of action inhibition in these patients are poorly understood. We performed event-related functional magnetic resonance imaging during a stop-signal reaction-time task in 14 uncomplicated adult Tourette patients and 15 healthy controls. In patients, we correlated activations in stop-signal reaction-time task with their individual motor tic frequency. Task performance was similar in both groups. Activation of dorsal premotor cortex was stronger in the StopSuccess than in the Go condition in healthy controls. This pattern was reversed in Tourette patients. A significant positive correlation was present between motor tic frequency and activations in the supplementary motor area during StopSuccess versus Go in patients. Inhibitory brain networks differ between healthy controls and Tourette patients. In the latter the supplementary motor area is probably a key relay of inhibitory processes mediating both suppression of tics and inhibition of voluntary action. © 2014 International Parkinson and Movement Disorder Society.

  14. STIR: Assessing and Training Response Inhibition Abilities

    Science.gov (United States)

    2014-07-30

    Learning to stop responding to alcohol cues reduces alcohol intake via reduced affective associations rather than increased response inhibition. Addiction ...requires an abstract application of the core learning principle1,2, and viable examples are often hard to find and/or assess. If exposure to non...inhibition training that expands upon previous successful “near transfer” response inhibition training efforts—such as treating alcohol addictions by

  15. Inhibition of cortiocosteroidogenesis by delta-9-tetrahydrocannabinol.

    Science.gov (United States)

    Warner, W; Harris, L S; Carchman, R A

    1977-12-01

    ACTH, cholera toxin, cyclic AMP but not pregnenolone-induced steroidogenesis in Y-1 functional mouse adrenal tumor cells was significantly inhibited by delta-9-tetrahydrocannabinol, cannabidiol, and cannabinol. The inhibition of steroidogenesis could not be correlated with a general depression in cell function or viability. The data suggest that cannabinoids inhibit corticosteroidogenesis at a site between the synthesis of cAMP and of pregnenolone.

  16. Inhibition of apparent photosynthesis by nitrogen oxides

    Energy Technology Data Exchange (ETDEWEB)

    Hill, A C; Bennett, J H

    1970-01-01

    The nitrogen oxides (NO/sub 2/ and NO) inhibited apparent photosynthesis of oats and alfalfa at concentrations below those required to cause visible injury. There appeared to be a threshold concentration of about 0.6 ppm for each pollutant. An additive effect in depressing apparent photosynthesis occurred when the plants were exposed to a mixture of NO and NO/sub 2/. Although NO produced a more rapid effect on the plants, lower concentrations of NO/sub 2/ were required to cause a given inhibition after 2 hour of exposure. Inhibition by nitric oxide was more closely related to its partial pressure than was inhibition by NO/sub 2/.

  17. Inhibition of photosynthesis by carbon monoxide and suspension of the carbon monoxide inhibition by light

    Energy Technology Data Exchange (ETDEWEB)

    Gewitz, H S; Voelker, W

    1963-08-01

    The experimental subject was the autotroph Chlorella pyrenoidosa. It was found that growth conditions determine whether the alga is inhibited by carbon monoxide or not. Respiration and photosynthesis are inhibited by carbon monoxide if the cells have grown rapidly under high light intensities. The inhibition of respiration and photosynthesis found in such cells is completely reversible. The inhibition depends not only on carbon monoxide pressure, but also on the oxygen pressure prevailing at the same time. 5 references, 1 figure, 3 tables.

  18. 7-Piperazinethylchrysin inhibits melanoma cell proliferation by ...

    African Journals Online (AJOL)

    In B16F10 and A375 cells, treatment with PEC caused the inhibition ... Conclusion: PEC inhibited melanoma cell proliferation, apparently by blocking the cell cycle at G0/G1 .... all statistical analyses. .... Financial support from the Department of.

  19. A Qualitative Approach to Enzyme Inhibition

    Science.gov (United States)

    Waldrop, Grover L.

    2009-01-01

    Most general biochemistry textbooks present enzyme inhibition by showing how the basic Michaelis-Menten parameters K[subscript m] and V[subscript max] are affected mathematically by a particular type of inhibitor. This approach, while mathematically rigorous, does not lend itself to understanding how inhibition patterns are used to determine the…

  20. Inhibition: Mental Control Process or Mental Resource?

    Science.gov (United States)

    Im-Bolter, Nancie; Johnson, Janice; Ling, Daphne; Pascual-Leone, Juan

    2015-01-01

    The current study tested 2 models of inhibition in 45 children with language impairment and 45 children with normally developing language; children were aged 7 to 12 years. Of interest was whether a model of inhibition as a mental-control process (i.e., executive function) or as a mental resource would more accurately reflect the relations among…

  1. The pharmacology of visuospatial attention and inhibition

    NARCIS (Netherlands)

    Logemann, H.N.A.

    2013-01-01

    Attention and inhibition are of vital importance in everyday functioning. Problems of attention and inhibition are central to disorders such as Attention Deficit/Hyperactivity Disorder (ADHD). Both bias and disengagement key components of visuospatial attention. Bias refers to neuronal signals that

  2. Inhibition of ethylene production by cobaltous ion

    International Nuclear Information System (INIS)

    Lau, O.L; Yang, S.F.

    1976-01-01

    The effect of Co 2+ on ethylene production by mung bean (Phaseolus aureus Roxb.) and by apple tissues was studied. Co 2+ , depending on concentrations applied, effectively inhibited ethylene production by both tissues. It also strongly inhibited the ethylene production induced by IAA, kinetin, IAA plus kinetin, Ca 2+ , kinetin plus Ca 2+ , or Cu 2+ treatments in mung bean hypocotyl segments. While Co 2+ greatly inhibited ethylene production, it had little effect on the respiration of apple tissue, indicating that Co 2+ does not exert its inhibitory effect as a general metabolic inhibitor. Ni 2+ , which belongs to the same group as Co 2+ in the periodic table, also markedly curtailed both the basal and the induced ethylene production by apple and mung bean hypocotyl tissues. In a system in which kinetin and Ca 2+ were applied together, kinetin greatly enhanced Ca 2+ uptake, thus enhancing ethylene production. Co 2+ , however, slightly inhibited the uptake of Ca 2+ but appreciably inhibited ethylene production, either in the presence or in the absence of kinetin. Tracer experiments using apple tissue indicated that Co 2+ strongly inhibited the in vivo conversion of L-[U-- 14 C]methionine to 14 C-ethylene. These data suggested that Co 2+ inhibited ethylene production by inhibiting the conversion of methionine to ethylene, a common step which is required for ethylene formation by higher plants. Co 2+ is known to promote elongation, leaf expansion, and hook opening in excised plant parts in response to applied auxins or cytokinins.Since ethylene is known to inhibit those growth phenomena, it is suggested that Co 2+ exerts its promotive effect, at least in part, by inhibiting ethylene formation

  3. Lysophospholipase inhibition by organophosphorus toxicants

    International Nuclear Information System (INIS)

    Quistad, Gary B.; Casida, John E.

    2004-01-01

    Lysophospholipases (LysoPLAs) are a large family of enzymes for removing lysophospholipids from cell membranes. Potent inhibitors are needed to define the importance of LysoPLAs as targets for toxicants and potential therapeutics. This study considers organophosphorus (OP) inhibitors with emphasis on mouse brain total LysoPLA activity relative to the mipafox-sensitive neuropathy target esterase (NTE)-LysoPLA recently established as 17% of the total activity and important in the action of OP delayed toxicants. The most potent inhibitors of total LysoPLA in mouse brain are isopropyl dodecylphosphonofluoridate (also for LysoPLA of Vibrio bacteria), ethyl octylphosphonofluoridate (EOPF), and two alkyl-benzodioxaphosphorin 2-oxides (BDPOs)[(S)-octyl and dodecyl] (IC50 2-8 nM). OP inhibitors acting in vitro and in vivo differentiate a more sensitive portion but not a distinct NTE-LysoPLA compared with total LysoPLA activity. For 10 active inhibitors, NTE-LysoPLA is 17-fold more sensitive than total LysoPLA, but structure-activity comparisons give a good correlation (r 2 = 0.94) of IC50 values, suggesting active site structural similarity or identity. In mice 4 h after intraperitoneal treatment with discriminating doses, EOPF, tribufos (a plant defoliant), and dodecanesulfonyl fluoride inhibit 41-57% of the total brain LysoPLA and 85-99% of the NTE-LysoPLA activity. Total LysoPLA as well as NTE-LysoPLA is decreased in activity in Nte +/- -haploinsufficient mice compared to their Nte +/+ littermates. The lysolecithin level of spinal cord but not brain is elevated significantly following EOPF treatment (3 mg/kg), thereby focusing attention on localized rather than general alterations in lysophospholipid metabolism in OP-induced hyperactivity and toxicity

  4. Regulation of spatial selectivity by crossover inhibition.

    Science.gov (United States)

    Cafaro, Jon; Rieke, Fred

    2013-04-10

    Signals throughout the nervous system diverge into parallel excitatory and inhibitory pathways that later converge on downstream neurons to control their spike output. Converging excitatory and inhibitory synaptic inputs can exhibit a variety of temporal relationships. A common motif is feedforward inhibition, in which an increase (decrease) in excitatory input precedes a corresponding increase (decrease) in inhibitory input. The delay of inhibitory input relative to excitatory input originates from an extra synapse in the circuit shaping inhibitory input. Another common motif is push-pull or "crossover" inhibition, in which increases (decreases) in excitatory input occur together with decreases (increases) in inhibitory input. Primate On midget ganglion cells receive primarily feedforward inhibition and On parasol cells receive primarily crossover inhibition; this difference provides an opportunity to study how each motif shapes the light responses of cell types that play a key role in visual perception. For full-field stimuli, feedforward inhibition abbreviated and attenuated responses of On midget cells, while crossover inhibition, though plentiful, had surprisingly little impact on the responses of On parasol cells. Spatially structured stimuli, however, could cause excitatory and inhibitory inputs to On parasol cells to increase together, adopting a temporal relation very much like that for feedforward inhibition. In this case, inhibitory inputs substantially abbreviated a cell's spike output. Thus inhibitory input shapes the temporal stimulus selectivity of both midget and parasol ganglion cells, but its impact on responses of parasol cells depends strongly on the spatial structure of the light inputs.

  5. Fear inhibition in high trait anxiety.

    Directory of Open Access Journals (Sweden)

    Merel Kindt

    Full Text Available Trait anxiety is recognized as an individual risk factor for the development of anxiety disorders but the neurobiological mechanisms remain unknown. Here we test whether trait anxiety is associated with impaired fear inhibition utilizing the AX+/BX- conditional discrimination procedure that allows for the independent evaluation of startle fear potentiation and inhibition of fear. Sixty undergraduate students participated in the study--High Trait Anxious: n = 28 and Low Trait Anxious: n = 32. We replicated earlier findings that a transfer of conditioned inhibition for startle responses requires contingency awareness. However, contrary to the fear inhibition hypothesis, our data suggest that high trait anxious individuals show a normal fear inhibition of conditioned startle responding. Only at the cognitive level the high trait anxious individuals showed evidence for impaired inhibitory learning of the threat cue. Together with other findings where impaired fear inhibition was only observed in those PTSD patients who were either high on hyperarousal symptoms or with current anxiety symptoms, we question whether impaired fear inhibition is a biomarker for the development of anxiety disorders.

  6. Should we stop thinking about inhibition? Searching for individual and age differences in inhibition ability.

    Science.gov (United States)

    Rey-Mermet, Alodie; Gade, Miriam; Oberauer, Klaus

    2018-04-01

    Inhibition is often conceptualized as a unitary construct reflecting the ability to ignore and suppress irrelevant information. At the same time, it has been subdivided into inhibition of prepotent responses (i.e., the ability to stop dominant responses) and resistance to distracter interference (i.e., the ability to ignore distracting information). The present study investigated the unity and diversity of inhibition as a psychometric construct, and tested the hypothesis of an inhibition deficit in older age. We measured inhibition in young and old adults with 11 established laboratory tasks: antisaccade, stop-signal, color Stroop, number Stroop, arrow flanker, letter flanker, Simon, global-local, positive and negative compatibility tasks, and n-2 repetition costs in task switching. In both age groups, the inhibition measures from individual tasks had good reliabilities, but correlated only weakly among each other. Structural equation modeling identified a 2-factor model with factors for inhibition of prepotent responses and resistance to distracter interference. Older adults scored worse in the inhibition of prepotent response, but better in the resistance to distracter interference. However, the model had low explanatory power. Together, these findings call into question inhibition as a psychometric construct and the hypothesis of an inhibition deficit in older age. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

  7. Inhibition of urinary calculi -- a spectroscopic study

    Science.gov (United States)

    Manciu, Felicia; Govani, Jayesh; Durrer, William; Reza, Layra; Pinales, Luis

    2008-10-01

    Although a considerable number of investigations have already been undertaken and many causes such as life habits, metabolic disorders, and genetic factors have been noted as sources that accelerate calculi depositions and aggregations, there are still plenty of unanswered questions regarding efficient inhibition and treatment mechanisms. Thus, in an attempt to acquire more insights, we propose here a detailed scientific study of kidney stone formation and growth inhibition based on a traditional medicine approach with Rotula Aquatica Lour (RAL) herbal extracts. A simplified single diffusion gel growth technique was used for synthesizing the samples for the present study. The unexpected Zn presence in the sample with RAL inhibitor, as revealed by XPS measurements, explains the inhibition process and the dramatic reflectance of the incident light observed in the infrared transmission studies. Raman data demonstrate potential binding of the inhibitor with the oxygen of the kidney stone. Photoluminescence results corroborate to provide additional evidence of Zn-related inhibition.

  8. Exogenously triggered response inhibition in developmental stuttering.

    Science.gov (United States)

    Eggers, Kurt; De Nil, Luc F; Van den Bergh, Bea R H

    2018-06-01

    The purpose of the present study was to examine relations between children's exogenously triggered response inhibition and stuttering. Participants were 18 children who stutter (CWS; mean age = 9;01 years) and 18 children who not stutter (CWNS; mean age = 9;01 years). Participants were matched on age (±3 months) and gender. Response inhibition was assessed by a stop signal task (Verbruggen, Logan, & Stevens, 2008). Results suggest that CWS, compared to CWNS, perform comparable to CWNS in a task where response control is externally triggered. Our findings seem to indicate that previous questionnaire-based findings (Eggers, De Nil, & Van den Bergh, 2010) of a decreased efficiency of response inhibition cannot be generalized to all types of response inhibition. Copyright © 2018 Elsevier Inc. All rights reserved.

  9. Hypnotic suggestibility, cognitive inhibition, and dissociation.

    Science.gov (United States)

    Dienes, Zoltán; Brown, Elizabeth; Hutton, Sam; Kirsch, Irving; Mazzoni, Giuliana; Wright, Daniel B

    2009-12-01

    We examined two potential correlates of hypnotic suggestibility: dissociation and cognitive inhibition. Dissociation is the foundation of two of the major theories of hypnosis and other theories commonly postulate that hypnotic responding is a result of attentional abilities (including inhibition). Participants were administered the Waterloo-Stanford Group Scale of Hypnotic Susceptibility, Form C. Under the guise of an unrelated study, 180 of these participants also completed: a version of the Dissociative Experiences Scale that is normally distributed in non-clinical populations; a latent inhibition task, a spatial negative priming task, and a memory task designed to measure negative priming. The data ruled out even moderate correlations between hypnotic suggestibility and all the measures of dissociation and cognitive inhibition overall, though they also indicated gender differences. The results are a challenge for existing theories of hypnosis.

  10. Corrosion inhibition by lithium zinc phosphate pigment

    International Nuclear Information System (INIS)

    Alibakhshi, E.; Ghasemi, E.; Mahdavian, M.

    2013-01-01

    Highlights: •Synthesis of lithium zinc phosphate (LZP) by chemical co-precipitation method. •Corrosion inhibition activity of pigments compare with zinc phosphate (ZP). •LZP showed superior corrosion inhibition effect in EIS measurements. •Evaluation of adhesion strength and dispersion stability. -- Abstract: Lithium zinc phosphate (LZP) has been synthesized through a co-precipitation process and characterized by XRD and IR spectroscopy. The inhibitive performances of this pigment for corrosion of mild steel have been discussed in comparison with the zinc phosphate (ZP) in the pigment extract solution by means of EIS and in the epoxy coating by means of salt spray. The EIS and salt spray results revealed the superior corrosion inhibitive effect of LZP compared to ZP. Moreover, adhesion strength and dispersion stability of the pigmented epoxy coating showed the advantage of LZP compared to ZP

  11. Human milk glycoconjugates that inhibit pathogens.

    Science.gov (United States)

    Newburg, D S

    1999-02-01

    Breast-fed infants have lower incidence of diarrhea, respiratory disease, and otitis media. The protection by human milk has long been attributed to the presence of secretory IgA. However, human milk contains large numbers and amounts of complex carbohydrates, including glycoproteins, glycolipids, glycosaminoglycans, mucins, and especially oligosaccharides. The oligosaccharides comprise the third most abundant solid constituent of human milk, and contain a myriad of structures. Complex carbohydrate moieties of glycoconjugates and oligosaccharides are synthesized by the many glycosyltransferases in the mammary gland; those with homology to cell surface glycoconjugate pathogen receptors may inhibit pathogen binding, thereby protecting the nursing infant. Several examples are reviewed: A fucosyloligosaccharide inhibits the diarrheagenic effect of stable toxin of Escherichia coli. A different fucosyloligosaccharide inhibits infection by Campylobacter jejuni. Binding of Streptococcus pneumoniae and of enteropathogenic E. coli to their respective receptors is inhibited by human milk oligosaccharides. The 46-kD glycoprotein, lactadherin, inhibits rotavirus binding and infectivity. Low levels of lactadherin in human milk are associated with a higher incidence of symptomatic rotavirus in breast-fed infants. A mannosylated glycopeptide inhibits binding by enterohemorrhagic E. coli. A glycosaminoglycan inhibits binding of gp120 to CD4, the first step in HIV infection. Human milk mucin inhibits binding by S-fimbriated E. coli. The ganglioside, GM1, reduces diarrhea production by cholera toxin and labile toxin of E. coli. The neutral glycosphingolipid, Gb3, binds to Shigatoxin. Thus, many complex carbohydrates of human milk may be novel antipathogenic agents, and the milk glycoconjugates and oligosaccharides may be a major source of protection for breastfeeding infants.

  12. Inhibition in the Human Auditory Cortex.

    Directory of Open Access Journals (Sweden)

    Koji Inui

    Full Text Available Despite their indispensable roles in sensory processing, little is known about inhibitory interneurons in humans. Inhibitory postsynaptic potentials cannot be recorded non-invasively, at least in a pure form, in humans. We herein sought to clarify whether prepulse inhibition (PPI in the auditory cortex reflected inhibition via interneurons using magnetoencephalography. An abrupt increase in sound pressure by 10 dB in a continuous sound was used to evoke the test response, and PPI was observed by inserting a weak (5 dB increase for 1 ms prepulse. The time course of the inhibition evaluated by prepulses presented at 10-800 ms before the test stimulus showed at least two temporally distinct inhibitions peaking at approximately 20-60 and 600 ms that presumably reflected IPSPs by fast spiking, parvalbumin-positive cells and somatostatin-positive, Martinotti cells, respectively. In another experiment, we confirmed that the degree of the inhibition depended on the strength of the prepulse, but not on the amplitude of the prepulse-evoked cortical response, indicating that the prepulse-evoked excitatory response and prepulse-evoked inhibition reflected activation in two different pathways. Although many diseases such as schizophrenia may involve deficits in the inhibitory system, we do not have appropriate methods to evaluate them; therefore, the easy and non-invasive method described herein may be clinically useful.

  13. Characterization of acetylcholinesterase-inhibition by itopride.

    Science.gov (United States)

    Iwanaga, Y; Kimura, T; Miyashita, N; Morikawa, K; Nagata, O; Itoh, Z; Kondo, Y

    1994-11-01

    Itopride is a gastroprokinetic benzamide derivative. This agent inhibited both electric eel acetylcholinesterase (AChE) and horse serum butyrylcholinesterase (BuChE). The IC50 of itopride with AChE (2.04 +/- 0.27 microM) was, however, 100-fold less than that with BuChE, whereas in the case of neostigmine with AChE (11.3 +/- 3.4 nM), it was 10-fold less. The recovery of AChE activity inhibited by 10(-7) M neostigmine was partial, but that inhibited by up to 3 x 10(-5) M itopride was complete when the reaction mixture was subjected to ultrafiltration. Double reciprocal plots of the experimental data showed that both Km and Vmax were affected by itopride, suggesting that the inhibition is a "mixed" type, although primarily being an uncompetitive one. The inhibitory effect of itopride on cholinesterase (ChE) activity in guinea pig gastrointestine was much weaker than that on pure AChE. However, in the presence of a low dose of diisopropyl fluorophosphate, just enough to inhibit BuChE but not AChE, the IC50s of itopride against ChE activities were found to be about 0.5 microM. In conclusion, itopride exerts reversible and a "mixed" type of inhibition preferably against AChE. The IC50 of itopride for electric eel and guinea pig gastrointestinal AChE inhibition was 200 times and 50 times as large as that of neostigmine, respectively.

  14. Aspartate inhibits Staphylococcus aureus biofilm formation.

    Science.gov (United States)

    Yang, Hang; Wang, Mengyue; Yu, Junping; Wei, Hongping

    2015-04-01

    Biofilm formation renders Staphylococcus aureus highly resistant to conventional antibiotics and host defenses. Four D-amino acids (D-Leu, D-Met, D-Trp and D-Tyr) have been reported to be able to inhibit biofilm formation and disassemble established S. aureus biofilms. We report here for the first time that both D- and L-isoforms of aspartate (Asp) inhibited S. aureus biofilm formation on tissue culture plates. Similar biofilm inhibition effects were also observed against other staphylococcal strains, including S. saprophyticus, S. equorum, S. chromogenes and S. haemolyticus. It was found that Asp at high concentrations (>10 mM) inhibited the growth of planktonic N315 cells, but at subinhibitory concentrations decreased the cellular metabolic activity without influencing cell growth. The decreased cellular metabolic activity might be the reason for the production of less protein and DNA in the matrix of the biofilms formed in the presence of Asp. However, varied inhibition efficacies of Asp were observed for biofilms formed by clinical staphylococcal isolates. There might be mechanisms other than decreasing the metabolic activity, e.g. the biofilm phenotypes, affecting biofilm formation in the presence of Asp. © FEMS 2015. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  15. Simvastatin inhibits Candida albicans biofilm in vitro.

    Science.gov (United States)

    Liu, Geoffrey; Vellucci, Vincent F; Kyc, Stephanie; Hostetter, Margaret K

    2009-12-01

    By inhibiting the conversion of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) to mevalonate, statins impair cholesterol metabolism in humans. We reasoned that statins might similarly interfere with the biosynthesis of ergosterol, the major sterol of the yeast cell membrane. As assessed by spectrophotometric and microscopic analysis, significant inhibition of biofilm production was noted after 16-h incubation with 1, 2.5, and 5 muM simvastatin, concentrations that did not affect growth, adhesion, or hyphal formation by C. albicans in vitro. Higher concentrations (10, 20, and 25 muM simvastatin) inhibited biofilm by >90% but also impaired growth. Addition of exogenous ergosterol (90 muM) overcame the effects of 1 and 2.5 muM simvastatin, suggesting that at least one mechanism of inhibition is interference with ergosterol biosynthesis. Clinical isolates from blood, skin, and mucosal surfaces produced biofilms; biofilms from bloodstream isolates were similarly inhibited by simvastatin. In the absence of fungicidal activity, simvastatin's interruption of a critical step in an essential metabolic pathway, highly conserved from yeast to man, has unexpected effects on biofilm production by a eukaryotic pathogen.

  16. Terbinafine inhibits gap junctional intercellular communication

    International Nuclear Information System (INIS)

    Lee, Ju Yeun; Yoon, Sei Mee; Choi, Eun Ju; Lee, Jinu

    2016-01-01

    Terbinafine is an antifungal agent that selectively inhibits fungal sterol synthesis by blocking squalene epoxidase. We evaluated the effect of terbinafine on gap junctional intercellular communication (GJIC). Fluorescence recovery after photobleaching (FRAP) and I-YFP GJIC assays revealed that terbinafine inhibits GJIC in a reversible and dose-dependent manner in FRT-Cx43 and LN215 cells. Treatment with terbinafine did not affect Cx43 phosphorylation status or intracellular Ca 2+ concentration, well-known action mechanisms of various GJIC blockers. While a structurally related chemical, naftifine, attenuated GJIC, epigallocatechin gallate, another potent squalene epoxidase inhibitor with a different structure, did not. These results suggest that terbinafine inhibits GJIC with a so far unknown mechanism of action. - Highlights: • In vitro pharmacological studies were performed on FRT-Cx43 and LN215 cells. • Terbinafine inhibits gap junctional intercellular communication in both cell lines. • The inhibitory effect of terbinafine is reversible and dose-dependent. • Treatment of terbinafine does not alter Cx43 phosphorylation or cytosolic Ca 2+ concentration. • Inhibition of squalene epoxidase is not involved in this new effect of terbinafine.

  17. Terbinafine inhibits gap junctional intercellular communication

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Ju Yeun, E-mail: whitewndus@naver.com [College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon 21983 (Korea, Republic of); Yoon, Sei Mee, E-mail: sei_mee@naver.com [College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon 21983 (Korea, Republic of); Department of Integrated OMICS for Biomedical Sciences, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-749 (Korea, Republic of); Choi, Eun Ju, E-mail: yureas@naver.com [College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon 21983 (Korea, Republic of); Lee, Jinu, E-mail: jinulee@yonsei.ac.kr [College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon 21983 (Korea, Republic of)

    2016-09-15

    Terbinafine is an antifungal agent that selectively inhibits fungal sterol synthesis by blocking squalene epoxidase. We evaluated the effect of terbinafine on gap junctional intercellular communication (GJIC). Fluorescence recovery after photobleaching (FRAP) and I-YFP GJIC assays revealed that terbinafine inhibits GJIC in a reversible and dose-dependent manner in FRT-Cx43 and LN215 cells. Treatment with terbinafine did not affect Cx43 phosphorylation status or intracellular Ca{sup 2+} concentration, well-known action mechanisms of various GJIC blockers. While a structurally related chemical, naftifine, attenuated GJIC, epigallocatechin gallate, another potent squalene epoxidase inhibitor with a different structure, did not. These results suggest that terbinafine inhibits GJIC with a so far unknown mechanism of action. - Highlights: • In vitro pharmacological studies were performed on FRT-Cx43 and LN215 cells. • Terbinafine inhibits gap junctional intercellular communication in both cell lines. • The inhibitory effect of terbinafine is reversible and dose-dependent. • Treatment of terbinafine does not alter Cx43 phosphorylation or cytosolic Ca{sup 2+} concentration. • Inhibition of squalene epoxidase is not involved in this new effect of terbinafine.

  18. Inhibition of ethylene production by putrescine alleviates aluminium-induced root inhibition in wheat plants.

    Science.gov (United States)

    Yu, Yan; Jin, Chongwei; Sun, Chengliang; Wang, Jinghong; Ye, Yiquan; Zhou, Weiwei; Lu, Lingli; Lin, Xianyong

    2016-01-08

    Inhibition of root elongation is one of the most distinct symptoms of aluminium (Al) toxicity. Although putrescine (Put) has been identified as an important signaling molecule involved in Al tolerance, it is yet unknown how Put mitigates Al-induced root inhibition. Here, the possible mechanism was investigated by using two wheat genotypes differing in Al resistance: Al-tolerant Xi Aimai-1 and Al-sensitive Yangmai-5. Aluminium caused more root inhibition in Yangmai-5 and increased ethylene production at the root apices compared to Xi Aimai-1, whereas the effects were significantly reversed by ethylene biosynthesis inhibitors. The simultaneous exposure of wheat seedlings to Al and ethylene donor, ethephon, or ethylene biosynthesis precursor, 1-aminocyclopropane-1-carboxylic acid (ACC), increased ethylene production and aggravated root inhibition, which was more pronounced in Xi Aimai-1. In contrast, Put treatment decreased ethylene production and alleviated Al-induced root inhibition in both genotypes, and the effects were more conspicuous in Yangmai-5. Furthermore, our results indicated that Al-induced ethylene production was mediated by ACC synthase (ACS) and ACC oxidase, and that Put decreased ethylene production by inhibiting ACS. Altogether, these findings indicate that ethylene is involved in Al-induced root inhibition and this process could be alleviated by Put through inhibiting ACS activity.

  19. Silver-Palladium Surfaces Inhibit Biofilm Formation

    DEFF Research Database (Denmark)

    Chiang, Wen-Chi; Schroll, Casper; Hilbert, Lisbeth Rischel

    2009-01-01

    Undesired biofilm formation is a major concern in many areas. In the present study, we investigated biofilm-inhibiting properties of a silver-palladium surface that kills bacteria by generating microelectric fields and electrochemical redox processes. For evaluation of the biofilm inhibition...... efficacy and study of the biofilm inhibition mechanism, the silver-sensitive Escherichia coli J53 and the silver-resistant E. coli J53[pMG101] strains were used as model organisms, and batch and flow chamber setups were used as model systems. In the case of the silver-sensitive strain, the silver......-palladium surfaces killed the bacteria and prevented biofilm formation under conditions of low or high bacterial load. In the case of the silver-resistant strain, the silver-palladium surfaces killed surface-associated bacteria and prevented biofilm formation under conditions of low bacterial load, whereas under...

  20. Inhibition of melanogenesis by Xanthium strumarium L.

    Science.gov (United States)

    Li, Hailan; Min, Young Sil; Park, Kyoung-Chan; Kim, Dong-Seok

    2012-01-01

    Xanthium strumarium L. (Asteraceae) is traditionally used in Korea to treat skin diseases. In this study, we investigated the effects of a X. strumarium stem extract on melanin synthesis. It inhibited melanin synthesis in a concentration-dependent manner, but it did not directly inhibit tyrosinase, the rate-limiting melanogenic enzyme, and instead downregulated microphthalmia-associated transcription factor (MITF) and tyrosinase expression. MITF, the master regulator of pigmentation, is a target of the Wnt signaling pathway, which includes glycogen synthase kinase 3β (GSK3β) and β-catenin. Hence, the influence of X. strumarium stem extract on GSK3β and β-catenin was further investigated. X. strumarium induced GSK3β phosphorylation (inactivation), but the level of β-catenin did not change. Moreover, a specific GSK3β inhibitor restored X. strumarium-induced melanin reduction. Hence, we suggest that X. strumarium inhibits melanin synthesis through downregulation of tyrosinase via GSK3β phosphorylation.

  1. Mapuche Herbal Medicine Inhibits Blood Platelet Aggregation

    Directory of Open Access Journals (Sweden)

    Susan Skanderup Falkenberg

    2012-01-01

    Full Text Available 12 plant species traditionally used by the Mapuche people in Chile to treat wounds and inflammations have been evaluated for their direct blood platelet inhibition. Seven of the 12 tested plant species showed platelet inhibitory effect in sheep blood, and four of these were also able to inhibit the ADP- (5.0 μM and collagen- (2.0 μg/mL induced aggregations in human blood. These four species in respective extracts (in brackets were Blechnum chilense (MeOH, Luma apiculata (H2O, Amomyrtus luma (DCM : MeOH 1 : 1 and Cestrum parqui (DCM : MeOH 1 : 1. The platelet aggregating inhibitory effects of A. luma (DCM : MeOH 1 : 1, and L. apiculata (H2O were substantial and confirmed by inhibition of platelet surface activation markers.

  2. Distractor inhibition: Evidence from lateralized readiness potentials.

    Science.gov (United States)

    Pramme, Lisa; Dierolf, Angelika M; Naumann, Ewald; Frings, Christian

    2015-08-01

    The present study investigated distractor inhibition on the level of stimulus representation. In a sequential distractor-to-distractor priming task participants had to respond to target letters flanked by distractor digits. Reaction time and stimulus-locked lateralized readiness potentials (S-LRPs) of probe responses were measured. Distractor-target onset asynchrony was varied. For RTs responses to probe targets were faster in the case of prime-distractor repetition compared to distractor changes indicating distractor inhibition. Benefits in RTs and the latency of S-LRP onsets for distractor repetition were also modulated by distractor-target onset asynchrony. For S-LRPs distractor inhibition was only present with a simultaneous onset of distractors and target. The results confirm previous results indicating inhibitory mechanisms of object-based selective attention on the level of distractor representations. Copyright © 2015 Elsevier Inc. All rights reserved.

  3. Terbinafine inhibits gap junctional intercellular communication.

    Science.gov (United States)

    Lee, Ju Yeun; Yoon, Sei Mee; Choi, Eun Ju; Lee, Jinu

    2016-09-15

    Terbinafine is an antifungal agent that selectively inhibits fungal sterol synthesis by blocking squalene epoxidase. We evaluated the effect of terbinafine on gap junctional intercellular communication (GJIC). Fluorescence recovery after photobleaching (FRAP) and I-YFP GJIC assays revealed that terbinafine inhibits GJIC in a reversible and dose-dependent manner in FRT-Cx43 and LN215 cells. Treatment with terbinafine did not affect Cx43 phosphorylation status or intracellular Ca(2+) concentration, well-known action mechanisms of various GJIC blockers. While a structurally related chemical, naftifine, attenuated GJIC, epigallocatechin gallate, another potent squalene epoxidase inhibitor with a different structure, did not. These results suggest that terbinafine inhibits GJIC with a so far unknown mechanism of action. Copyright © 2016 Elsevier Inc. All rights reserved.

  4. Inhibition of aluminum corrosion using Opuntia extract

    International Nuclear Information System (INIS)

    El-Etre, A.Y.

    2003-01-01

    The inhibitive action of the mucilage extracted from the modified stems of prickly pears, toward acid corrosion of aluminum, is tested using weight loss, thermometry, hydrogen evolution and polarization techniques. It was found that the extract acts as a good corrosion inhibitor for aluminum corrosion in 2.0 M HCl solution. The inhibition action of the extract was discussed in view of Langmuir adsorption isotherm. It was found that the adsorption of the extract on aluminum surface is a spontaneous process. The inhibition efficiency (IE) increases as the extract concentration is increased. The effect of temperature on the IE was studied. It was found that the presence of extract increases the activation energy of the corrosion reaction. Moreover, the thermodynamic parameters of the adsorption process were calculated. It was found also that the Opuntia extract provides a good protection to aluminum against pitting corrosion in chloride ion containing solutions

  5. Mapuche herbal medicine inhibits blood platelet aggregation.

    Science.gov (United States)

    Falkenberg, Susan Skanderup; Tarnow, Inge; Guzman, Alfonso; Mølgaard, Per; Simonsen, Henrik Toft

    2012-01-01

    12 plant species traditionally used by the Mapuche people in Chile to treat wounds and inflammations have been evaluated for their direct blood platelet inhibition. Seven of the 12 tested plant species showed platelet inhibitory effect in sheep blood, and four of these were also able to inhibit the ADP- (5.0 μM) and collagen- (2.0 μg/mL) induced aggregations in human blood. These four species in respective extracts (in brackets) were Blechnum chilense (MeOH), Luma apiculata (H(2)O), Amomyrtus luma (DCM : MeOH 1 : 1) and Cestrum parqui (DCM : MeOH 1 : 1). The platelet aggregating inhibitory effects of A. luma (DCM : MeOH 1 : 1), and L. apiculata (H(2)O) were substantial and confirmed by inhibition of platelet surface activation markers.

  6. Inhibition of intestinal disaccharidase activity by pentoses

    DEFF Research Database (Denmark)

    Halschou-Jensen, Kia

    on carbohydrate- ingesting enzymes activity in vitro and possible effects on human postprandial blood response. In paper 1 the effects of sugar beet polyphenols from molasses and the potential inhibition of sucrase activity in vitro, was investigated. Two different polyphenol-rich fractions from chromatographic...... separation of molasses from sugar beets and pure ferulic acid were tested. We found no effects of the two fractions of molasses. The pure ferulic acid indicated an inhibition of sucrase in vitr. Both in vitro and in vivo studies have investigated the effects of L-arabinose and D-xylose on carbohydrate...

  7. Sprout inhibition in roots, tubers and bulbs

    International Nuclear Information System (INIS)

    Luna C, P.C.

    1992-05-01

    The treatment with ionizing radiations to low dose impedes that appear sprouts in the tubers (potatoes); bulbs (onion and garlic) and in roots like the ginger and the yucca. The purpose is to inhibit the germination during the process of manipulation and storage, and this way to avoid the lost ones post crop of these products. The radiation dose required to inhibit the germination goes to depend of: the development conditions, the differences of variety, of the storage state of the bulbs and the conditions of cured and storage. (Author)

  8. Mapuche Herbal Medicine Inhibits Blood Platelet Aggregation

    OpenAIRE

    Falkenberg, Susan Skanderup; Tarnow, Inge; Guzman, Alfonso; Mølgaard, Per; Simonsen, Henrik Toft

    2012-01-01

    12 plant species traditionally used by the Mapuche people in Chile to treat wounds and inflammations have been evaluated for their direct blood platelet inhibition. Seven of the 12 tested plant species showed platelet inhibitory effect in sheep blood, and four of these were also able to inhibit the ADP- (5.0??M) and collagen- (2.0??g/mL) induced aggregations in human blood. These four species in respective extracts (in brackets) were Blechnum chilense (MeOH), Luma apiculata (H2O), Amomyrtus l...

  9. Peptide inhibition of human cytomegalovirus infection

    Directory of Open Access Journals (Sweden)

    Morris Cindy A

    2011-02-01

    Full Text Available Abstract Background Human cytomegalovirus (HCMV is the most prevalent congenital viral infection in the United States and Europe causing significant morbidity and mortality to both mother and child. HCMV is also an opportunistic pathogen in immunocompromised individuals, including human immunodeficiency virus (HIV- infected patients with AIDS, and solid organ and allogeneic stem cell transplantation recipients. Current treatments for HCMV-associated diseases are insufficient due to the emergence of drug-induced resistance and cytotoxicity, necessitating novel approaches to limit HCMV infection. The aim of this study was to develop therapeutic peptides targeting glycoprotein B (gB, a major glycoprotein of HCMV that is highly conserved across the Herpesviridae family, that specifically inhibit fusion of the viral envelope with the host cell membrane preventing HCMV entry and infection. Results Using the Wimley-White Interfacial Hydrophobicity Scale (WWIHS, several regions within gB were identified that display a high potential to interact with lipid bilayers of cell membranes and hydrophobic surfaces within proteins. The ability of synthetic peptides analogous to WWIHS-positive sequences of HCMV gB to inhibit viral infectivity was evaluated. Human foreskin fibroblasts (HFF were infected with the Towne-GFP strain of HCMV (0.5 MOI, preincubated with peptides at a range of concentrations (78 nm to 100 μM, and GFP-positive cells were visualized 48 hours post-infection by fluorescence microscopy and analyzed quantitatively by flow cytometry. Peptides that inhibited HCMV infection demonstrated different inhibitory concentration curves indicating that each peptide possesses distinct biophysical properties. Peptide 174-200 showed 80% inhibition of viral infection at a concentration of 100 μM, and 51% and 62% inhibition at concentrations of 5 μM and 2.5 μM, respectively. Peptide 233-263 inhibited infection by 97% and 92% at concentrations of 100

  10. Inhibition of barley grain germination by light

    NARCIS (Netherlands)

    Roth-Bejerano, N.; Meulen, R.M. van der; Wang, M.

    1996-01-01

    Intact grains of barley (Hordeum distichum cv. Triumph) germinated rapidly in the dark or when exposed to brief daily light breaks in the temperature range 15-25°C, although germination proceeded less rapidly at low temperatures. Prolonged illumination (16 h/day) or continuous light inhibited

  11. Probenazole treatment inhibits anthocyanins biosynthesis via ...

    African Journals Online (AJOL)

    It has been found that anthocyanins were accumulated in Arabidopsis under drought or salt stress. In this study, such accumulation was found to be inhibited by external applied probenazole (3-allyloxy-1, 2-benzisothiazole-1,1-dioxide, PBZ), which is the active ingredient in oryzemate used for the protection of rice from ...

  12. Salinomycin, a polyether ionophoric antibiotic, inhibits adipogenesis

    International Nuclear Information System (INIS)

    Szkudlarek-Mikho, Maria; Saunders, Rudel A.; Yap, Sook Fan; Ngeow, Yun Fong; Chin, Khew-Voon

    2012-01-01

    Highlights: ► Salinomycin inhibits preadipocyte differentiation into adipocytes. ► Salinomycin inhibits transcriptional regulation of adipogenesis. ► Pharmacological effects of salinomycin suggest toxicity in cancer therapy. -- Abstract: The polyether ionophoric antibiotics including monensin, salinomycin, and narasin, are widely used in veterinary medicine and as food additives and growth promoters in animal husbandry including poultry farming. Their effects on human health, however, are not fully understood. Recent studies showed that salinomycin is a cancer stem cell inhibitor. Since poultry consumption has risen sharply in the last three decades, we asked whether the consumption of meat tainted with growth promoting antibiotics might have effects on adipose cells. We showed in this report that the ionophoric antibiotics inhibit the differentiation of preadipocytes into adipocytes. The block of differentiation is not due to the induction of apoptosis nor the inhibition of cell proliferation. In addition, salinomycin also suppresses the transcriptional activity of the CCAAT/enhancer binding proteins and the peroxisome proliferator-activated receptor γ. These results suggest that the ionophoric antibiotics can be exploited as novel anti-obesity therapeutics and as pharmacological probes for the study of adipose biology. Further, the pharmacological effects of salinomycin could be a harbinger of its toxicity on the adipose tissue and other susceptible target cells in cancer therapy.

  13. Illustrating Enzyme Inhibition Using Gibbs Energy Profiles

    Science.gov (United States)

    Bearne, Stephen L.

    2012-01-01

    Gibbs energy profiles have great utility as teaching and learning tools because they present students with a visual representation of the energy changes that occur during enzyme catalysis. Unfortunately, most textbooks divorce discussions of traditional kinetic topics, such as enzyme inhibition, from discussions of these same topics in terms of…

  14. Microbial Metabolism and Inhibition Studies of Phenobarbital

    African Journals Online (AJOL)

    Erah

    techniques, high performance liquid chromatography (HPLC), mass spectrometry (MS) ... Keywords: Microbial metabolism, Phenobarbital, Inhibition studies, Rhizopus stolonifer, CYP 2C9, .... 24 h of incubation 0.5 ml of drug solution was ... mode, positive: spray voltage, 3.5 KV: ... Rhizopus stolonifer showed an extra peak at.

  15. Luteoloside Inhibits Proliferation of Human Chronic Myeloid ...

    African Journals Online (AJOL)

    Purpose: To investigate the effects of luteoloside on the proliferation of human chronic ..... Zhang N, Wang D, Zhu Y, Wang J, Lin H. Inhibition ... Han X. Protection of Luteolin-7-O-Glucoside Against ... Hwang YJ, Lee EJ, Kim HR, Hwang KA.

  16. Nickel Inhibits Mitochondrial Fatty Acid Oxidation

    Science.gov (United States)

    Uppala, Radha; McKinney, Richard W.; Brant, Kelly A.; Fabisiak, James P.; Goetzman, Eric S.

    2015-01-01

    Nickel exposure is associated with changes in cellular energy metabolism which may contribute to its carcinogenic properties. Here, we demonstrate that nickel strongly represses mitochondrial fatty acid oxidation—the pathway by which fatty acids are catabolized for energy—in both primary human lung fibroblasts and mouse embryonic fibroblasts. At the concentrations used, nickel suppresses fatty acid oxidation without globally suppressing mitochondrial function as evidenced by increased glucose oxidation to CO2. Pre-treatment with L-carnitine, previously shown to prevent nickel-induced mitochondrial dysfunction in neuroblastoma cells, did not prevent the inhibition of fatty acid oxidation. The effect of nickel on fatty acid oxidation occurred only with prolonged exposure (>5 hr), suggesting that direct inhibition of the active sites of metabolic enzymes is not the mechanism of action. Nickel is a known hypoxia-mimetic that activates hypoxia inducible factor-1α (HIF1α). Nickel-induced inhibition of fatty acid oxidation was blunted in HIF1α knockout fibroblasts, implicating HIF1α as one contributor to the mechanism. Additionally, nickel down-regulated the protein levels of the key fatty acid oxidation enzyme very long-chain acyl-CoA dehydrogenase (VLCAD) in a dose-dependent fashion. In conclusion, inhibition of fatty acid oxidation by nickel, concurrent with increased glucose metabolism, represents a form of metabolic reprogramming that may contribute to nickel-induced carcinogenesis. PMID:26051273

  17. Inhibiting Intuitive Thinking in Mathematics Education

    Science.gov (United States)

    Thomas, Michael O. J.

    2015-01-01

    The papers in this issue describe recent collaborative research into the role of inhibition of intuitive thinking in mathematics education. This commentary reflects on this research from a mathematics education perspective and draws attention to some of the challenges that arise in collaboration between research fields with different cultures,…

  18. Salinomycin, a polyether ionophoric antibiotic, inhibits adipogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Szkudlarek-Mikho, Maria; Saunders, Rudel A. [Department of Medicine, Biochemistry and Cancer Biology, Center for Diabetes and Endocrine Research, College of Medicine, University of Toledo, Toledo, OH 43614 (United States); Yap, Sook Fan [Faculty of Medicine and Health Sciences, Department of Pre-Clinical Sciences, University of Tunku Abdul Rahman (Malaysia); Ngeow, Yun Fong [Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603 (Malaysia); Chin, Khew-Voon, E-mail: khew-voon.chin@utoledo.edu [Department of Medicine, Biochemistry and Cancer Biology, Center for Diabetes and Endocrine Research, College of Medicine, University of Toledo, Toledo, OH 43614 (United States)

    2012-11-30

    Highlights: Black-Right-Pointing-Pointer Salinomycin inhibits preadipocyte differentiation into adipocytes. Black-Right-Pointing-Pointer Salinomycin inhibits transcriptional regulation of adipogenesis. Black-Right-Pointing-Pointer Pharmacological effects of salinomycin suggest toxicity in cancer therapy. -- Abstract: The polyether ionophoric antibiotics including monensin, salinomycin, and narasin, are widely used in veterinary medicine and as food additives and growth promoters in animal husbandry including poultry farming. Their effects on human health, however, are not fully understood. Recent studies showed that salinomycin is a cancer stem cell inhibitor. Since poultry consumption has risen sharply in the last three decades, we asked whether the consumption of meat tainted with growth promoting antibiotics might have effects on adipose cells. We showed in this report that the ionophoric antibiotics inhibit the differentiation of preadipocytes into adipocytes. The block of differentiation is not due to the induction of apoptosis nor the inhibition of cell proliferation. In addition, salinomycin also suppresses the transcriptional activity of the CCAAT/enhancer binding proteins and the peroxisome proliferator-activated receptor {gamma}. These results suggest that the ionophoric antibiotics can be exploited as novel anti-obesity therapeutics and as pharmacological probes for the study of adipose biology. Further, the pharmacological effects of salinomycin could be a harbinger of its toxicity on the adipose tissue and other susceptible target cells in cancer therapy.

  19. Undecylenic Acid Inhibits Morphogenesis of Candida albicans

    OpenAIRE

    McLain, Nealoo; Ascanio, Rhoda; Baker, Carol; Strohaver, Robert A.; Dolan, Joseph W.

    2000-01-01

    Resilient liners are frequently used to treat denture stomatitis, a condition often associated with Candida albicans infections. Of 10 liners tested, 2 were found to inhibit the switch from the yeast form to hyphae and a third was found to stimulate this switch. The inhibitor was determined to be undecylenic acid.

  20. Undecylenic acid inhibits morphogenesis of Candida albicans.

    Science.gov (United States)

    McLain, N; Ascanio, R; Baker, C; Strohaver, R A; Dolan, J W

    2000-10-01

    Resilient liners are frequently used to treat denture stomatitis, a condition often associated with Candida albicans infections. Of 10 liners tested, 2 were found to inhibit the switch from the yeast form to hyphae and a third was found to stimulate this switch. The inhibitor was determined to be undecylenic acid.

  1. Cellulase Inhibition by High Concentrations of Monosaccharides

    DEFF Research Database (Denmark)

    Hsieh, Chia-Wen; Cannella, David; Jørgensen, Henning

    2014-01-01

    Biological degradation of biomass on an industrial scale culminates in high concentrations of end products. It is known that the accumulation of glucose and cellobiose, end products of hydrolysis, inhibit cellulases and decrease glucose yields. Aside from these end products, however, other monosa...

  2. Inhibiting Translation One Protein at a Time.

    Science.gov (United States)

    Disney, Matthew D

    2017-06-01

    Historically, translational inhibitors have been confined to anti-bacterials that globally affect translation. Lintner et al. demonstrate that small molecules can specifically inhibit translation of a single disease-associated protein by stalling the ribosome's nascent chain [1], opening up a new therapeutic strategy for 'undruggable' proteins. Copyright © 2017 Elsevier Ltd. All rights reserved.

  3. Polysulfonate suramin inhibits Zika virus infection.

    Science.gov (United States)

    Tan, Chee Wah; Sam, I-Ching; Chong, Wei Lim; Lee, Vannajan Sanghiran; Chan, Yoke Fun

    2017-07-01

    Zika virus (ZIKV) is an arthropod-borne flavivirus that causes newborn microcephaly and Guillian-Barré syndrome in adults. No therapeutics are available to treat ZIKV infection or other flaviviruses. In this study, we explored the inhibitory effect of glycosaminoglycans and analogues against ZIKV infection. Highly sulfated heparin, dextran sulfate and suramin significantly inhibited ZIKV infection in Vero cells. De-sulfated heparin analogues lose inhibitory effect, implying that sulfonate groups are critical for viral inhibition. Suramin, an FDA-approved anti-parasitic drug, inhibits ZIKV infection with 3-5 log 10  PFU viral reduction with IC 50 value of ∼2.5-5 μg/ml (1.93 μM-3.85 μM). A time-of-drug-addition study revealed that suramin remains potent even when administrated at 1-24 hpi. Suramin inhibits ZIKV infection by preventing viral adsorption, entry and replication. Molecular dynamics simulation revealed stronger interaction of suramin with ZIKV NS3 helicase than with the envelope protein. Suramin warrants further investigation as a potential antiviral candidate for ZIKV infection. Heparan sulfate (HS) is a cellular attachment receptor for multiple flaviviruses. However, no direct ZIKV-heparin interaction was observed in heparin-binding analysis, and downregulate or removal of cellular HS with sodium chlorate or heparinase I/III did not inhibit ZIKV infection. This indicates that cell surface HS is not utilized by ZIKV as an attachment receptor. Copyright © 2017 Elsevier B.V. All rights reserved.

  4. Neural Synchrony during Response Production and Inhibition

    Science.gov (United States)

    Müller, Viktor; Anokhin, Andrey P.

    2012-01-01

    Inhibition of irrelevant information (conflict monitoring) and/or of prepotent actions is an essential component of adaptive self-organized behavior. Neural dynamics underlying these functions has been studied in humans using event-related brain potentials (ERPs) elicited in Go/NoGo tasks that require a speeded motor response to the Go stimuli and withholding a prepotent response when a NoGo stimulus is presented. However, averaged ERP waveforms provide only limited information about the neuronal mechanisms underlying stimulus processing, motor preparation, and response production or inhibition. In this study, we examine the cortical representation of conflict monitoring and response inhibition using time-frequency analysis of electroencephalographic (EEG) recordings during continuous performance Go/NoGo task in 50 young adult females. We hypothesized that response inhibition would be associated with a transient boost in both temporal and spatial synchronization of prefrontal cortical activity, consistent with the role of the anterior cingulate and lateral prefrontal cortices in cognitive control. Overall, phase synchronization across trials measured by Phase Locking Index and phase synchronization between electrode sites measured by Phase Coherence were the highest in the Go and NoGo conditions, intermediate in the Warning condition, and the lowest under Neutral condition. The NoGo condition was characterized by significantly higher fronto-central synchronization in the 300–600 ms window, whereas in the Go condition, delta- and theta-band synchronization was higher in centro-parietal regions in the first 300 ms after the stimulus onset. The present findings suggest that response production and inhibition is supported by dynamic functional networks characterized by distinct patterns of temporal and spatial synchronization of brain oscillations. PMID:22745691

  5. WEE1 inhibition sensitizes osteosarcoma to radiotherapy

    International Nuclear Information System (INIS)

    PosthumaDeBoer, Jantine; Würdinger, Thomas; Graat, Harm CA; Beusechem, Victor W van; Helder, Marco N; Royen, Barend J van; Kaspers, Gertjan JL

    2011-01-01

    The use of radiotherapy in osteosarcoma (OS) is controversial due to its radioresistance. OS patients currently treated with radiotherapy generally are inoperable, have painful skeletal metastases, refuse surgery or have undergone an intralesional resection of the primary tumor. After irradiation-induced DNA damage, OS cells sustain a prolonged G 2 cell cycle checkpoint arrest allowing DNA repair and evasion of cell death. Inhibition of WEE1 kinase leads to abrogation of the G 2 arrest and could sensitize OS cells to irradiation induced cell death. WEE1 expression in OS was investigated by gene-expression data analysis and immunohistochemistry of tumor samples. WEE1 expression in OS cell lines and human osteoblasts was investigated by Western blot. The effect of WEE1 inhibition on the radiosensitivity of OS cells was assessed by cell viability and caspase activation analyses after combination treatment. The presence of DNA damage was visualized using immunofluorescence microscopy. Cell cycle effects were investigated by flow cytometry and WEE1 kinase regulation was analyzed by Western blot. WEE1 expression is found in the majority of tested OS tissue samples. Small molecule drug PD0166285 inhibits WEE1 kinase activity. In the presence of WEE1-inhibitor, irradiated cells fail to repair their damaged DNA, and show higher levels of caspase activation. The inhibition of WEE1 effectively abrogates the irradiation-induced G 2 arrest in OS cells, forcing the cells into premature, catastrophic mitosis, thus enhancing cell death after irradiation treatment. We show that PD0166285, a small molecule WEE1 kinase inhibitor, can abrogate the G 2 checkpoint in OS cells, pushing them into mitotic catastrophe and thus sensitizing OS cells to irradiation-induced cell death. This suggests that WEE1 inhibition may be a promising strategy to enhance the radiotherapy effect in patients with OS

  6. Neural synchrony during response production and inhibition.

    Directory of Open Access Journals (Sweden)

    Viktor Müller

    Full Text Available Inhibition of irrelevant information (conflict monitoring and/or of prepotent actions is an essential component of adaptive self-organized behavior. Neural dynamics underlying these functions has been studied in humans using event-related brain potentials (ERPs elicited in Go/NoGo tasks that require a speeded motor response to the Go stimuli and withholding a prepotent response when a NoGo stimulus is presented. However, averaged ERP waveforms provide only limited information about the neuronal mechanisms underlying stimulus processing, motor preparation, and response production or inhibition. In this study, we examine the cortical representation of conflict monitoring and response inhibition using time-frequency analysis of electroencephalographic (EEG recordings during continuous performance Go/NoGo task in 50 young adult females. We hypothesized that response inhibition would be associated with a transient boost in both temporal and spatial synchronization of prefrontal cortical activity, consistent with the role of the anterior cingulate and lateral prefrontal cortices in cognitive control. Overall, phase synchronization across trials measured by Phase Locking Index and phase synchronization between electrode sites measured by Phase Coherence were the highest in the Go and NoGo conditions, intermediate in the Warning condition, and the lowest under Neutral condition. The NoGo condition was characterized by significantly higher fronto-central synchronization in the 300-600 ms window, whereas in the Go condition, delta- and theta-band synchronization was higher in centro-parietal regions in the first 300 ms after the stimulus onset. The present findings suggest that response production and inhibition is supported by dynamic functional networks characterized by distinct patterns of temporal and spatial synchronization of brain oscillations.

  7. Contrasting neural effects of aging on proactive and reactive response inhibition

    NARCIS (Netherlands)

    Bloemendaal, Mirjam; Zandbelt, Bram; Wegman, Joost; Rest, van de O.; Cools, Roshan; Aarts, Esther

    2016-01-01

    Two distinct forms of response inhibition may underlie observed deficits in response inhibition in aging. We assessed whether age-related neurocognitive impairments in response inhibition reflect deficient reactive inhibition (outright stopping) or also deficient proactive inhibition

  8. Mullerian Inhibiting Substances (MIS) Augments IFN-gamma Mediated Inhibition of Breast Cancer Cell Growth

    National Research Council Canada - National Science Library

    Gupta, Vandana

    2006-01-01

    MIS is a member of the TGF family. The purpose of this study is to test the hypothesis that MIS and IFN-gamma might be more effective in the inhibition of breast cancer cell growth than either agent alone...

  9. Mullerian Inhibiting Substance (MIS) Augments IFN-gamma Mediated Inhibition of Breast Cancer Cell Growth

    National Research Council Canada - National Science Library

    Gupta, Vandana

    2004-01-01

    Mullerian Inhibiting Substance (MIS), a member of the TGFB family regulates growth, differentiation, and apoptosis in many cell types In the male embryo, MIS causes regression of the Mullerian duct...

  10. Adrenocortical Carcinoma: False Positive in an I-123 Metaiodobenzylguanidine Scan

    Energy Technology Data Exchange (ETDEWEB)

    Rey, Cristina Rodriguez; Candil, Aida Ortega; Galvan, Eliseo Vano; Martin, Maria Nieves Cabrera; Delgado, Jose Luis Carreras [Clinico San Carlos Hospital, Madrid (Spain)

    2016-06-15

    A 55-year-old man with a personal his history of left pheochromocytoma 2 years previously presented with an abdominal ultrasound showed a large left upper quadrant solid mass (calipers), with heterogeneous echogenicity and central cystic degeneration areas or necrosis. F-18 Fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT was performed as ACC was suspected. ACC is an uncommon malignant neoplasm of unknown cause; however, smoking and oral contraceptives may be risk factors. Patients usually present with advanced-stage disease and have poor prognosis, with a 2-year recurrence rate that ranges form 73 to 86 %. An MIBG scan was performed after injection of 185 MBq of I-123 MIBG intravenously. Single photon emission tomography (SPECT)/CT scan showed abnormal isotope accumulation in the tumor region. The patient underwent total resection of the tumor. The histology was of ACC, with areas of necrosis and cystic areas, so the result of the MIBG scan was a false positive. Authors divided false-positive MIBG studies into three categories. The first category is neuroendocrine lesions other than pheochromocytomas (tumors of the APUD series). the second category consists in adrenal lesions other than pheochromocytomas (adenomas, ACC) the reasons for this abnormal uptake are unclear. The third category consists of tracer uptake adjacent to the adrenal due to abnormalities in the route of excretion.

  11. Evaluation of adrenocortical function in Florida manatees (Trichechus manatus latirostris)

    Science.gov (United States)

    Tripp, K.M.; Verstegen, J.P.; Deutsch, C.; Bonde, Robert K.; de Wit, M.; Manire, Charles A.; Gaspard, J.; Harr, K.E.

    2011-01-01

    The study objectives were to determine the predominant manatee glucocorticoid; validate assays to measure this glucocorticoid and adrenocorticotropic hormone (ACTH); determine diagnostic thresholds to distinguish physiological vs. pathological concentrations; identify differences associated with sex, age class, female reproductive status, capture time, and lactate; and determine the best methods for manatee biologists and clinicians to diagnose stress. Cortisol is the predominant manatee glucocorticoid. IMMULITE 1000 assays for cortisol and ACTH were validated. Precision yielded intra- and inter-assay coefficients of variation for serum cortisol: ≤23.5 and ≤16.7%; and ACTH: ≤6.9 and ≤8.5%. Accuracy resulted in a mean adjusted R(2)≥0.87 for serum cortisol and ≥0.96 for ACTH. Assay analytical sensitivities for cortisol (0.1 µg/dl) and ACTH (10.0 pg/ml) were verified. Methods were highly correlated with another IMMULITE 1000 for serum cortisol (r=0.97) and ACTH (r=0.98). There was no significant variation in cortisol or ACTH with sex or age class and no correlation with female progesterone concentrations. Cortisol concentrations were highest in unhealthy manatees, chronically stressed by disease or injury. ACTH was greatest in healthy free-ranging or short-term rehabilitating individuals, peracutely stressed by capture and handling. Cortisol concentrations ≥1.0 µg/dl were diagnostic of chronic stress; ACTH concentrations ≥87.5 pg/ml were diagnostic of peracute stress. In healthy long-term captive manatees, cortisol (0.4±0.2 µg/dl) and ACTH (47.7±15.9 pg/ml) concentrations were lower than healthy free-ranging, short-term rehabilitated or unhealthy manatees. Capture time was not significantly correlated with cortisol; ACTH correlation was borderline significant. Cortisol and ACTH were positively correlated with lactate.

  12. Bilateral primary adrenocortical carcinoma complicated by Addisonian crisis: case report

    International Nuclear Information System (INIS)

    Foster, M.; Nolan, R.L.; Hong, H.H.

    2001-01-01

    Primary adrenal carcinoma is a rare malignancy. Primary adrenal insufficiency (i.e. Addison's disease) is a rare complication of bilateral infiltration. We report a case of primary bilateral adrenal carcinoma complicated by an episode of primary adrenal insufficiency. (author)

  13. Pheochromocytoma and Adrenocortical Adenoma in the Same Gland

    Directory of Open Access Journals (Sweden)

    Wei-Ren Hwang

    2007-07-01

    Full Text Available A right adrenal tumor was found incidentally during abdominal computed tomography exam in a 51-year-old female patient, who had had diabetes and hypertension for more than 10 years. The computed tomography scan was arranged for possible pancreatic lesion by a neurologist. Norepinephrine level was high in the plasma and urine. Vanillylmandelic acid level was elevated in the urine. Diurnal cortisol rhythm, plasma adrenocorticotropic hormone and urine free cortisol were all normal, but the plasma cortisol concentration could not be suppressed after a standard low-dose dexamethasone suppression test. Therefore, adrenal cortical adenoma with subclinical Cushing's syndrome was highly suspected; however, further imaging studies, including magnetic resonance image and 131I-6β-iodomethylnorcholesterol adrenal scintigraphy failed to discriminate an additional tumor. After right adrenalectomy, a small adrenal cortical adenoma and a large pheochromocytoma were noted. This is an extremely rare case of an adrenal incidentaloma consisting of both medullary and cortical tumors in the same gland.

  14. Clinical and prognostic aspects of adrenocortical neoplasms in childhood.

    Science.gov (United States)

    Teinturier, C; Pauchard, M S; Brugières, L; Landais, P; Chaussain, J L; Bougnères, P F

    1999-02-01

    A retrospective study of 54 children was undertaken to define the clinical presentation and secretory patterns of adrenal tumors and to evaluate the outcome of surgical resection and medical therapy. Different factors were studied in univariate and multivariate analysis by using the Cox proportional hazard model. Median age at diagnosis was 4 years. Boys and girls were affected equally. The disease was revealed by virilization (61%) or by a palpable mass (39%) with a 0.1-5.5 year delay from initial symptoms. At initial examination, we found that 76% of children were virilized. Ninety-four percent of the tested tumors secreted androgens, which were associated with glucocorticoids in 36%. Adrenal tumors in children were smaller than in adults. Half of them measured less than 10 cm. There were recurrences in 40% of children. The survival rate at 5 years was 49%, 70% if resection was microscopically complete and 7% if not (P < 0.001). In children, rare adrenal tumors have different diagnostic and prognostic characteristics than in adults; however, recurrences remain frequent. The efficacy of chemotherapy, mainly o,p'-DDD (Mitotane), remains to be evaluated in comparative trials.

  15. The adrenocortical response of tufted puffin chicks to nutritional deficits

    Science.gov (United States)

    Kitaysky, A.S.; Romano, Marc D.; Piatt, John F.; Wingfield, J.C.; Kikuchi, M.

    2005-01-01

    In several seabirds, nutritional state of a nest-bound chick is negatively correlated with the activity of its hypothalamus-pituitary-adrenal (HPA) axis. Increased corticosterone (cort) secretion has been shown to facilitate changes in behavior that allow hungry chicks to obtain more food from parents. However, if parents are not willing/able to buffer their young from temporary food shortages, increased cort secretion could be detrimental to undernourished chicks. In a system where parents are insensitive to chick demands, low benefits and high costs of activation of the HPA-axis in hungry chicks should lead to a disassociation of the nutritional state of the young and the activity of its HPA-axis. We tested this novel hypothesis for the tufted puffin (Fratercula cirrhata), a seabird with intermittent provisioning of a nest-bound semi-precocial chick. We examined the HPA-axis activity of captive chicks exposed to the following: (1) a short-term (24 h) food deprivation; and (2) an array of prolonged (3 weeks) restrictions in feeding regimens. We found that in response to a short-term food deprivation chicks decreased baseline levels of cort and thyroid hormones. In response to prolonged restrictions, food-limited chicks exhibited signs of nutritional deficit: they had lower body mass, endogenous lipid reserves, and thyroid hormone titers compared to chicks fed ad libitum. However, baseline and maximum acute stress-induced levels of cort were also lower in food-restricted chicks compared to those of chicks fed ad libitum. These results support a major prediction of the study hypothesis that puffin chicks suppress HPA-axis activity in response to short- and long-term nutritional deficits. This physiological adaptation may allow a chick to extend its development in the nest, while eluding detrimental effects of chronic cort elevation. 

  16. Equol inhibits growth, induces atresia, and inhibits steroidogenesis of mouse antral follicles in vitro

    International Nuclear Information System (INIS)

    Mahalingam, Sharada; Gao, Liying; Gonnering, Marni; Helferich, William; Flaws, Jodi A.

    2016-01-01

    Equol is a non-steroidal estrogen metabolite produced by microbial conversion of daidzein, a major soy isoflavone, in the gut of some humans and many animal species. Isoflavones and their metabolites can affect endogenous estradiol production, action, and metabolism, potentially influencing ovarian follicle function. However, no studies have examined the effects of equol on intact ovarian antral follicles, which are responsible for sex steroid synthesis and further development into ovulatory follicles. Thus, the present study tested the hypothesis that equol inhibits antral follicle growth, increases follicle atresia, and inhibits steroidogenesis in the adult mouse ovary. To test this hypothesis, antral follicles isolated from adult CD-1 mice were cultured with vehicle control (dimethyl sulfoxide; DMSO) or equol (600 nM, 6 μM, 36 μM, and 100 μM) for 48 and 96 h. Every 24 h, follicle diameters were measured to monitor growth. At 48 and 96 h, the culture medium was subjected to measurement of hormone levels, and the cultured follicles were subjected to gene expression analysis. Additionally, follicles were histologically evaluated for signs of atresia after 96 h of culture. The results indicate that equol (100 μM) inhibited follicle growth, altered the mRNA levels of bcl2-associated X protein and B cell leukemia/lymphoma 2, and induced follicle atresia. Further, equol decreased the levels of estradiol, testosterone, androstenedione, and progesterone, and it decreased mRNA levels of cholesterol side-chain cleavage, steroid 17-α-hydroxalase, and aromatase. Collectively, these data indicate that equol inhibits growth, increases atresia, and inhibits steroidogenesis of cultured mouse antral follicles. - Highlights: • Equol exposure inhibits antral follicle growth. • Equol exposure increases follicle atresia. • Equol exposure inhibits sex steroid hormone levels. • Equol exposure inhibits mRNA levels of certain steroidogenic enzymes.

  17. Equol inhibits growth, induces atresia, and inhibits steroidogenesis of mouse antral follicles in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Mahalingam, Sharada, E-mail: mahalin2@illinois.edu [Department of Comparative Biosciences, College of Veterinary Medicine, University of Illinois, 2001 S. Lincoln Ave, Urbana, IL 61802 (United States); Gao, Liying, E-mail: lgao@uiuc.edu [Department of Comparative Biosciences, College of Veterinary Medicine, University of Illinois, 2001 S. Lincoln Ave, Urbana, IL 61802 (United States); Gonnering, Marni, E-mail: mgonne2@illinois.edu [Department of Comparative Biosciences, College of Veterinary Medicine, University of Illinois, 2001 S. Lincoln Ave, Urbana, IL 61802 (United States); Helferich, William, E-mail: helferic@illinois.edu [Department of Food Science and Human Nutrition, University of Illinois, 905 S. Goodwin, Urbana, IL 61801 (United States); Flaws, Jodi A., E-mail: jflaws@illinois.edu [Department of Comparative Biosciences, College of Veterinary Medicine, University of Illinois, 2001 S. Lincoln Ave, Urbana, IL 61802 (United States)

    2016-03-15

    Equol is a non-steroidal estrogen metabolite produced by microbial conversion of daidzein, a major soy isoflavone, in the gut of some humans and many animal species. Isoflavones and their metabolites can affect endogenous estradiol production, action, and metabolism, potentially influencing ovarian follicle function. However, no studies have examined the effects of equol on intact ovarian antral follicles, which are responsible for sex steroid synthesis and further development into ovulatory follicles. Thus, the present study tested the hypothesis that equol inhibits antral follicle growth, increases follicle atresia, and inhibits steroidogenesis in the adult mouse ovary. To test this hypothesis, antral follicles isolated from adult CD-1 mice were cultured with vehicle control (dimethyl sulfoxide; DMSO) or equol (600 nM, 6 μM, 36 μM, and 100 μM) for 48 and 96 h. Every 24 h, follicle diameters were measured to monitor growth. At 48 and 96 h, the culture medium was subjected to measurement of hormone levels, and the cultured follicles were subjected to gene expression analysis. Additionally, follicles were histologically evaluated for signs of atresia after 96 h of culture. The results indicate that equol (100 μM) inhibited follicle growth, altered the mRNA levels of bcl2-associated X protein and B cell leukemia/lymphoma 2, and induced follicle atresia. Further, equol decreased the levels of estradiol, testosterone, androstenedione, and progesterone, and it decreased mRNA levels of cholesterol side-chain cleavage, steroid 17-α-hydroxalase, and aromatase. Collectively, these data indicate that equol inhibits growth, increases atresia, and inhibits steroidogenesis of cultured mouse antral follicles. - Highlights: • Equol exposure inhibits antral follicle growth. • Equol exposure increases follicle atresia. • Equol exposure inhibits sex steroid hormone levels. • Equol exposure inhibits mRNA levels of certain steroidogenic enzymes.

  18. Proactive modulation of long-interval intracortical inhibition during response inhibition

    Science.gov (United States)

    Cowie, Matthew J.; MacDonald, Hayley J.; Cirillo, John

    2016-01-01

    Daily activities often require sudden cancellation of preplanned movement, termed response inhibition. When only a subcomponent of a whole response must be suppressed (required here on Partial trials), the ensuing component is markedly delayed. The neural mechanisms underlying partial response inhibition remain unclear. We hypothesized that Partial trials would be associated with nonselective corticomotor suppression and that GABAB receptor-mediated inhibition within primary motor cortex might be responsible for the nonselective corticomotor suppression contributing to Partial trial response delays. Sixteen right-handed participants performed a bimanual anticipatory response inhibition task while single- and paired-pulse transcranial magnetic stimulation was delivered to elicit motor evoked potentials in the left first dorsal interosseous muscle. Lift times, amplitude of motor evoked potentials, and long-interval intracortical inhibition were examined across the different trial types (Go, Stop-Left, Stop-Right, Stop-Both). Go trials produced a tight distribution of lift times around the target, whereas those during Partial trials (Stop-Left and Stop-Right) were substantially delayed. The modulation of motor evoked potential amplitude during Stop-Right trials reflected anticipation, suppression, and subsequent reinitiation of movement. Importantly, suppression was present across all Stop trial types, indicative of a “default” nonselective inhibitory process. Compared with blocks containing only Go trials, inhibition increased when Stop trials were introduced but did not differ between trial types. The amount of inhibition was positively correlated with lift times during Stop-Right trials. Tonic levels of inhibition appear to be proactively modulated by task context and influence the speed at which unimanual responses occur after a nonselective “brake” is applied. PMID:27281744

  19. Cell Cycle Inhibition To Treat Sleeping Sickness

    Directory of Open Access Journals (Sweden)

    Conrad L. Epting

    2017-09-01

    Full Text Available African trypanosomiasis is caused by infection with the protozoan parasite Trypanosoma brucei. During infection, this pathogen divides rapidly to high density in the bloodstream of its mammalian host in a manner similar to that of leukemia. Like all eukaryotes, T. brucei has a cell cycle involving the de novo synthesis of DNA regulated by ribonucleotide reductase (RNR, which catalyzes the conversion of ribonucleotides into their deoxy form. As an essential enzyme for the cell cycle, RNR is a common target for cancer chemotherapy. We hypothesized that inhibition of RNR by genetic or pharmacological means would impair parasite growth in vitro and prolong the survival of infected animals. Our results demonstrate that RNR inhibition is highly effective in suppressing parasite growth both in vitro and in vivo. These results support drug discovery efforts targeting the cell cycle, not only for African trypanosomiasis but possibly also for other infections by eukaryotic pathogens.

  20. Product inhibition of five Hypocrea jecorina cellulases

    DEFF Research Database (Denmark)

    Murphy, Leigh; Westh, Peter; Bohlin, Christina

    2013-01-01

    Product inhibition of cellulolytic enzymes has been deemed a critical factor in the industrial saccharification of cellulosic biomass. Several investigations have addressed this problem using crude enzyme preparations or commercial (mixed) cellulase products, but quantitative information...... on individual cellulases hydrolyzing insoluble cellulose remains insufficient. Such knowledge is necessary to pinpoint and quantify inhibitory weak-links in cellulose hydrolysis, but has proven challenging to come by. Here we show that product inhibition of mono-component cellulases hydrolyzing unmodified...... cellulose may be monitored by calorimetry. The key advantage of this approach is that it directly measures the rate of hydrolysis while being essentially blind to the background of added product. We investigated the five major cellulases from Hypocrea jecorina (anamorph: Tricoderma reesei), Cel7A (formerly...

  1. How x rays inhibit amphibian limb regeneration

    International Nuclear Information System (INIS)

    Maden, M.; Wallace, H.

    1976-01-01

    The effects of an inhibiting dose of 2,000 rad of x-rays on the regenerating limbs of axolotl larvae have been examined in a histological and cytological study. Particular attention was paid to the mitotic indices of normal and irradiated epidermal and blastemal cells. Both the characteristic pattern of epidermal mitotic stimulation which normally follows amputation and the later increase in blastemal mitoses are suppressed by irradiation. In most cells the effects are permanent, but in a small proportion a mitotic delay is induced and upon subsequent division chromosome damage in the form of micronuclei is revealed. Thus irradiated cells which do divide almost certainly die. These results are discussed in relation to other theories of x-ray inhibition of regeneration with particular reference to the view that irradiated cells can be reactivated

  2. Myrtenal inhibits acetylcholinesterase, a known Alzheimer target.

    Science.gov (United States)

    Kaufmann, Dorothea; Dogra, Anudeep Kaur; Wink, Michael

    2011-10-01

    Inhibition of acetylcholinesterase (AChE) is a common treatment for early stages of the most general form of dementia, Alzheimer's disease. In this study selected components of essential oils, which carry a variety of important functional groups, were tested for their in-vitro anti-acetylcholinesterase activity. In-vitro anti-acetylcholinesterase activity was measured by an adapted version of Ellman's colorimetric assay. 1,8-cineole, carvacrol, myrtenal and verbenone apparently inhibited AChE; the highest inhibitory activity was observed for myrtenal (IC50 = 0.17 mm). This is the first study showing the AChE inhibitory activity of myrtenal. Our investigations provided evidence for the efficacy of monoterpenes as inhibitors of AChE. © 2011 The Authors. JPP © 2011 Royal Pharmaceutical Society.

  3. Theobromine inhibits sensory nerve activation and cough.

    Science.gov (United States)

    Usmani, Omar S; Belvisi, Maria G; Patel, Hema J; Crispino, Natascia; Birrell, Mark A; Korbonits, Márta; Korbonits, Dezso; Barnes, Peter J

    2005-02-01

    Cough is a common and protective reflex, but persistent coughing is debilitating and impairs quality of life. Antitussive treatment using opioids is limited by unacceptable side effects, and there is a great need for more effective remedies. The present study demonstrates that theobromine, a methylxanthine derivative present in cocoa, effectively inhibits citric acid-induced cough in guinea-pigs in vivo. Furthermore, in a randomized, double-blind, placebo-controlled study in man, theobromine suppresses capsaicin-induced cough with no adverse effects. We also demonstrate that theobromine directly inhibits capsaicin-induced sensory nerve depolarization of guinea-pig and human vagus nerve suggestive of an inhibitory effect on afferent nerve activation. These data indicate the actions of theobromine appear to be peripherally mediated. We conclude theobromine is a novel and promising treatment, which may form the basis for a new class of antitussive drugs.

  4. Direct renin inhibition in chronic kidney disease

    DEFF Research Database (Denmark)

    Persson, Frederik; Rossing, Peter; Parving, Hans-Henrik

    2013-01-01

    that renin inhibition could hold potential for improved treatment in patients with chronic kidney disease, with diabetic nephropathy as an obvious group of patients to investigate, as the activity of the renin-angiotensin-aldosterone system is enhanced in these patients and as there is an unmet need....... In addition, combination treatment seemed safe and effective also in patients with impaired kidney function. These initial findings formed the basis for the design of a large morbidity and mortality trial investigating aliskiren as add-on to standard treatment. The study has just concluded, but was terminated...... early as a beneficial effect was unlikely and there was an increased frequency of side effects. Also in non-diabetic kidney disease a few intervention studies have been carried out, but there is no ongoing hard outcome study. In this review we provide the current evidence for renin inhibition in chronic...

  5. Extinction Generates Outcome-Specific Conditioned Inhibition.

    Science.gov (United States)

    Laurent, Vincent; Chieng, Billy; Balleine, Bernard W

    2016-12-05

    Extinction involves altering a previously established predictive relationship between a cue and its outcome by repeatedly presenting that cue alone. Although it is widely accepted that extinction generates some form of inhibitory learning [1-4], direct evidence for this claim has been lacking, and the nature of the associative changes induced by extinction have, therefore, remained a matter of debate [5-8]. In the current experiments, we used a novel behavioral approach that we recently developed and that provides a direct measure of conditioned inhibition [9] to compare the influence of extinguished and non-extinguished cues on choice between goal-directed actions. Using this approach, we provide direct evidence that extinction generates outcome-specific conditioned inhibition. Furthermore, we demonstrate that this inhibitory learning is controlled by the infralimbic cortex (IL); inactivation of the IL using M4 DREADDs abolished outcome-specific inhibition and rendered the cue excitatory. Importantly, we found that context modulated this inhibition. Outside its extinction context, the cue was excitatory and functioned as a specific predictor of its previously associated outcome, biasing choice toward actions earning the same outcome. In its extinction context, however, the cue acted as a specific inhibitor and biased choice toward actions earning different outcomes. Context modulation of these excitatory and inhibitory memories was mediated by the dorsal hippocampus (HPC), suggesting that the HPC and IL act in concert to control the influence of conditioned inhibitors on choice. These findings demonstrate for the first time that extinction turns a cue into a net inhibitor that can influence choice via counterfactual action-outcome associations. Copyright © 2016 Elsevier Ltd. All rights reserved.

  6. Fermentation of lignocellulosic hydrolysates: Inhibition and detoxification

    Energy Technology Data Exchange (ETDEWEB)

    Palmqvist, E.

    1998-02-01

    The ethanol yield and productivity obtained during fermentation of lignocellulosic hydrolysates is decreased due to the presence of inhibiting compounds, such as weak acids, furans and phenolic compounds produced during hydrolysis. Evaluation of the effect of various biological, physical and chemical detoxification treatments by fermentation assays using Saccharomyces cerevisiae was used to characterise inhibitors. Inhibition of fermentation was decreased after removal of the non-volatile compounds, pre-fermentation by the filamentous fungus Trichoderma reesei, treatment with the lignolytic enzyme laccase, extraction with ether, and treatment with alkali. Yeast growth in lignocellulosic hydrolysates was inhibited below a certain fermentation pH, most likely due to high concentrations of undissociated weak acids. The effect of individual compounds were studied in model fermentations. Furfural is reduced to furfuryl alcohol by yeast dehydrogenases, thereby affecting the intracellular redox balance. As a result, acetaldehyde accumulated during furfural reduction, which most likely contributed to inhibition of growth. Acetic acid (10 g 1{sup -1}) and furfural (3 g 1{sup -1}) interacted antagonistically causing decreased specific growth rate, whereas no significant individual or interaction effects were detected by the lignin-derived compound 4-hydroxybenzoic acid (2 g 1{sup -1}). By maintaining a high cell mass density in the fermentor, the process was less sensitive to inhibitors affecting growth and to fluctuations in fermentation pH, and in addition the depletion rate of bioconvertible inhibitors was increased. A theoretical ethanol yield and high productivity was obtained in continuous fermentation of spruce hydrolysate when the cell mass concentration was maintained at a high level by applying cell recirculation 164 refs, 16 figs, 5 tabs

  7. Osthole inhibits bone metastasis of breast cancer

    OpenAIRE

    Wu, Chunyu; Sun, Zhenping; Guo, Baofeng; Ye, Yiyi; Han, Xianghui; Qin, Yuenong; Liu, Sheng

    2017-01-01

    Bone is one of the most common sites for breast cancer metastasis, which greatly contributes to patient morbidity and mortality. Osthole, a major extract from Cnidium monnieri (L.), exhibits many biological and pharmacological activities, however, its potential as a therapeutic agent in the treatment of breast cancer bone metastases remain poorly understood. In this study, we set out to investigate whether osthole could inhibit breast cancer metastasis to bone in mice and clarified the potent...

  8. Fermented Broth in Tyrosinase- and Melanogenesis Inhibition

    OpenAIRE

    Chin-Feng Chan; Ching-Cheng Huang; Ming-Yuan Lee; Yung-Sheng Lin

    2014-01-01

    Fermented broth has a long history of applications in the food, pharmaceutical and cosmetic industries. Recently, the use of fermented broth in skin care products is in ascendance. This review investigates the efficacy of fermented broth in inhibiting tyrosinase and melanogenesis. Possible active ingredients and hypopigmentation mechanisms of fermented broth are discussed, and potential applications of fermented broth in the cosmetic industry are also addressed.

  9. Fermented Broth in Tyrosinase- and Melanogenesis Inhibition

    Directory of Open Access Journals (Sweden)

    Chin-Feng Chan

    2014-08-01

    Full Text Available Fermented broth has a long history of applications in the food, pharmaceutical and cosmetic industries. Recently, the use of fermented broth in skin care products is in ascendance. This review investigates the efficacy of fermented broth in inhibiting tyrosinase and melanogenesis. Possible active ingredients and hypopigmentation mechanisms of fermented broth are discussed, and potential applications of fermented broth in the cosmetic industry are also addressed.

  10. 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....

  11. Caffeine Inhibits Acetylcholinesterase, But Not Butyrylcholinesterase

    Directory of Open Access Journals (Sweden)

    Petr Dobes

    2013-05-01

    Full Text Available Caffeine is an alkaloid with a stimulant effect in the body. It can interfere in transmissions based on acetylcholine, epinephrine, norepinephrine, serotonin, dopamine and glutamate. Clinical studies indicate that it can be involved in the slowing of Alzheimer disease pathology and some other effects. The effects are not well understood. In the present work, we focused on the question whether caffeine can inhibit acetylcholinesterase (AChE and/or, butyrylcholinesterase (BChE, the two enzymes participating in cholinergic neurotransmission. A standard Ellman test with human AChE and BChE was done for altering concentrations of caffeine. The test was supported by an in silico examination as well. Donepezil and tacrine were used as standards. In compliance with Dixon’s plot, caffeine was proved to be a non-competitive inhibitor of AChE and BChE. However, inhibition of BChE was quite weak, as the inhibition constant, Ki, was 13.9 ± 7.4 mol/L. Inhibition of AChE was more relevant, as Ki was found to be 175 ± 9 µmol/L. The predicted free energy of binding was −6.7 kcal/mol. The proposed binding orientation of caffeine can interact with Trp86, and it can be stabilize by Tyr337 in comparison to the smaller Ala328 in the case of human BChE; thus, it can explain the lower binding affinity of caffeine for BChE with reference to AChE. The biological relevance of the findings is discussed.

  12. Inhibition of methane production by Methanobacterium formicicum

    Energy Technology Data Exchange (ETDEWEB)

    Hobson, P N; Shaw, B G

    1976-01-01

    The effects of volatile fatty acids, ammonia and copper on methane production by growing cultures of Methanobacterium formicicum were studied. Acetate and butyrate were not inhibitory, but propionate was inhibitory above certain concentrations, as was ammonia. Copper was inhibitory, but inhibitory concentrations are difficult to define as varying amounts may be precipitated as the sulphide. The results are compared with those from piggery-waste digesters and it is suggested that failure of farm-waste digesters from such inhibitions is unlikely.

  13. Evidence of dopaminergic processing of executive inhibition.

    Directory of Open Access Journals (Sweden)

    Rajendra D Badgaiyan

    Full Text Available Inhibition of unwanted response is an important function of the executive system. Since the inhibitory system is impaired in patients with dysregulated dopamine system, we examined dopamine neurotransmission in the human brain during processing of a task of executive inhibition. The experiment used a recently developed dynamic molecular imaging technique to detect and map dopamine released during performance of a modified Eriksen's flanker task. In this study, young healthy volunteers received an intravenous injection of a dopamine receptor ligand ((11C-raclopride after they were positioned in the PET camera. After the injection, volunteers performed the flanker task under Congruent and Incongruent conditions in a single scan session. They were required to inhibit competing options to select an appropriate response in the Incongruent but not in the Congruent condition. The PET data were dynamically acquired during the experiment and analyzed using two variants of the simplified reference region model. The analysis included estimation of a number of receptor kinetic parameters before and after initiation of the Incongruent condition. We found increase in the rate of ligand displacement (from receptor sites and decrease in the ligand binding potential in the Incongruent condition, suggesting dopamine release during task performance. These changes were observed in small areas of the putamen and caudate bilaterally but were most significant on the dorsal aspect of the body of left caudate. The results provide evidence of dopaminergic processing of executive inhibition and demonstrate that neurochemical changes associated with cognitive processing can be detected and mapped in a single scan session using dynamic molecular imaging.

  14. Inhibition of enveloped viruses infectivity by curcumin.

    Directory of Open Access Journals (Sweden)

    Tzu-Yen Chen

    Full Text Available Curcumin, a natural compound and ingredient in curry, has antiinflammatory, antioxidant, and anticarcinogenic properties. Previously, we reported that curcumin abrogated influenza virus infectivity by inhibiting hemagglutination (HA activity. This study demonstrates a novel mechanism by which curcumin inhibits the infectivity of enveloped viruses. In all analyzed enveloped viruses, including the influenza virus, curcumin inhibited plaque formation. In contrast, the nonenveloped enterovirus 71 remained unaffected by curcumin treatment. We evaluated the effects of curcumin on the membrane structure using fluorescent dye (sulforhodamine B; SRB-containing liposomes that mimic the viral envelope. Curcumin treatment induced the leakage of SRB from these liposomes and the addition of the influenza virus reduced the leakage, indicating that curcumin disrupts the integrity of the membranes of viral envelopes and of liposomes. When testing liposomes of various diameters, we detected higher levels of SRB leakage from the smaller-sized liposomes than from the larger liposomes. Interestingly, the curcumin concentration required to reduce plaque formation was lower for the influenza virus (approximately 100 nm in diameter than for the pseudorabies virus (approximately 180 nm and the vaccinia virus (roughly 335 × 200 × 200 nm. These data provide insights on the molecular antiviral mechanisms of curcumin and its potential use as an antiviral agent for enveloped viruses.

  15. Imitation inhibition in children with Tourette syndrome.

    Science.gov (United States)

    Brandt, Valerie Cathérine; Moczydlowski, Agnes; Jonas, Melanie; Boelmans, Kai; Bäumer, Tobias; Brass, Marcel; Münchau, Alexander

    2017-08-12

    Echopraxia, that is, the open and automatic imitation of other peoples' actions, is common in patients with Gilles de la Tourette syndrome, autism spectrum disorder, and also those with frontal lobe lesions. While systematic reaction time tasks have confirmed increased automatic imitation in the latter two groups, adult patients with Tourette syndrome appear to compensate for automatic imitation tendencies by an overall slowing in response times. However, whether children with Tourette syndrome are already able to inhibit automatic imitation tendencies has not been investigated. Fifteen children with Tourette syndrome and 15 healthy children (aged 7-12 years) performed an imitation inhibition paradigm. Participants were asked to respond to an auditory cue by lifting their index finger or their little finger. Participants were simultaneously presented with either compatible or incompatible visual stimuli. Overall responses in children with Tourette syndrome were slower than in healthy children. Although responses were faster in compatible than in incompatible trials in both groups, this 'interference effect' was smaller in children with Tourette syndrome. Children with Tourette syndrome have a smaller interference effect than healthy children, indicating an enhanced ability to behaviourally control automatic imitation tendencies at the cost of reacting slower. The results suggest that children with Tourette syndrome already employ different or additional inhibition strategies compared to healthy children. © 2017 The British Psychological Society.

  16. Inhibition of Enveloped Viruses Infectivity by Curcumin

    Science.gov (United States)

    Wen, Hsiao-Wei; Ou, Jun-Lin; Chiou, Shyan-Song; Chen, Jo-Mei; Wong, Min-Liang; Hsu, Wei-Li

    2013-01-01

    Curcumin, a natural compound and ingredient in curry, has antiinflammatory, antioxidant, and anticarcinogenic properties. Previously, we reported that curcumin abrogated influenza virus infectivity by inhibiting hemagglutination (HA) activity. This study demonstrates a novel mechanism by which curcumin inhibits the infectivity of enveloped viruses. In all analyzed enveloped viruses, including the influenza virus, curcumin inhibited plaque formation. In contrast, the nonenveloped enterovirus 71 remained unaffected by curcumin treatment. We evaluated the effects of curcumin on the membrane structure using fluorescent dye (sulforhodamine B; SRB)-containing liposomes that mimic the viral envelope. Curcumin treatment induced the leakage of SRB from these liposomes and the addition of the influenza virus reduced the leakage, indicating that curcumin disrupts the integrity of the membranes of viral envelopes and of liposomes. When testing liposomes of various diameters, we detected higher levels of SRB leakage from the smaller-sized liposomes than from the larger liposomes. Interestingly, the curcumin concentration required to reduce plaque formation was lower for the influenza virus (approximately 100 nm in diameter) than for the pseudorabies virus (approximately 180 nm) and the vaccinia virus (roughly 335 × 200 × 200 nm). These data provide insights on the molecular antiviral mechanisms of curcumin and its potential use as an antiviral agent for enveloped viruses. PMID:23658730

  17. Scaling Up Cortical Control Inhibits Pain

    Directory of Open Access Journals (Sweden)

    Jahrane Dale

    2018-05-01

    Full Text Available Summary: Acute pain evokes protective neural and behavioral responses. Chronic pain, however, disrupts normal nociceptive processing. The prefrontal cortex (PFC is known to exert top-down regulation of sensory inputs; unfortunately, how individual PFC neurons respond to an acute pain signal is not well characterized. We found that neurons in the prelimbic region of the PFC increased firing rates of the neurons after noxious stimulations in free-moving rats. Chronic pain, however, suppressed both basal spontaneous and pain-evoked firing rates. Furthermore, we identified a linear correlation between basal and evoked firing rates of PFC neurons, whereby a decrease in basal firing leads to a nearly 2-fold reduction in pain-evoked response in chronic pain states. In contrast, enhancing basal PFC activity with low-frequency optogenetic stimulation scaled up prefrontal outputs to inhibit pain. These results demonstrate a cortical gain control system for nociceptive regulation and establish scaling up prefrontal outputs as an effective neuromodulation strategy to inhibit pain. : Dale et al. find that acute pain increases activity levels in the prefrontal cortex. Chronic pain reduces both basal spontaneous and pain-evoked activity in this region, whereas neurostimulation to restore basal activities can in turn enhance nociception-evoked prefrontal activities to inhibit pain. Keywords: chronic pain, neuromodulation, prefrontal cortex, PFC, cortical gain control

  18. Pharmacological inhibition of feline immunodeficiency virus (FIV).

    Science.gov (United States)

    Mohammadi, Hakimeh; Bienzle, Dorothee

    2012-05-01

    Feline immunodeficiency virus (FIV) is a member of the retroviridae family of viruses and causes an acquired immunodeficiency syndrome (AIDS) in domestic and non-domestic cats worldwide. Genome organization of FIV and clinical characteristics of the disease caused by the virus are similar to those of human immunodeficiency virus (HIV). Both viruses infect T lymphocytes, monocytes and macrophages, and their replication cycle in infected cells is analogous. Due to marked similarity in genomic organization, virus structure, virus replication and disease pathogenesis of FIV and HIV, infection of cats with FIV is a useful tool to study and develop novel drugs and vaccines for HIV. Anti-retroviral drugs studied extensively in HIV infection have targeted different steps of the virus replication cycle: (1) inhibition of virus entry into susceptible cells at the level of attachment to host cell surface receptors and co-receptors; (2) inhibition of fusion of the virus membrane with the cell membrane; (3) blockade of reverse transcription of viral genomic RNA; (4) interruption of nuclear translocation and viral DNA integration into host genomes; (5) prevention of viral transcript processing and nuclear export; and (6) inhibition of virion assembly and maturation. Despite much success of anti-retroviral therapy slowing disease progression in people, similar therapy has not been thoroughly investigated in cats. In this article we review current pharmacological approaches and novel targets for anti-lentiviral therapy, and critically assess potentially suitable applications against FIV infection in cats.

  19. Wnt signaling inhibits CTL memory programming.

    Science.gov (United States)

    Xiao, Zhengguo; Sun, Zhifeng; Smyth, Kendra; Li, Lei

    2013-12-01

    Induction of functional CTLs is one of the major goals for vaccine development and cancer therapy. Inflammatory cytokines are critical for memory CTL generation. Wnt signaling is important for CTL priming and memory formation, but its role in cytokine-driven memory CTL programming is unclear. We found that wnt signaling inhibited IL-12-driven CTL activation and memory programming. This impaired memory CTL programming was attributed to up-regulation of eomes and down-regulation of T-bet. Wnt signaling suppressed the mTOR pathway during CTL activation, which was different to its effects on other cell types. Interestingly, the impaired memory CTL programming by wnt was partially rescued by mTOR inhibitor rapamycin. In conclusion, we found that crosstalk between wnt and the IL-12 signaling inhibits T-bet and mTOR pathways and impairs memory programming which can be recovered in part by rapamycin. In addition, direct inhibition of wnt signaling during CTL activation does not affect CTL memory programming. Therefore, wnt signaling may serve as a new tool for CTL manipulation in autoimmune diseases and immune therapy for certain cancers. Copyright © 2013 Elsevier Ltd. All rights reserved.

  20. Response inhibition in motor conversion disorder.

    Science.gov (United States)

    Voon, Valerie; Ekanayake, Vindhya; Wiggs, Edythe; Kranick, Sarah; Ameli, Rezvan; Harrison, Neil A; Hallett, Mark

    2013-05-01

    Conversion disorders (CDs) are unexplained neurological symptoms presumed to be related to a psychological issue. Studies focusing on conversion paralysis have suggested potential impairments in motor initiation or execution. Here we studied CD patients with aberrant or excessive motor movements and focused on motor response inhibition. We also assessed cognitive measures in multiple domains. We compared 30 CD patients and 30 age-, sex-, and education-matched healthy volunteers on a motor response inhibition task (go/no go), along with verbal motor response inhibition (color-word interference) and measures of attention, sustained attention, processing speed, language, memory, visuospatial processing, and executive function including planning and verbal fluency. CD patients had greater impairments in commission errors on the go/no go task (P conversion. Patients with nonepileptic seizures, a different form of conversion disorder, are commonly reported to have lower IQ and multiple cognitive deficits. Our results point toward potential differences between conversion disorder subgroups. © 2013 Movement Disorder Society. Copyright © 2013 Movement Disorder Society.

  1. The Kinetics of Carrier Transport Inhibition

    DEFF Research Database (Denmark)

    Rosenberg, T.; Wilbrandt, Robert Walter

    1962-01-01

    The kinetical treatment of enzymatic carrier transports as given in previous communications has been extended to conditions of inhibition. Various possible types of inhibitors have been considered differing in the site of attack (enzyme or carrier), in the mode of action (competing with the subst......The kinetical treatment of enzymatic carrier transports as given in previous communications has been extended to conditions of inhibition. Various possible types of inhibitors have been considered differing in the site of attack (enzyme or carrier), in the mode of action (competing...... with the substrate for the enzyme or the carrier or for both, competing with the carrier for the enzyme, or non-competitive) and in the ability of penetrating the membrane. Experiments are reported on the inhibition of glucose and fructose transport across the human red cell membrane by phlorizine, phloretine...... and polyphloretinephosphate. The results of the analysis for these inhibitors indicate a substrate competitive mode of action. The effect of reversing the transport direction by interchanging the substrate concentration has been treated for the case of a non-penetrating substrate competitive inhibitor in the external medium...

  2. Trace element inhibition of phytase activity.

    Science.gov (United States)

    Santos, T; Connolly, C; Murphy, R

    2015-02-01

    Nowadays, 70 % of global monogastric feeds contains an exogenous phytase. Phytase supplementation has enabled a more efficient utilisation of phytate phosphorous (P) and reduction of P pollution. Trace minerals, such as iron (Fe), zinc (Zn), copper (Cu) and manganese (Mn) are essential for maintaining health and immunity as well as being involved in animal growth, production and reproduction. Exogenous sources of phytase and trace elements are regularly supplemented to monogastric diets and usually combined in a premix. However, the possibility for negative interaction between individual components within the premix is high and is often overlooked. Therefore, this initial study focused on assessing the potential in vitro interaction between inorganic and organic chelated sources of Fe, Zn, Cu and Mn with three commercially available phytase preparations. Additionally, this study has investigated if the degree of enzyme inhibition was dependent of the type of chelated sources. A highly significant relationship between phytase inhibition, trace mineral type as well as mineral source and concentration, p phytases for Fe and Zn, as well as for Cu with E. coli and Aspergillus niger phytases. Different chelate trace mineral sources demonstrated diversifying abilities to inhibit exogenous phytase activity.

  3. Bioassays for the determination of nitrification inhibition

    Energy Technology Data Exchange (ETDEWEB)

    Grunditz, Camilla

    1999-07-01

    Requirements for nitrogen reduction in wastewater treatment plants were introduced in Sweden in the early 1990's. This was a governmental move to reduce the nitrogen discharges to the Baltic and Kattegat in order to prevent eutrophication. The nitrification process in wastewater treatment plants is performed by nitrifying bacteria. These are susceptible to inhibition and it is of great importance that the influent water does not contain toxic compounds. Therefore, there is a need for assays for the determination of nitrification inhibition. This thesis describes the development and applications of such bioassays. Pure cultures of Nitrosomonas sp. and Nitrobacter sp. were isolated from activated sludge of a wastewater treatment plant. These cultures were used as test organisms in the development of bioassays for nitrification inhibition measurements. The assays are based on two different principles; cell suspensions of the bacteria, performed in test tubes, and mediated amperometric biosensors with the bacteria immobilised. Ammonia oxidation and nitrite oxidation are studied separately without interference from other organisms, which makes it easier to interpret the results. The cell suspension assays were applied to samples of industrial and municipal wastewater. The Nitrosomonas and Nitrobacter assays showed to have different inhibition patterns. A large percentage of the Swedish municipal wastewater treatment plants were found to receive inhibitory influent water, but the inhibition level was generally low. Compared to an assay based on activated sludge, the screening method, the pure culture assays found more samples of influent water strongly inhibitory or stimulating. The highest correlation was found between the screening method and the Nitrosomonas assay. The Nitrobacter assay was found to be the most sensitive method. Assessment of toxicity of a number of chemical substances was studied using the biosensors, together with the cell suspension assays

  4. Inhibition of Breast Cancer Metastasis by Heregulin-Beta 1

    National Research Council Canada - National Science Library

    Yu, Dihua

    1999-01-01

    The major goal of this Idea proposal is to determine whether and how HRG-Beta1 inhibits breast cancer metastasis and to identify the functional domains that are sufficient for inhibition of breast cancer metastasis...

  5. A specific bioassay for the inhibition of flowering.

    Science.gov (United States)

    Blake, J

    1972-06-01

    A bioassay for the inhibition of flowering involving the in vitro culture of excised, partially-induced, apices of Viscaria candida is described. This bioassay has been used to detect flowering inhibition in extracts from Kalanchoe blossfeldiana.

  6. Differential effects of cognitive inhibition and intelligence on creativity

    OpenAIRE

    Benedek, Mathias; Franz, Fabiola; Heene, Moritz; Neubauer, Aljoscha C.

    2012-01-01

    There are different conceptions about how cognitive inhibition is related to creativity. Creativity has either been associated with effective inhibition, or with disinhibition, or with an adaptive engagement of inhibition. In this study, we examined the relationship of cognitive inhibition, assessed by means of the random motor generation task, with different measures of creativity. We also analyzed whether this relation is mediated by intelligence. We generally found a positive correlation o...

  7. Attention Inhibition Training Can Reduce Betel-Nut Chewing Time

    OpenAIRE

    Ho, Ming-Chou; Li, Ren-Hau; Tang, Tze-Chun

    2011-01-01

    Betel nut (or areca) is the fourth most commonly used drug worldwide after tobacco, alcohol, and caffeine. Many chemical ingredients of betel nut are carcinogenic. We examined whether the manipulation of attentional inhibition toward the areca-related stimuli could affect betel-nut chewing time. Three matched groups of habitual chewers were recruited: inhibit-areca, inhibit-non-areca, and control. This study consisted of a Go/No-Go task for inhibition training, followed by a taste test for ob...

  8. Use of bacillus subtilis strains to inhibit postharvest pathogenic fungi

    International Nuclear Information System (INIS)

    Arras, G.; Gambella, F.; Demontis, S.; Petretto, A.

    1995-01-01

    An isolate (87) of the bacillus subtilis strains isolated from cold stored citrus fruit 13 proved to inhibit the growth in vitro of the penicillium italicum used in the experiment (from 50.6% to 92.2%) and to inhibit botrytis cinerea (from 65.3% to 95.9%). A further test, superimposing on plates containing PDA strains Nos. 13, 173, and 160, totally inhibited the fungi. Tested in vivo on artificially bruised oranges, they significantly inhibited two fungi

  9. The development of children's inhibition: Does parenting matter?

    OpenAIRE

    Roskam, I.; Stievenart, Marie; Meunier, J.-C.; Noël, M.-P.

    2014-01-01

    Whereas a large body of research has investigated the maturation of inhibition in relation to the prefrontal cortex, far less research has been devoted to environmental factors that could contribute to inhibition improvement. The aim of the current study was to test whether and to what extent parenting matters for inhibition development from 2 to 8. years of age. Data were collected from 421 families, with 348 mother-child dyads and 342 father-child dyads participating. Children's inhibition ...

  10. Contour detection based on nonclassical receptive field inhibition

    NARCIS (Netherlands)

    Grigorescu, Cosmin; Petkov, Nicolai; Westenberg, Michel A.

    We propose a biologically motivated computational step, called nonclassical receptive field (non-CRF) inhibition, more generally surround inhibition or suppression, to improve contour detection in machine vision. Non-CRF inhibition is exhibited by 80% of the orientation-selective neurons in the

  11. The Effectiveness of Reward and Punishment Contingencies on Response Inhibition

    Science.gov (United States)

    Costantini, Arthur F.; Hoving, Kenneth L.

    1973-01-01

    The relative effectiveness of reward and punishment on the development of response inhibition was evaluated developmentally with kindergarteners and second graders. Removal of positive reinforcers was apparently more effective than reward in producing inhibiting at both age levels. Transfer of inhibition training was also evaluated. (DP)

  12. Effect of Adenine Concentration on the Corrosion Inhibition of Aisi ...

    African Journals Online (AJOL)

    This gave a surface coverage of 0.8956 and corrosion penetration rate of 0.022132mm/yr. Hence, the best adenine concentration for the corrosion inhibition of alloys 304L in 1.0M sulphuric acid solution to obtain optimum inhibition efficiency is 0.011M. Keywords: Corrosion, AISI 304L Steel, Inhibition efficiency, Degree of ...

  13. Inhibition of acetylcholinesterase activity by essential oil from Citrus paradisi.

    Science.gov (United States)

    Miyazawa, M; Tougo, H; Ishihara, M

    2001-01-01

    Inhibition of acetylcholinesterase (AChE) activity by essential oils of Citrus paradisi (grapefruit pink in USA) was studied. Inhibition of AChE was measured by the colorimetric method. Nootkatone and auraptene were isolated from C. paradisi oil and showed 17-24% inhibition of AChE activity at the concentration of 1.62 microg/mL.

  14. Inhibition and Adsorption impact of Leave Extracts of Cnidoscolus ...

    African Journals Online (AJOL)

    Corrosion inhibition in the presence of alokaloid and non alkaloid extracts of Cnidoscolus aconitifolius in 1M HCl was studied using the weight loss and hydrogen evolution techniques at 303, 313 and 333 K. The results obtained revealed that the inhibition efficiency decreased with increase in temperature. Inhibition ...

  15. A fusion-inhibiting peptide against Rift Valley fever virus inhibits multiple, diverse viruses.

    Directory of Open Access Journals (Sweden)

    Jeffrey W Koehler

    Full Text Available For enveloped viruses, fusion of the viral envelope with a cellular membrane is critical for a productive infection to occur. This fusion process is mediated by at least three classes of fusion proteins (Class I, II, and III based on the protein sequence and structure. For Rift Valley fever virus (RVFV, the glycoprotein Gc (Class II fusion protein mediates this fusion event following entry into the endocytic pathway, allowing the viral genome access to the cell cytoplasm. Here, we show that peptides analogous to the RVFV Gc stem region inhibited RVFV infectivity in cell culture by inhibiting the fusion process. Further, we show that infectivity can be inhibited for diverse, unrelated RNA viruses that have Class I (Ebola virus, Class II (Andes virus, or Class III (vesicular stomatitis virus fusion proteins using this single peptide. Our findings are consistent with an inhibition mechanism similar to that proposed for stem peptide fusion inhibitors of dengue virus in which the RVFV inhibitory peptide first binds to both the virion and cell membranes, allowing it to traffic with the virus into the endocytic pathway. Upon acidification and rearrangement of Gc, the peptide is then able to specifically bind to Gc and prevent fusion of the viral and endocytic membranes, thus inhibiting viral infection. These results could provide novel insights into conserved features among the three classes of viral fusion proteins and offer direction for the future development of broadly active fusion inhibitors.

  16. Curcumin inhibits aggregation of alpha-synuclein.

    Science.gov (United States)

    Pandey, Neeraj; Strider, Jeffrey; Nolan, William C; Yan, Sherry X; Galvin, James E

    2008-04-01

    Aggregation of amyloid-beta protein (Abeta) is a key pathogenic event in Alzheimer's disease (AD). Curcumin, a constituent of the Indian spice Turmeric is structurally similar to Congo Red and has been demonstrated to bind Abeta amyloid and prevent further oligomerization of Abeta monomers onto growing amyloid beta-sheets. Reasoning that oligomerization kinetics and mechanism of amyloid formation are similar in Parkinson's disease (PD) and AD, we investigated the effect of curcumin on alpha-synuclein (AS) protein aggregation. In vitro model of AS aggregation was developed by treatment of purified AS protein (wild-type) with 1 mM Fe3+ (Fenton reaction). It was observed that the addition of curcumin inhibited aggregation in a dose-dependent manner and increased AS solubility. The aggregation-inhibiting effect of curcumin was next investigated in cell culture utilizing catecholaminergic SH-SY5Y cell line. A model system was developed in which the red fluorescent protein (DsRed2) was fused with A53T mutant of AS and its aggregation examined under different concentrations of curcumin. To estimate aggregation in an unbiased manner, a protocol was developed in which the images were captured automatically through a high-throughput cell-based screening microscope. The obtained images were processed automatically for aggregates within a defined dimension of 1-6 microm. Greater than 32% decrease in mutant alpha-synuclein aggregation was observed within 48 h subsequent to curcumin addition. Our data suggest that curcumin inhibits AS oligomerization into higher molecular weight aggregates and therefore should be further explored as a potential therapeutic compound for PD and related disorders.

  17. Interferon-γ Inhibits Ebola Virus Infection.

    Directory of Open Access Journals (Sweden)

    Bethany A Rhein

    Full Text Available Ebola virus outbreaks, such as the 2014 Makona epidemic in West Africa, are episodic and deadly. Filovirus antivirals are currently not clinically available. Our findings suggest interferon gamma, an FDA-approved drug, may serve as a novel and effective prophylactic or treatment option. Using mouse-adapted Ebola virus, we found that murine interferon gamma administered 24 hours before or after infection robustly protects lethally-challenged mice and reduces morbidity and serum viral titers. Furthermore, we demonstrated that interferon gamma profoundly inhibits Ebola virus infection of macrophages, an early cellular target of infection. As early as six hours following in vitro infection, Ebola virus RNA levels in interferon gamma-treated macrophages were lower than in infected, untreated cells. Addition of the protein synthesis inhibitor, cycloheximide, to interferon gamma-treated macrophages did not further reduce viral RNA levels, suggesting that interferon gamma blocks life cycle events that require protein synthesis such as virus replication. Microarray studies with interferon gamma-treated human macrophages identified more than 160 interferon-stimulated genes. Ectopic expression of a select group of these genes inhibited Ebola virus infection. These studies provide new potential avenues for antiviral targeting as these genes that have not previously appreciated to inhibit negative strand RNA viruses and specifically Ebola virus infection. As treatment of interferon gamma robustly protects mice from lethal Ebola virus infection, we propose that interferon gamma should be further evaluated for its efficacy as a prophylactic and/or therapeutic strategy against filoviruses. Use of this FDA-approved drug could rapidly be deployed during future outbreaks.

  18. Interferon-γ Inhibits Ebola Virus Infection.

    Science.gov (United States)

    Rhein, Bethany A; Powers, Linda S; Rogers, Kai; Anantpadma, Manu; Singh, Brajesh K; Sakurai, Yasuteru; Bair, Thomas; Miller-Hunt, Catherine; Sinn, Patrick; Davey, Robert A; Monick, Martha M; Maury, Wendy

    2015-01-01

    Ebola virus outbreaks, such as the 2014 Makona epidemic in West Africa, are episodic and deadly. Filovirus antivirals are currently not clinically available. Our findings suggest interferon gamma, an FDA-approved drug, may serve as a novel and effective prophylactic or treatment option. Using mouse-adapted Ebola virus, we found that murine interferon gamma administered 24 hours before or after infection robustly protects lethally-challenged mice and reduces morbidity and serum viral titers. Furthermore, we demonstrated that interferon gamma profoundly inhibits Ebola virus infection of macrophages, an early cellular target of infection. As early as six hours following in vitro infection, Ebola virus RNA levels in interferon gamma-treated macrophages were lower than in infected, untreated cells. Addition of the protein synthesis inhibitor, cycloheximide, to interferon gamma-treated macrophages did not further reduce viral RNA levels, suggesting that interferon gamma blocks life cycle events that require protein synthesis such as virus replication. Microarray studies with interferon gamma-treated human macrophages identified more than 160 interferon-stimulated genes. Ectopic expression of a select group of these genes inhibited Ebola virus infection. These studies provide new potential avenues for antiviral targeting as these genes that have not previously appreciated to inhibit negative strand RNA viruses and specifically Ebola virus infection. As treatment of interferon gamma robustly protects mice from lethal Ebola virus infection, we propose that interferon gamma should be further evaluated for its efficacy as a prophylactic and/or therapeutic strategy against filoviruses. Use of this FDA-approved drug could rapidly be deployed during future outbreaks.

  19. Cannabidiol inhibits angiogenesis by multiple mechanisms.

    Science.gov (United States)

    Solinas, M; Massi, P; Cantelmo, A R; Cattaneo, M G; Cammarota, R; Bartolini, D; Cinquina, V; Valenti, M; Vicentini, L M; Noonan, D M; Albini, A; Parolaro, D

    2012-11-01

    Several studies have demonstrated anti-proliferative and pro-apoptotic actions of cannabinoids on various tumours, together with their anti-angiogenic properties. The non-psychoactive cannabinoid cannabidiol (CBD) effectively inhibits the growth of different types of tumours in vitro and in vivo and down-regulates some pro-angiogenic signals produced by glioma cells. As its anti-angiogenic properties have not been thoroughly investigated to date, and given its very favourable pharmacological and toxicological profile, here, we evaluated the ability of CBD to modulate tumour angiogenesis. Firstly, we evaluated the effect of CBD on human umbilical vein endothelial cell (HUVEC) proliferation and viability - through [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay and FACS analysis - and in vitro motility - both in a classical Boyden chamber test and in a wound-healing assay. We next investigated CBD effects on different angiogenesis-related proteins released by HUVECs, using an angiogenesis array kit and an ELISA directed at MMP2. Then we evaluated its effects on in vitro angiogenesis in treated HUVECs invading a Matrigel layer and in HUVEC spheroids embedded into collagen gels, and further characterized its effects in vivo using a Matrigel sponge model of angiogenesis in C57/BL6 mice. CBD induced HUVEC cytostasis without inducing apoptosis, inhibited HUVEC migration, invasion and sprouting in vitro, and angiogenesis in vivo in Matrigel sponges. These effects were associated with the down-modulation of several angiogenesis-related molecules. This study reveals that CBD inhibits angiogenesis by multiple mechanisms. Its dual effect on both tumour and endothelial cells supports the hypothesis that CBD has potential as an effective agent in cancer therapy. © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.

  20. Vitamin K3 (menadione) redox cycling inhibits cytochrome P450-mediated metabolism and inhibits parathion intoxication

    Energy Technology Data Exchange (ETDEWEB)

    Jan, Yi-Hua [Department of Environmental and Occupational Medicine, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ (United States); Richardson, Jason R., E-mail: jricha3@eohsi.rutgers.edu [Department of Environmental and Occupational Medicine, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ (United States); Baker, Angela A. [Department of Environmental and Occupational Medicine, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ (United States); Mishin, Vladimir [Department of Pharmacology and Toxicology, Rutgers University, Piscataway, NJ (United States); Heck, Diane E. [Department of Environmental Health Science, New York Medical College, Valhalla, NY (United States); Laskin, Debra L. [Department of Pharmacology and Toxicology, Rutgers University, Piscataway, NJ (United States); Laskin, Jeffrey D., E-mail: jlaskin@eohsi.rutgers.edu [Department of Environmental and Occupational Medicine, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ (United States)

    2015-10-01

    Parathion, a widely used organophosphate insecticide, is considered a high priority chemical threat. Parathion toxicity is dependent on its metabolism by the cytochrome P450 system to paraoxon (diethyl 4-nitrophenyl phosphate), a cytotoxic metabolite. As an effective inhibitor of cholinesterases, paraoxon causes the accumulation of acetylcholine in synapses and overstimulation of nicotinic and muscarinic cholinergic receptors, leading to characteristic signs of organophosphate poisoning. Inhibition of parathion metabolism to paraoxon represents a potential approach to counter parathion toxicity. Herein, we demonstrate that menadione (methyl-1,4-naphthoquinone, vitamin K3) is a potent inhibitor of cytochrome P450-mediated metabolism of parathion. Menadione is active in redox cycling, a reaction mediated by NADPH-cytochrome P450 reductase that preferentially uses electrons from NADPH at the expense of their supply to the P450s. Using human recombinant CYP 1A2, 2B6, 3A4 and human liver microsomes, menadione was found to inhibit the formation of paraoxon from parathion. Administration of menadione bisulfite (40 mg/kg, ip) to rats also reduced parathion-induced inhibition of brain cholinesterase activity, as well as parathion-induced tremors and the progression of other signs and symptoms of parathion poisoning. These data suggest that redox cycling compounds, such as menadione, have the potential to effectively mitigate the toxicity of organophosphorus pesticides including parathion which require cytochrome P450-mediated activation. - Highlights: • Menadione redox cycles with cytochrome P450 reductase and generates reactive oxygen species. • Redox cycling inhibits cytochrome P450-mediated parathion metabolism. • Short term administration of menadione inhibits parathion toxicity by inhibiting paraoxon formation.

  1. Vitamin K3 (menadione) redox cycling inhibits cytochrome P450-mediated metabolism and inhibits parathion intoxication

    International Nuclear Information System (INIS)

    Jan, Yi-Hua; Richardson, Jason R.; Baker, Angela A.; Mishin, Vladimir; Heck, Diane E.; Laskin, Debra L.; Laskin, Jeffrey D.

    2015-01-01

    Parathion, a widely used organophosphate insecticide, is considered a high priority chemical threat. Parathion toxicity is dependent on its metabolism by the cytochrome P450 system to paraoxon (diethyl 4-nitrophenyl phosphate), a cytotoxic metabolite. As an effective inhibitor of cholinesterases, paraoxon causes the accumulation of acetylcholine in synapses and overstimulation of nicotinic and muscarinic cholinergic receptors, leading to characteristic signs of organophosphate poisoning. Inhibition of parathion metabolism to paraoxon represents a potential approach to counter parathion toxicity. Herein, we demonstrate that menadione (methyl-1,4-naphthoquinone, vitamin K3) is a potent inhibitor of cytochrome P450-mediated metabolism of parathion. Menadione is active in redox cycling, a reaction mediated by NADPH-cytochrome P450 reductase that preferentially uses electrons from NADPH at the expense of their supply to the P450s. Using human recombinant CYP 1A2, 2B6, 3A4 and human liver microsomes, menadione was found to inhibit the formation of paraoxon from parathion. Administration of menadione bisulfite (40 mg/kg, ip) to rats also reduced parathion-induced inhibition of brain cholinesterase activity, as well as parathion-induced tremors and the progression of other signs and symptoms of parathion poisoning. These data suggest that redox cycling compounds, such as menadione, have the potential to effectively mitigate the toxicity of organophosphorus pesticides including parathion which require cytochrome P450-mediated activation. - Highlights: • Menadione redox cycles with cytochrome P450 reductase and generates reactive oxygen species. • Redox cycling inhibits cytochrome P450-mediated parathion metabolism. • Short term administration of menadione inhibits parathion toxicity by inhibiting paraoxon formation.

  2. Saw palmetto ethanol extract inhibits adipocyte differentiation.

    Science.gov (United States)

    Villaverde, Nicole; Galvis, Adriana; Marcano, Adriana; Priestap, Horacio A; Bennett, Bradley C; Barbieri, M Alejandro

    2013-07-01

    The fruits of saw palmetto have been used for the treatment of a variety of urinary and reproductive system problems. In this study we investigated whether the fruit extracts affect in vitro adipogenesis. Saw palmetto ethanol extract inhibited the lipid droplet accumulation by induction media in a dose-dependent manner, and it also attenuated the protein expressions of C-EBPα and PPARγ. Phosphorylation of Erk1/2 and Akt1 were also decreased by saw palmetto ethanol extract. This report suggests that saw palmetto extracts selectively affect the adipocyte differentiation through the modulation of several key factors that play a critical role during adipogenesis.

  3. Irradiation inhibits the regeneration of aneurogenic limbs

    International Nuclear Information System (INIS)

    Wallace, H.; Maden, M.

    1976-01-01

    The developing arms of axolotl larvae from the 2-digit stage onward and the aneurogenic arms of surgically denervated larvae maintained in parabiosis are able to regenerate after amputation. Such regeneration is uniformly inhibited by local irradiation of the arm, whether innervated or not. This demonstration refutes a recent hypothesis that x-rays interfere with a special activity of nerves required for regeneration, and supports the earlier concept that x-rays act directly on those cells which must proliferate to form the regenerated tissues

  4. Inhibition of sulfate reduction in paddy soils

    Energy Technology Data Exchange (ETDEWEB)

    Vamos, R

    1958-12-13

    The hydrogen sulfide formed in waterlogged soils is a serious problem in rice cultivation. It inhibits the uptake of water and nutrients and may even cause root-rot. Results can best be obtained by preventing the formation of hydrogen sulfide. It is formed mainly by reduction of sulfate for which the cellulose-butyric acid fermentation provides the hydrogen source. Addition of ammonium or potassium nitrate prevents the formation of H/sub 2/S. The hydrogen produced by butyric acid fermentation is used to reduce nitrate and consequently cannot be utilized by the sulfate-reducing bacteria as a source of energy. 6 references.

  5. Vaginal Lactobacillus isolates inhibit uropathogenic Escherichia coli.

    OpenAIRE

    Atassi , Fabrice; Brassart , Dominique; Grob , Philipp; Graf , Federico; Servin , Alain ,

    2006-01-01

    The purpose of this study was to investigate the antibacterial activities of Lactobacillus jensenii KS119.1 and KS121.1, and Lactobacillus gasserii KS120.1 and KS124.3 strains isolated from the vaginal microflora of healthy women, against uropathogenic, diffusely adhering Afa/Dr Escherichia coli (Afa/Dr DAEC) strains IH11128 and 7372 involved in recurrent cystitis. We observed that some of the Lactobacillus isolates inhibited the growth and decreased the viability of E. coli IH11128 and 7372....

  6. Research on inhibition of corneal neovascularization

    Directory of Open Access Journals (Sweden)

    Zhang-Hui Yang

    2015-12-01

    Full Text Available Corneal transparency is the basis of the normal physiological functions.However, corneal neovascularization(CNVmay occur in the infection, mechanical and chemical injury or under other pathological conditions,which make the cornea lose original transparency and severe visual impairment. In recent years, along with the development of immunology, molecular biology, biochemistry and other disciplines, there is more in-depth understanding on the CNV, and clinical treatment of CNV has made new breakthroughs. This article provides an overview of the inhibition of CNV.

  7. Na+/K+-ATPase: Activity and inhibition

    Science.gov (United States)

    Čolović, M.; Krstić, D.; Krinulović, K.; Momić, T.; Savić, J.; Vujačić, A.; Vasić, V.

    2009-09-01

    The aim of the study was to give an overview of the mechanism of inhibition of Na+/K+-ATPase activity induced by some specific and non specific inhibitors. For this purpose, the effects of some ouabain like compounds (digoxin, gitoxin), noble metals complexes ([PtCl2DMSO2], [AuCl4]-, [PdCl4]2-, [PdCl(dien)]+, [PdCl(Me4dien)]+), transition metal ions (Cu2+, Zn2+, Fe2+, Co2+), and heavy metal ions (Hg2+, Pb2+, Cd2+) on the activity of Na+/K+-ATPase from rat synaptic plasma membranes (SPM), porcine cerebral cortex and human erythrocytes were discussed.

  8. Inhibition of human aromatase complex (CYP19) by antiepileptic drugs

    DEFF Research Database (Denmark)

    Jacobsen, Naja Wessel; Halling-Sørensen, Bent; Birkved, Franziska Maria A Kramer

    2008-01-01

    of 1.4-49.7 mM. Carbamazepine, gabapentin, primidone, topiramate and vigabatrin showed no inhibition. Additionally, binary drug combinations were tested to investigate if combination therapy could potentiate the aromatase inhibition. Additive inhibition was seen in combination experiments...... with valproate and phenobarbital. When adding carbamazepine to a range of valproate concentrations no additional inhibition was seen. The data for some of the AEDs show that side effects on steroid synthesis in humans due to inhibition of aromatase should be considered....

  9. Australine, a pyrrolizidine alkaloid that inhibits amyloglucosidase and glycoprotein processing

    International Nuclear Information System (INIS)

    Tropea, J.E.; Molyneux, R.J.; Kaushal, G.P.; Pan, Y.T.; Mitchell, M.; Elbein, A.D.

    1989-01-01

    Australine is a polyhydroxylated pyrrolizidine alkaloid that was isolated from the seeds of the Australian tree Castanospermum australe and characterized by NMR and X-ray diffraction analysis. Since swainsonine and catanospermine are polyhydroxylated indolizidine alkaloids that inhibit specific glycosidases, the authors tested australine against a variety of exoglycosidases to determine whether it would inhibit any of these enzymes. This alkaloid proved to be a good inhibitor of the α-glucosidase amyloglucosidase (50% inhibition at 5.8 μM), but it did not inhibit β-glucosidase, α- or β-mannosidase, or α- or β-galactosidase. The inhibition of amyloglucosidase was of a competitive nature. Australine also inhibited the glycoprotein processing enzyme glucosidase I, but had only slight activity toward glucosidase II. When incubated with cultured cells, this alkaloid inhibited glycoprotein processing at the glucosidase I step and caused the accumulation of glycoproteins with Glc 3 Man 7-9 (GlcNAc) 2 -oligosaccharides

  10. Sprouting inhibition of rhizomes by gamma irradiation

    International Nuclear Information System (INIS)

    Hilmy, Nazly; Chosdu, Rahayu

    1985-01-01

    Sprouting inhibition by gamma irradiation to prolong the storage life of 4 species of rhizomes, namely curcuma domestica, kaemferia galanga, curcuma xanthoriza and curcuma aeruginosa, has been carried out. Two groups of samples were used, freshly harvested rhizomes and fresh rhizomes which have been stored for about two weeks. The samples were packed in a plastic net bag, each contained about 100 grams of rhizomes. Irradiation was carried out at room temperature at the doses of 0, 0.02, 0.04, 0.06, 0.08, 0.10, 0.15, 0.20 and 0.25 kGy. Post irradiation storage was done at room temperature with relative humidity ranging between 85 and 95%. The results showed that irradiation doses of 0.06 to 0.08 kGy was sufficient to inhibit sprouting of freshly harvested rhizomes and prolonged its storage life for 6 weeks, while in the other group sprouting still occured at the dose of 0.25 kGy. Irradiation dose up to 0.25 kGy did not cause significant effect on moisture and volatile oil contents, as well as volatile oil characteristics of the samples. About 50% of weight losses were found either in irradiated or unirradiated samples after being stored for 8 weeks. Odour and texture were evaluated organoleptically while mould growth and insect damage were observed visually. (author)

  11. Inhibition of DNA replication by ultraviolet light

    International Nuclear Information System (INIS)

    Edenberg, H.J.

    1976-01-01

    DNA replication in ultraviolet-irradiated HeLa cells was studied by two different techniques: measurements of the kinetics of semiconservative DNA synthesis, and DNA fiber autoradiography. In examining the kinetics of semiconservative DNA synthesis, density label was used to avoid measuring the incorporation due to repair replication. The extent of inhibition varied with time. After doses of less than 10 J/m 2 the rate was initially depressed but later showed some recovery. After higher doses, a constant, low rate of synthesis was seen for at least the initial 6 h. An analysis of these data indicated that the inhibition of DNA synthesis could be explained by replication forks halting at pyrimidine dimers. DNA fiber autoradiography was used to further characterize replication after ultraviolet irradiation. The average length of labeled segments in irradiated cells increased in the time immediately after irradiation, and then leveled off. This is the predicted pattern if DNA synthesis in each replicon continued at its previous rate until a lesion is reached, and then halted. The frequency of lesions that block synthesis is approximately the same as the frequency of pyrimidine dimers

  12. Soluble Aβ aggregates can inhibit prion propagation.

    Science.gov (United States)

    Sarell, Claire J; Quarterman, Emma; Yip, Daniel C-M; Terry, Cassandra; Nicoll, Andrew J; Wadsworth, Jonathan D F; Farrow, Mark A; Walsh, Dominic M; Collinge, John

    2017-11-01

    Mammalian prions cause lethal neurodegenerative diseases such as Creutzfeldt-Jakob disease (CJD) and consist of multi-chain assemblies of misfolded cellular prion protein (PrP C ). Ligands that bind to PrP C can inhibit prion propagation and neurotoxicity. Extensive prior work established that certain soluble assemblies of the Alzheimer's disease (AD)-associated amyloid β-protein (Aβ) can tightly bind to PrP C , and that this interaction may be relevant to their toxicity in AD. Here, we investigated whether such soluble Aβ assemblies might, conversely, have an inhibitory effect on prion propagation. Using cellular models of prion infection and propagation and distinct Aβ preparations, we found that the form of Aβ assemblies which most avidly bound to PrP in vitro also inhibited prion infection and propagation. By contrast, forms of Aβ which exhibit little or no binding to PrP were unable to attenuate prion propagation. These data suggest that soluble aggregates of Aβ can compete with prions for binding to PrP C and emphasize the bidirectional nature of the interplay between Aβ and PrP C in Alzheimer's and prion diseases. Such inhibitory effects of Aβ on prion propagation may contribute to the apparent fall-off in the incidence of sporadic CJD at advanced age where cerebral Aβ deposition is common. © 2017 The Authors.

  13. Ketose induced respiratory inhibition in isolated hepatocytes.

    Science.gov (United States)

    Martínez, P; Carrascosa, J M; Núñez de Castro, I

    1987-06-01

    The addition of 10 mM fructose or 10 mM tagatose to a suspension of hepatocytes caused respiratory inhibition, whereas no change in oxygen uptake was observed following the addition of glucose. However, incubations in the presence of fructose showed a high, aerobic glycolytic activity. Tagatose is phosphorylated to tagatose 1-phosphate but is not further metabolized by cell free liver extract. Moreover, the addition of fructose to glucagon treated cells also caused the Crabtree-like effect. The concentration of adenine nucleotides and inorganic phosphate (Pi) in the mitochondrial and cytosolic compartments during incubation (time 30 min) was determined by the digitonin fractionation procedure. In the presence of 10 mM fructose or tagatose, the total adenine nucleotide pools decreased by 40%; however, glucose produced no change. The addition of ketoses diminished the asymmetric distribution of extramitochondrial (ATP/ADP)e ratio and intramitochondrial (ATP/ADP)i ratio. At the same time the total mitochondrial Pi fell from 17 mM to 6-7 mM. The mitochondrial membrane potential (-161 mV) in the presence of fructose showed no changes during the 30 min experimental period. An increase in the NADH/NAD+ ratio was observed. These results suggest that in hepatocytes the inhibition of respiration is not necessarily linked with the enhanced aerobic glycolysis, by competition for common substrates.

  14. Lactam inhibiting Streptococcus mutans growth on titanium

    Energy Technology Data Exchange (ETDEWEB)

    Xavier, J.G.; Geremias, T.C.; Montero, J.F.D. [Center for Research on Dental Implants (CEPID), School of Dentistry (ODT), Federal University of Santa Catarina - UFSC, Florianópolis/SC, 88040-900 (Brazil); Vahey, B.R. [Herman Ostrow School of Dentistry of USC, 925 W 34 St, Los Angeles, CA 90089 (United States); Benfatti, C.A.M.; Souza, J.C.M.; Magini, R.S. [Center for Research on Dental Implants (CEPID), School of Dentistry (ODT), Federal University of Santa Catarina - UFSC, Florianópolis/SC, 88040-900 (Brazil); Pimenta, A.L., E-mail: andrea@intelab.ufsc.br [Department of Biologia, ERRMECe, Université de Cergy Pontoise, 2, Av. Adolphe Chauvin 95302 Cergy, Pontoise (France); Integrated Laboratories Technologies (InteLab), Dept. Chemical and Food Engineering (EQA), Federal University of Santa Catarina - UFSC, Florianópolis/SC, 88040-970 (Brazil)

    2016-11-01

    The aim of this work was to analyze the activity of novel synthetic lactams on preventing biofilm formation on titanium surfaces. Titanium (Ti6Al4V) samples were exposed to Streptococcus mutans cultures in the presence or absence of a synthetic lactam. After 48 h incubation, planktonic growth was determined by spectrophotometry. Biofilm was evaluated by crystal violet staining and colony forming units (CFU·ml{sup −1}), followed by scanning electron microscopy (SEM). Results showed that the average of adhered viable cells was approximately 1.5 × 10{sup 2} CFU/ml in the presence of lactam and 4 × 10{sup 2} CFU/ml in its absence. This novel compound was considerable active in reducing biofilm formation over titanium surfaces, indicating its potential for the development of antimicrobial drugs targeting the inhibition of the initial stages of bacterial biofilms on dental implants abutments. - Highlights: • A novel synthetic compound is tested on preventing biofilm formation on titanium surfaces • Biofilm inhibition has been achieved on titanium surfaces containing the novel compound. • Planktonic growth of S. mutans was not affected by the presence of lactams on titanium.

  15. Universal water-dilutable inhibited protective lubricants

    International Nuclear Information System (INIS)

    Mamtseva, M.V.; Kardash, N.V.; Latynina, M.B.

    1993-01-01

    In the interest of environmental protection, improvement of working conditions, and reduced fire hazard in production operations, water-based protective lubricants are now available in a wide assortment, and the production volume has increased greatly. The term water-dilutable inhibited protective lubricants (WDIPL) means water-soluble, water-emulsifiable, or water-dispersible products with the dual function of reducing friction and wear and protecting metal surfaces against corrosion for specified periods of time. According to the standard Unified System of Protection Against Corrosion and Aging (COST 9.103-78), WDIPLs are classed as products for the temporary corrosion protection of metals and end-items. In the general class of WDIPLs one can identify water-dilutable combination corrosion inhibitors, film-forming inhibited petroleum compositions (FIPC-d), detergent-preservative fluids, operational-preservative lubricating-cooling process compounds (ICPC), and, finally, universal multifunctional products. Combined corrosion inhibitors may consist of water-soluble organic and inorganic compounds; water/oil and oil-soluble surfactants - corrosion inhibitors of the chemisorption type or donor and/or acceptor types; shielding inhibitors of the adsorption type; and fast-acting water-displacing components. 23 refs

  16. Salinomycin, A Polyether Ionophoric Antibiotic, Inhibits Adipogenesis

    Science.gov (United States)

    Szkudlarek-Mikho, Maria; Saunders, Rudel A.; Yap, Sook Fan; Ngeow, Yun Fong; Chin, Khew-Voon

    2012-01-01

    The polyether ionophoric antibiotics including monensin, salinomycin, and narasin, are widely used in veterinary medicine and as food additives and growth promoters in animal husbandry including poultry farming. Their effects on human health, however, are not fully understood. Recent studies showed that salinomycin is a cancer stem cell inhibitor. Since poultry consumption has risen sharply in the last three decades, we asked whether the consumption of meat tainted with growth promoting antibiotics might have effects on adipose cells. We showed in this report that the ionophoric antibiotics inhibit the differentiation of preadipocytes into adipocytes. The block of differentiation is not due to the induction of apoptosis nor the inhibition of cell proliferation. In addition, salinomycin also suppresses the transcriptional activity of the CCAAT/enhancer binding proteins and the peroxisome proliferator-activated receptor γ. These results suggest that the ionophoric antibiotics can be exploited as novel anti-obesity therapeutics and as pharmacological probes for the study of adipose biology. Further, the pharmacological effects of salinomycin could be a harbinger of its toxicity on the adipose tissue and other susceptible target cells in cancer therapy. PMID:23123626

  17. Structural basis of kynurenine 3-monooxygenase inhibition.

    Science.gov (United States)

    Amaral, Marta; Levy, Colin; Heyes, Derren J; Lafite, Pierre; Outeiro, Tiago F; Giorgini, Flaviano; Leys, David; Scrutton, Nigel S

    2013-04-18

    Inhibition of kynurenine 3-monooxygenase (KMO), an enzyme in the eukaryotic tryptophan catabolic pathway (that is, kynurenine pathway), leads to amelioration of Huntington's-disease-relevant phenotypes in yeast, fruitfly and mouse models, as well as in a mouse model of Alzheimer's disease. KMO is a flavin adenine dinucleotide (FAD)-dependent monooxygenase and is located in the outer mitochondrial membrane where it converts l-kynurenine to 3-hydroxykynurenine. Perturbations in the levels of kynurenine pathway metabolites have been linked to the pathogenesis of a spectrum of brain disorders, as well as cancer and several peripheral inflammatory conditions. Despite the importance of KMO as a target for neurodegenerative disease, the molecular basis of KMO inhibition by available lead compounds has remained unknown. Here we report the first crystal structure of Saccharomyces cerevisiae KMO, in the free form and in complex with the tight-binding inhibitor UPF 648. UPF 648 binds close to the FAD cofactor and perturbs the local active-site structure, preventing productive binding of the substrate l-kynurenine. Functional assays and targeted mutagenesis reveal that the active-site architecture and UPF 648 binding are essentially identical in human KMO, validating the yeast KMO-UPF 648 structure as a template for structure-based drug design. This will inform the search for new KMO inhibitors that are able to cross the blood-brain barrier in targeted therapies against neurodegenerative diseases such as Huntington's, Alzheimer's and Parkinson's diseases.

  18. PD-1 checkpoint inhibition: Toxicities and management.

    Science.gov (United States)

    Hahn, Andrew W; Gill, David M; Agarwal, Neeraj; Maughan, Benjamin L

    2017-12-01

    With the recent approval of 5 PD-1/PD-L1 inhibitors for a number of malignancies, PD-1 axis inhibition is drastically changing the treatment landscape of immunotherapy in cancer. As PD-1/PD-L1 are involved in peripheral immune tolerance, inhibition of this immune checkpoint has led to novel immune-related adverse events including colitis, hepatitis, pneumonitis, rash, and endocrinopathies among many others. In this seminar, we will analyze the incidence of immune-related adverse events for nivolumab, pembrolizumab, atezolizumab, durvalumab, and avelumab. Then, we will discuss the specific management of the most common immune-mediated adverse events including colitis, hepatitis, pneumonitis, rash, endocrinopathies, nephritis, and neurologic toxicities. Immune-related adverse events are frequently treated with immunosuppressive medication such as steroids and mycofenolate mofetil. There are specific immune-related adverse events which are frequently seen by the treating oncologist from checkpoint inhibitors. It is essential to understand the recommended treatment options to minimize toxicity and mortality from this important class of anti-neoplastic therapies. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. Platelets Inhibit Migration of Canine Osteosarcoma Cells.

    Science.gov (United States)

    Bulla, S C; Badial, P R; Silva, R C; Lunsford, K; Bulla, C

    2017-01-01

    The interaction between platelets and tumour cells is important for tumour growth and metastasis. Thrombocytopenia or antiplatelet treatment negatively impact on cancer metastasis, demonstrating potentially important roles for platelets in tumour progression. To our knowledge, there is no information regarding the role of platelets in cancer progression in dogs. This study was designed to test whether canine platelets affected the migratory behaviour of three canine osteosarcoma cell lines and to give insights of molecular mechanisms. Intact platelets, platelet lysate and platelet releasate inhibited the migration of canine osteosarcoma cell lines. Addition of blood leucocytes to the platelet samples did not alter the inhibitory effect on migration. Platelet treatment also significantly downregulated the transcriptional levels of SNAI2 and TWIST1 genes. The interaction between canine platelets or molecules released during platelet activation and these tumour cell lines inhibits their migration, which suggests that canine platelets might antagonize metastasis of canine osteosarcoma. This effect is probably due to, at least in part, downregulation of genes related to epithelial-mesenchymal transition. Copyright © 2016. Published by Elsevier Ltd.

  20. Kaempferol inhibits thrombosis and platelet activation.

    Science.gov (United States)

    Choi, Jun-Hui; Park, Se-Eun; Kim, Sung-Jun; Kim, Seung

    2015-08-01

    The objectives of the present study were to investigate whether kaempferol affects pro-coagulant proteinase activity, fibrin clot formation, blood clot and thrombin (or collagen/epinephrine)-stimulated platelet activation, thrombosis, and coagulation in ICR (Imprinting Control Region) mice and SD (Sprague-Dawley) rats. Kaempferol significantly inhibited the enzymatic activities of thrombin and FXa by 68 ± 1.6% and 52 ± 2.4%, respectively. Kaempferol also inhibited fibrin polymer formation in turbidity. Microscopic analysis was performed using a fluorescent conjugate. Kaempferol completely attenuated phosphorylation of extracellular signal-regulated kinase (ERK) 1/2, p38, c-Jun N-terminal kinase (JNK) 1/2, and phosphoinositide 3-kinase (PI3K)/PKB (AKT) in thrombin-stimulated platelets and delayed aggregation time (clotting) by 34.6% in an assay of collagen/epinephrine-stimulated platelet activation. Moreover, kaempferol protected against thrombosis development in 3 animal models, including collagen/epinephrine- and thrombin-induced acute thromboembolism models and an FeCl3-induced carotid arterial thrombus model. The ex vivo anticoagulant effect of kaempferol was further confirmed in ICR mice. This study demonstrated that kaempferol may be clinically useful due to its ability to reduce or prevent thrombotic challenge. Copyright © 2015 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

  1. Lactam inhibiting Streptococcus mutans growth on titanium

    International Nuclear Information System (INIS)

    Xavier, J.G.; Geremias, T.C.; Montero, J.F.D.; Vahey, B.R.; Benfatti, C.A.M.; Souza, J.C.M.; Magini, R.S.; Pimenta, A.L.

    2016-01-01

    The aim of this work was to analyze the activity of novel synthetic lactams on preventing biofilm formation on titanium surfaces. Titanium (Ti6Al4V) samples were exposed to Streptococcus mutans cultures in the presence or absence of a synthetic lactam. After 48 h incubation, planktonic growth was determined by spectrophotometry. Biofilm was evaluated by crystal violet staining and colony forming units (CFU·ml −1 ), followed by scanning electron microscopy (SEM). Results showed that the average of adhered viable cells was approximately 1.5 × 10 2 CFU/ml in the presence of lactam and 4 × 10 2 CFU/ml in its absence. This novel compound was considerable active in reducing biofilm formation over titanium surfaces, indicating its potential for the development of antimicrobial drugs targeting the inhibition of the initial stages of bacterial biofilms on dental implants abutments. - Highlights: • A novel synthetic compound is tested on preventing biofilm formation on titanium surfaces • Biofilm inhibition has been achieved on titanium surfaces containing the novel compound. • Planktonic growth of S. mutans was not affected by the presence of lactams on titanium.

  2. Periostin Limits Tumor Response to VEGFA Inhibition.

    Science.gov (United States)

    Keklikoglou, Ioanna; Kadioglu, Ece; Bissinger, Stefan; Langlois, Benoît; Bellotti, Axel; Orend, Gertraud; Ries, Carola H; De Palma, Michele

    2018-03-06

    Resistance to antiangiogenic drugs limits their applicability in cancer therapy. Here, we show that revascularization and progression of pancreatic neuroendocrine tumors (PNETs) under extended vascular-endothelial growth factor A (VEGFA) blockade are dependent on periostin (POSTN), a matricellular protein expressed by stromal cells. Genetic deletion of Postn in RIP1-Tag2 mice blunted tumor rebounds of M2-like macrophages and αSMA + stromal cells in response to prolonged VEGFA inhibition and suppressed PNET revascularization and progression on therapy. POSTN deficiency also impeded the upregulation of basic fibroblast growth factor (FGF2), an adaptive mechanism previously implicated in PNET evasion from antiangiogenic therapy. Higher POSTN expression correlated with markers of M2-like macrophages in human PNETs, and depleting macrophages with a colony-stimulating factor 1 receptor (CSF1R) antibody inhibited PNET revascularization and progression under VEGFA blockade despite continued POSTN production. These findings suggest a role for POSTN in orchestrating resistance to anti-VEGFA therapy in PNETs. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

  3. Heat enhances radiation inhibition of wound healing

    International Nuclear Information System (INIS)

    Twomey, P.; Hill, S.; Joiner, M.; Hobson, B.; Denekamp, J.

    1987-01-01

    To study the effect of hyperthermia on the inhibition of healing by radiation, the authors used 2 models of wound tensile strength in mice. In one, tensile strength of 1 cm strips of wounded skin was measured. In the other, strength was measured on 2 by 1 by .3 cm surgical prosthetic sponges of polyvinyl alcohol which has been cut, resutured, and implanted subcutaneously. Granulation tissue grows into the pores of the sponges which gradually fill with collagen. Tensile strength in both models was measured on day 14 using a constant strain extensiometer. The wounds were given graduated doses of ortho-voltage radiation with or without hyperthermia. Maximum radiation sensitivity occurred during the period of rapid neovascularization in the first 5 days after wounding, when a loss of 80% in wound strength occurred with doses less than 20 gray. For single radiation doses given 48 hours after wounding, the authors found a steep dose-response curve with half maximum reduction in strength occurring in both models at approximately 10 gray. Hyperthermia was produced in two ways. Skin wounds were heated in a circulating water bath. In the sponge model, more uniform heating occurs with an RF generator scaled to the mouse. At a dose of 43 C for 30 minutes, no inhibition of healing by heat alone was found. However the combination of heat and radiation produced definite enhancement of radiation damage, with thermal enhancement ratios of up to 1.9 being observed

  4. Periostin Limits Tumor Response to VEGFA Inhibition

    Directory of Open Access Journals (Sweden)

    Ioanna Keklikoglou

    2018-03-01

    Full Text Available Resistance to antiangiogenic drugs limits their applicability in cancer therapy. Here, we show that revascularization and progression of pancreatic neuroendocrine tumors (PNETs under extended vascular-endothelial growth factor A (VEGFA blockade are dependent on periostin (POSTN, a matricellular protein expressed by stromal cells. Genetic deletion of Postn in RIP1-Tag2 mice blunted tumor rebounds of M2-like macrophages and αSMA+ stromal cells in response to prolonged VEGFA inhibition and suppressed PNET revascularization and progression on therapy. POSTN deficiency also impeded the upregulation of basic fibroblast growth factor (FGF2, an adaptive mechanism previously implicated in PNET evasion from antiangiogenic therapy. Higher POSTN expression correlated with markers of M2-like macrophages in human PNETs, and depleting macrophages with a colony-stimulating factor 1 receptor (CSF1R antibody inhibited PNET revascularization and progression under VEGFA blockade despite continued POSTN production. These findings suggest a role for POSTN in orchestrating resistance to anti-VEGFA therapy in PNETs.

  5. Inhibition by acrolein of light-induced stomatal opening through inhibition of inward-rectifying potassium channels in Arabidopsis thaliana.

    Science.gov (United States)

    Islam, Md Moshiul; Ye, Wenxiu; Matsushima, Daiki; Khokon, Md Atiqur Rahman; Munemasa, Shintaro; Nakamura, Yoshimasa; Murata, Yoshiyuki

    2015-01-01

    Acrolein is a reactive α,β-unsaturated aldehyde derived from lipid peroxides, which are produced in plants under a variety of stress. We investigated effects of acrolein on light-induced stomatal opening using Arabidopsis thaliana. Acrolein inhibited light-induced stomatal opening in a dose-dependent manner. Acrolein at 100 μM inhibited plasma membrane inward-rectifying potassium (Kin) channels in guard cells. Acrolein at 100 μM inhibited Kin channel KAT1 expressed in a heterologous system using Xenopus leaves oocytes. These results suggest that acrolein inhibits light-induced stomatal opening through inhibition of Kin channels in guard cells.

  6. 3-Bromopyruvate inhibits human gastric cancer tumor growth in nude mice via the inhibition of glycolysis.

    Science.gov (United States)

    Xian, Shu-Lin; Cao, Wei; Zhang, Xiao-Dong; Lu, Yun-Fei

    2015-02-01

    Tumor cells primarily depend upon glycolysis in order to gain energy. Therefore, the inhibition of glycolysis may inhibit tumor growth. Our previous study demonstrated that 3-bromopyruvate (3-BrPA) inhibited gastric cancer cell proliferation in vitro . However, the ability of 3-BrPA to suppress tumor growth in vivo, and its underlying mechanism, have yet to be elucidated. The aim of the present study was to investigate the inhibitory effect of 3-BrPA in an animal model of gastric cancer. It was identified that 3-BrPA exhibited strong inhibitory effects upon xenograft tumor growth in nude mice. In addition, the antitumor function of 3-BrPA exhibited a dose-effect association, which was similar to that of the chemotherapeutic agent, 5-fluorouracil. Furthermore, 3-BrPA exhibited low toxicity in the blood, liver and kidneys of the nude mice. The present study hypothesized that the inhibitory effect of 3-BrPA is achieved through the inhibition of hexokinase activity, which leads to the downregulation of B-cell lymphoma 2 (Bcl-2) expression, the upregulation of Bcl-2-associated X protein expression and the subsequent activation of caspase-3. These data suggest that 3-BrPA may be a novel therapy for the treatment of gastric cancer.

  7. Does SGLT2 inhibition with dapagliflozin overcome individual therapy resistance to RAAS inhibition?

    NARCIS (Netherlands)

    Petrykiv, Sergei; Laverman, Gozewijn D.; de Zeeuw, Dick; Heerspink, Hiddo J. L.

    Individual patients show a large variation in their response to renin-angiotensin-aldosteron system (RAAS) inhibition (RAASi), both in surrogates such as albuminuria and in hard renal outcomes. Sodium-glucose co-transporter 2 inhibitors (SGLT2) have been shown to lower albuminuria and to confer

  8. Ketoconazole inhibits the cellular uptake of anandamide via inhibition of FAAH at pharmacologically relevant concentrations.

    Directory of Open Access Journals (Sweden)

    Emmelie Björklund

    Full Text Available The antifungal compound ketoconazole has, in addition to its ability to interfere with fungal ergosterol synthesis, effects upon other enzymes including human CYP3A4, CYP17, lipoxygenase and thromboxane synthetase. In the present study, we have investigated whether ketoconazole affects the cellular uptake and hydrolysis of the endogenous cannabinoid receptor ligand anandamide (AEA.The effects of ketoconazole upon endocannabinoid uptake were investigated using HepG2, CaCo2, PC-3 and C6 cell lines. Fatty acid amide hydrolase (FAAH activity was measured in HepG2 cell lysates and in intact C6 cells. Ketoconazole inhibited the uptake of AEA by HepG2 cells and CaCo2 cells with IC50 values of 17 and 18 µM, respectively. In contrast, it had modest effects upon AEA uptake in PC-3 cells, which have a low expression of FAAH. In cell-free HepG2 lysates, ketoconazole inhibited FAAH activity with an IC50 value (for the inhibitable component of 34 µM.The present study indicates that ketoconazole can inhibit the cellular uptake of AEA at pharmacologically relevant concentrations, primarily due to its effects upon FAAH. Ketoconazole may be useful as a template for the design of dual-action FAAH/CYP17 inhibitors as a novel strategy for the treatment of prostate cancer.

  9. Glyphosate and AMPA inhibit cancer cell growth through inhibiting intracellular glycine synthesis.

    Science.gov (United States)

    Li, Qingli; Lambrechts, Mark J; Zhang, Qiuyang; Liu, Sen; Ge, Dongxia; Yin, Rutie; Xi, Mingrong; You, Zongbing

    2013-01-01

    Glycine is a nonessential amino acid that is reversibly converted from serine intracellularly by serine hydroxymethyltransferase. Glyphosate and its degradation product, aminomethylphosphonic acid (AMPA), are analogs to glycine, thus they may inhibit serine hydroxymethyltransferase to decrease intracellular glycine synthesis. In this study, we found that glyphosate and AMPA inhibited cell growth in eight human cancer cell lines but not in two immortalized human normal prostatic epithelial cell lines. AMPA arrested C4-2B and PC-3 cancer cells in the G1/G0 phase and inhibited entry into the S phase of the cell cycle. AMPA also promoted apoptosis in C4-2B and PC-3 cancer cell lines. AMPA upregulated p53 and p21 protein levels as well as procaspase 9 protein levels in C4-2B cells, whereas it downregulated cyclin D3 protein levels. AMPA also activated caspase 3 and induced cleavage of poly (adenosine diphosphate [ADP]-ribose) polymerase. This study provides the first evidence that glyphosate and AMPA can inhibit proliferation and promote apoptosis of cancer cells but not normal cells, suggesting that they have potentials to be developed into a new anticancer therapy.

  10. Inhibition of autophagy induced by proteasome inhibition increases cell death in human SHG-44 glioma cells.

    Science.gov (United States)

    Ge, Peng-Fei; Zhang, Ji-Zhou; Wang, Xiao-Fei; Meng, Fan-Kai; Li, Wen-Chen; Luan, Yong-Xin; Ling, Feng; Luo, Yi-Nan

    2009-07-01

    The ubiquitin-proteasome system (UPS) and lysosome-dependent macroautophagy (autophagy) are two major intracellular pathways for protein degradation. Recent studies suggest that proteasome inhibitors may reduce tumor growth and activate autophagy. Due to the dual roles of autophagy in tumor cell survival and death, the effect of autophagy on the destiny of glioma cells remains unclear. In this study, we sought to investigate whether inhibition of the proteasome can induce autophagy and the effects of autophagy on the fate of human SHG-44 glioma cells. The proteasome inhibitor MG-132 was used to induce autophagy in SHG-44 glioma cells, and the effect of autophagy on the survival of SHG-44 glioma cells was investigated using an autophagy inhibitor 3-MA. Cell viability was measured by MTT assay. Apoptosis and cell cycle were detected by flow cytometry. The expression of autophagy related proteins was determined by Western blot. MG-132 inhibited cell proliferation, induced cell death and cell cycle arrest at G(2)/M phase, and activated autophagy in SHG-44 glioma cells. The expression of autophagy-related Beclin-1 and LC3-I was significantly up-regulated and part of LC3-I was converted into LC3-II. However, when SHG-44 glioma cells were co-treated with MG-132 and 3-MA, the cells became less viable, but cell death and cell numbers at G(2)/M phase increased. Moreover, the accumulation of acidic vesicular organelles was decreased, the expression of Beclin-1 and LC3 was significantly down-regulated and the conversion of LC3-II from LC3-I was also inhibited. Inhibition of the proteasome can induce autophagy in human SHG-44 glioma cells, and inhibition of autophagy increases cell death. This discovery may shed new light on the effect of autophagy on modulating the fate of SHG-44 glioma cells.Acta Pharmacologica Sinica (2009) 30: 1046-1052; doi: 10.1038/aps.2009.71.

  11. Inhibition of GRP78 abrogates radioresistance in oropharyngeal carcinoma cells after EGFR inhibition by cetuximab.

    Directory of Open Access Journals (Sweden)

    Chaonan Sun

    Full Text Available The EGFR-specific mAb cetuximab is one of the most effective treatments for oropharyngeal carcinoma, while patient responses to EGFR inhibitors given alone are modest. Combination treatment with radiation can improve the efficacy of treatment through increasing radiosensitivity, while resistance to radiation after administration of cetuximab limits its efficiency. Radiation and drugs can damage the endoplasmic reticulum (ER homeostatic state and result in ER stress (ERS, subsequently causing resistance to radiation and drugs. Whether the ERS pathway is involved in radioresistance after administration of cetuximab has not been reported. Herein, we show that cetuximab could increase the radiosensitivity of FaDu cells but not Detroit562 cells. In addition, cetuximab inhibited the radiation-induced activation of the ERS signalling pathway IRE1α/ATF6-GRP78 in FaDu cells, while this effect was absent in Detroit562 cells. Silencing GRP78 increased the radiosensitivity of oropharyngeal carcinoma cells and inhibited radiation-induced DNA double-strand-break (DSB repair and autophagy. More interestingly, silencing GRP78 abrogated resistance to cetuximab and radiation in Detroit562 cells and had a synergistic effect with cetuximab in increasing the radiosensitivity of FaDu cells. Immunohistochemistry showed that overexpression of both GRP78 and EGFR was associated with a poor prognosis in oropharyngeal carcinoma patients (P<0.05. Overall, the results of this study show that radioresistance after EGFR inhibition by cetuximab is mediated by the ERS signalling pathway IRE1α/ATF6-GRP78. This suppression was consequently unable to inhibit radiation-induced DSB repair and autophagy in oropharyngeal carcinoma cells, which conferred resistance to radiotherapy and cetuximab. These results suggest that the cooperative effects of radiotherapy and cetuximab could be further improved by inhibiting GRP78 in non-responsive oropharyngeal carcinoma patients.

  12. A novel approach to inhibit bone resorption

    DEFF Research Database (Denmark)

    Panwar, Preety; Søe, Kent; Guido, Rafael VC

    2016-01-01

    BACKGROUND AND PURPOSE: Cathepsin K (CatK) is a major drug target for the treatment of osteoporosis. Potent active site-directed inhibitors have been developed and showed variable success in clinical trials. These inhibitors block the entire activity of CatK and thus may interfere with other...... pathways. The present study investigates the antiresorptive effect of an exosite inhibitor that selectively inhibits only the therapeutically relevant collagenase activity of CatK. EXPERIMENTAL APPROACH: Human osteoclasts and fibroblasts were used to analyse the effect of the exosite inhibitor, ortho......-dihydrotanshinone (DHT1), and the active site inhibitor, odanacatib (ODN), on bone resorption and TGF-ß1 degradation. Cell cultures, Western blot, light and scanning electron microscopy as well as energy dispersive X-ray spectroscopy, molecular modelling and enzymatic assays were used to evaluate the inhibitors. KEY...

  13. Diclofenac inhibits 27-hydroxycholesterol-induced inflammation.

    Science.gov (United States)

    Kim, Bo-Young; Son, Yonghae; Eo, Seong-Kug; Park, Young Chul; Kim, Koanhoi

    2016-09-23

    27-Hydroxycholesterol (27OHChol) is a cholesterol oxidation product that induces inflammation. In the current study we investigated the effects of diclofenac on inflammatory responses caused by 27OHChol using human monocyte/macrophage (THP-1) cells. Transcription and secretion of CCL2, CCL3, and CCL4 chemokines enhanced by 27OHChol were significantly attenuated by diclofenac in a concentration dependent manner. Migrations of monocytic cells and CCR5-positive Jurkat T cells were reduced proportionally to the concentrations of diclofenac. Superproduction of CCL2 and monocytic cell migration induced by 27OHChol plus LPS were significantly attenuated by diclofenac. Diclofenac also attenuated transcription of MMP-9 and release of its active gene product. These results indicate that diclofenac inhibits 27OHChol-induced inflammatory responses, thereby suppressing inflammation in a milieu rich in cholesterol oxidation products. Copyright © 2016 Elsevier Inc. All rights reserved.

  14. Isoform-specific inhibition of cyclophilins.

    Science.gov (United States)

    Daum, Sebastian; Schumann, Michael; Mathea, Sebastian; Aumüller, Tobias; Balsley, Molly A; Constant, Stephanie L; de Lacroix, Boris Féaux; Kruska, Fabian; Braun, Manfred; Schiene-Fischer, Cordelia

    2009-07-07

    Cyclophilins belong to the enzyme class of peptidyl prolyl cis-trans isomerases which catalyze the cis-trans isomerization of prolyl bonds in peptides and proteins in different folding states. Cyclophilins have been shown to be involved in a multitude of cellular functions like cell growth, proliferation, and motility. Among the 20 human cyclophilin isoenzymes, the two most abundant members of the cyclophilin family, CypA and CypB, exhibit specific cellular functions in several inflammatory diseases, cancer development, and HCV replication. A small-molecule inhibitor on the basis of aryl 1-indanylketones has now been shown to discriminate between CypA and CypB in vitro. CypA binding of this inhibitor has been characterized by fluorescence anisotropy- and isothermal titration calorimetry-based cyclosporin competition assays. Inhibition of CypA- but not CypB-mediated chemotaxis of mouse CD4(+) T cells by the inhibitor provided biological proof of discrimination in vivo.

  15. Inhibition of cellular oxidation by fluoride

    Energy Technology Data Exchange (ETDEWEB)

    Borei, H

    1945-01-01

    An attempt has been made to investigate the inhibition by fluoride of the oxidative processes which occur in the cell by way of the cytochrome oxidase-cytochrome system. Some chemical and physical properties of the fluoride ion are discussed, together with certain quantitative methods for the determination of fluoride. An exhaustive review of the literature concerning the effect of fluoride on enzymic processes has been compiled. The experiments have shown that the point of the attack by fluoride is to be found among the cytochromes. The inhibitory mechanism appears to be such that the haemoprotein is prevented from taking part in the preceding and succeeding links in the reaction chain. The blocking action leaves the prosthetic group of the haemoprotein completely unchanged. The experimental results indicate the formation of a fluorophosphoprotein complex, analogous to that found in the case of enolase. Magnesium may possibly play a part in this process.

  16. Inhibition of Neurogenesis by Zika virus Infection.

    Science.gov (United States)

    Ahmad, Fahim; Siddiqui, Amna; Kamal, Mohammad A; Sohrab, Sayed S

    2018-02-01

    The association between Zika virus infection and neurological disorder has raised urgent global alarm. The ongoing epidemic has triggered quick responses in the scientific community. The first case of Zika virus was reported in 2015 from Brazil and now has spread over 30 countries. Nearly four hundred cases of travel-associated Zika virus infection have also been reported in the United States. Zika virus is primarily transmitted by mosquito belongs to the genus Aedes that are widely distributed throughout the world including the Southern United States. Additionally, the virus can also be transmitted from males to females by sexual contact. The epidemiological investigations during the current outbreak found a causal link between infection in pregnant women and development of microcephaly in their unborn babies. This finding is a cause for grave concern since microcephaly is a serious neural developmental disorder that can lead to significant post-natal developmental abnormalities and disabilities. Recently, published data indicate that Zika virus infection affects the growth of fetal neural progenitor cells and cerebral neurons that results in malformation of cerebral cortex leading to microcephaly. Recently, it has been reported that Zika virus infection deregulates the signaling pathway of neuronal cell and inhibit the neurogenesis resulting into dementia. In this review we have discussed about the information about cellular and molecular mechanisms in neurodegeneration of human neuronal cells and inhibit the neurogenesis. Additionally, this information will be very helpful further not only in neuro-scientific research but also designing and development of management strategies for microcephaly and other mosquito borne disease. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  17. Spice phenolics inhibit human PMNL 5-lipoxygenase.

    Science.gov (United States)

    Prasad, N Satya; Raghavendra, R; Lokesh, B R; Naidu, K Akhilender

    2004-06-01

    A wide variety of phenolic compounds and flavonoids present in spices possess potent antioxidant, antimutagenic and anticarcinogenic activities. We examined whether 5-lipoxygenase (5-LO), the key enzyme involved in biosynthesis of leukotrienes is a possible target for the spices. Effect of aqueous extracts of turmeric, cloves, pepper, chili, cinnamon, onion and also their respective active principles viz., curcumin, eugenol, piperine, capsaicin, cinnamaldehyde, quercetin, and allyl sulfide were tested on human PMNL 5-LO activity by spectrophotomeric and HPLC methods. The formation of 5-LO product 5-HETE was significantly inhibited in a concentration-dependent manner with IC(50) values of 0.122-1.44 mg for aqueous extracts of spices and 25-83 microM for active principles, respectively. The order of inhibitory activity was of quercetin>eugenol>curcumin>cinnamaldehyde>piperine>capsaicin>allyl sulfide. Quercetin, eugenol and curcumin with one or more phenolic ring and methoxy groups in their structure showed high inhibitory effect, while the non-phenolic spice principle allyl sulfide showed least inhibitory effect on 5-LO. The inhibitory effect of quercetin, curcumin and eugenol was similar to that of synthetic 5-LO inhibitors-phenidone and NDGA. Moreover, the inhibitory potency of aqueous extracts of spice correlated with the active principles of their respective spices. The synergistic or antagonistic effect of mixtures of spice active principles and spice extracts were investigated and all the combinations of spice active principles/extracts exerted synergistic effect in inhibiting 5-LO activity. These findings clearly suggest that phenolic compounds present in spices might have physiological role in modulating 5-LO pathway.

  18. Inhibition of Zika Virus Replication by Silvestrol

    Directory of Open Access Journals (Sweden)

    Fabian Elgner

    2018-03-01

    Full Text Available The Zika virus (ZIKV outbreak in 2016 in South America with specific pathogenic outcomes highlighted the need for new antiviral substances with broad-spectrum activities to react quickly to unexpected outbreaks of emerging viral pathogens. Very recently, the natural compound silvestrol isolated from the plant Aglaia foveolata was found to have very potent antiviral effects against the (−-strand RNA-virus Ebola virus as well as against Corona- and Picornaviruses with a (+-strand RNA-genome. This antiviral activity is based on the impaired translation of viral RNA by the inhibition of the DEAD-box RNA helicase eukaryotic initiation factor-4A (eIF4A which is required to unwind structured 5´-untranslated regions (5′-UTRs of several proto-oncogenes and thereby facilitate their translation. Zika virus is a flavivirus with a positive-stranded RNA-genome harboring a 5′-capped UTR with distinct secondary structure elements. Therefore, we investigated the effects of silvestrol on ZIKV replication in A549 cells and primary human hepatocytes. Two different ZIKV strains were used. In both infected A549 cells and primary human hepatocytes, silvestrol has the potential to exert a significant inhibition of ZIKV replication for both analyzed strains, even though the ancestor strain from Uganda is less sensitive to silvestrol. Our data might contribute to identify host factors involved in the control of ZIKV infection and help to develop antiviral concepts that can be used to treat a variety of viral infections without the risk of resistances because a host protein is targeted.

  19. Notch Inhibits Osteoblast Differentiation and Causes Osteopenia

    Science.gov (United States)

    Zanotti, Stefano; Smerdel-Ramoya, Anna; Stadmeyer, Lisa; Durant, Deena; Radtke, Freddy; Canalis, Ernesto

    2008-01-01

    Notch receptors are determinants of cell fate decisions. To define the role of Notch in the adult skeleton, we created transgenic mice overexpressing the Notch intracellular domain (NICD) under the control of the type I collagen promoter. First-generation transgenics were small and osteopenic. Bone histomorphometry revealed that NICD caused a decrease in bone volume, secondary to a reduction in trabecular number; osteoblast and osteoclast number were decreased. Low fertility of founder mice and lethality of young pups did not allow the complete establishment of transgenic lines. To characterize the effect of Notch overexpression in vitro, NICD was induced in osteoblasts and stromal cells from Rosanotch mice, in which a STOP cassette flanked by loxP sites is upstream of NICD, by transduction with an adenoviral vector expressing Cre recombinase (Cre) under the control of the cytomegalovirus (CMV) promoter (Ad-CMV-Cre). NICD impaired osteoblastogenesis and inhibited Wnt/β-catenin signaling. To determine the effects of notch1 deletion in vivo, mice in which notch1 was flanked by loxP sequences (notch1loxP/loxP) were mated with mice expressing Cre recombinase under the control of the osteocalcin promoter. Conditional null notch1 mice had no obvious skeletal phenotype, possibly because of rescue by notch2; however, 1-month-old females exhibited a modest increase in osteoclast surface and eroded surface. Osteoblasts from notch1loxP/loxP mice, transduced with Ad-CMV-Cre and transfected with Notch2 small interfering RNA, displayed increased alkaline phosphatase activity. In conclusion, Notch signaling in osteoblasts causes osteopenia and impairs osteo-blastogenesis by inhibiting the Wnt/β-catenin pathway. PMID:18420737

  20. Cartilage proteoglycans inhibit fibronectin-mediated adhesion

    Science.gov (United States)

    Rich, A. M.; Pearlstein, E.; Weissmann, G.; Hoffstein, S. T.

    1981-09-01

    Normal tissues and organs show, on histological examination, a pattern of cellular and acellular zones that is characteristic and unique for each organ or tissue. This pattern is maintained in health but is sometimes destroyed by disease. For example, in mobile joints, the articular surfaces consist of relatively acellular hyaline cartilage, and the joint space is enclosed by a capsule of loose connective tissue with a lining of fibroblasts and macrophages. In the normal joint these cells are confined to the synovial lining and the articular surface remains acellular. In in vitro culture, macrophages and their precursor monocytes are very adhesive, and fibroblasts can migrate and overgrow surfaces such as collagen or plastic used for tissue culture. The fibroblasts adhere to collagen by means of fibronectin, which they synthesize and secrete1. Because the collagen of cartilage is capable of binding serum fibronectin2 and fibronectin is present in cartilage during its development3, these cells should, in theory, slowly migrate from the synovial lining to the articular surface. It is their absence from the articular cartilage in normal circumstances, and then presence in such pathological states as rheumatoid arthritis, that is striking. We therefore set out to determine whether a component of cartilage could prevent fibroblast adherence in a defined adhesion assay. As normal cartilage is composed of 50% proteoglycans and 50% collagen by dry weight4, we tested the possibility that the proteoglycans in cartilage inhibit fibroblast adhesion to collagen. We present here evidence that fibroblast spreading and adhesion to collagenous substrates is inhibited by cartilage proteoglycans.

  1. Inhibition of MAO by fractions and constituents of hypericum extract.

    Science.gov (United States)

    Bladt, S; Wagner, H

    1994-10-01

    The inhibition of monoamine oxidase (MAO) by six fractions from hypericum extract and three characteristic constituents (as pure substances) were analyzed in vitro and ex vivo to study the antidepressive mechanism of action. Rat brain homogenates were used as the in vitro model, while the ex vivo analysis was performed after intraperitoneal application of the test substances to albino rats. Massive inhibition of MAO-A could be shown with the total extract and all fractions only at the concentration of 10(-3) mol/L. At 10(-4) mol/L, one fraction rich in flavonoides showed an inhibition of 39%, and all other fractions demonstrated less than 25% inhibition. Using pure hypericin as well as in all ex vivo experiments, no relevant inhibiting effects could be shown. From the results it can be concluded that the clinically proven antidepressive effect of hypericum extract cannot be explained in terms of MAO inhibition.

  2. Gliclazide directly inhibits arginine-induced glucagon release

    DEFF Research Database (Denmark)

    Cejvan, Kenan; Coy, David H; Holst, Jens Juul

    2002-01-01

    Arginine-stimulated insulin and somatostatin release is enhanced by the sulfonylurea gliclazide. In contrast, gliclazide inhibits the glucagon response. The aim of the present study was to investigate whether this inhibition of glucagon release was mediated by a direct suppressive effect of glicl......Arginine-stimulated insulin and somatostatin release is enhanced by the sulfonylurea gliclazide. In contrast, gliclazide inhibits the glucagon response. The aim of the present study was to investigate whether this inhibition of glucagon release was mediated by a direct suppressive effect....... In islet perifusions with DC-41-33, arginine-induced glucagon release was inhibited by 66%. We therefore concluded that gliclazide inhibits glucagon release by a direct action on the pancreatic A cell....

  3. Molecular mechanisms of DNA repair inhibition by caffeine

    Energy Technology Data Exchange (ETDEWEB)

    Selby, C.P.; Sancar, A. (Univ. of North Carolina School of Medicine, Chapel Hill (USA))

    1990-05-01

    Caffeine potentiates the mutagenic and lethal effects of genotoxic agents. It is thought that this is due, at least in some organisms, to inhibition of DNA repair. However, direct evidence for inhibition of repair enzymes has been lacking. Using purified Escherichia coli DNA photolyase and (A)BC excinuclease, we show that the drug inhibits photoreactivation and nucleotide excision repair by two different mechanisms. Caffeine inhibits photoreactivation by interfering with the specific binding of photolyase to damaged DNA, and it inhibits nucleotide excision repair by promoting nonspecific binding of the damage-recognition subunit, UvrA, of (A)BC excinuclease. A number of other intercalators, including acriflavin and ethidium bromide, appear to inhibit the excinuclease by a similar mechanism--that is, by trapping the UvrA subunit in nonproductive complexes on undamaged DNA.

  4. Inhibition of Action, Thought, and Emotion: A Selective Neurobiological Review

    OpenAIRE

    Dillon, Daniel; Pizzagalli, Diego

    2007-01-01

    The neural bases of inhibitory function are reviewed, covering data from paradigms assessing inhibition of motor responses (antisaccade, go/nogo, stop-signal), cognitive sets (e.g., Wisconsin Card Sort Test), and emotion (fear extinction). The frontal cortex supports performance on these paradigms, but the specific neural circuitry varies: response inhibition depends upon fronto-basal ganglia networks, inhibition of cognitive sets is supported by orbitofrontal cortex, and retention of fear ex...

  5. High molecular weight polysaccharide that binds and inhibits virus

    Science.gov (United States)

    Konowalchuk, Thomas W

    2014-01-14

    This invention provides a high molecular weight polysaccharide capable of binding to and inhibiting virus and related pharmaceutical formulations and methods on inhibiting viral infectivity and/or pathogenicity, as well as immunogenic compositions. The invention further methods of inhibiting the growth of cancer cells and of ameliorating a symptom of aging. Additionally, the invention provides methods of detecting and/or quantifying and/or isolating viruses.

  6. Inhibition of poliovirus RNA synthesis by brefeldin A.

    OpenAIRE

    Maynell, L A; Kirkegaard, K; Klymkowsky, M W

    1992-01-01

    Brefeldin A (BFA), a fungal metabolite that blocks transport of newly synthesized proteins from the endoplasmic reticulum, was found to inhibit poliovirus replication 10(5)- to 10(6)-fold. BFA does not inhibit entry of poliovirus into the cell or translation of viral RNA. Poliovirus RNA synthesis, however, is completely inhibited by BFA. A specific class of membranous vesicles, with which the poliovirus replication complex is physically associated, is known to proliferate in poliovirus-infect...

  7. Chemical mechanism of the fluoride-inhibition of fermentation

    Energy Technology Data Exchange (ETDEWEB)

    Warburg, O; Christian, W

    1941-08-01

    Among the fluoride-sensitive fermentation elements, enolase is the most sensitive. An investigation was made, quantitatively, of fluoride inhibition for chemically pure magnesium-enolase using an optical enolase test. Data show that the effective compound for fluoride inhibition is a complex magnesium-fluoro-phosphate and that the magnesium-fluoro-phosphate inhibits fermentation by combining proportionally to its concentration with the ferment-protein in a dissociating manner.

  8. High molecular weight polysaccharide that binds and inhibits virus

    Energy Technology Data Exchange (ETDEWEB)

    Konowalchuk, Thomas W.; Konowalchuk, Jack

    2017-07-18

    This invention provides a high molecular weight polysaccharide capable of binding to and inhibiting virus and related pharmaceutical formulations and methods of inhibiting viral infectivity and/or pathogenicity, as well as immunogenic compositions. The invention further includes methods of inhibiting the growth of cancer cells and of ameliorating a symptom of aging. Additionally, the invention provides methods of detecting and/or quantifying and/or isolating viruses.

  9. A speculated cause of respiratory inhibition in infants.

    Science.gov (United States)

    Minowa, Hideki; Arai, Ikuyo; Yasuhara, Hajime; Ebisu, Reiko; Ohgitani, Ayako

    2018-10-01

    In our previous studies, we documented that threatened premature labor and asymmetrical intrauterine growth restriction were risk factors for respiratory inhibition. The goal of this study was to determine the cause of respiratory inhibition by considering perinatal risk factors. We examined 1497 infants with a gestational age of 36 weeks or greater. All infants were monitored using pulse oximetry and examined via cranial sonography. Respiratory inhibition was defined as severe hypoxemia caused by respiratory inhibition immediately after crying or gastroesophageal reflux or as a respiratory pause during feeding. We examined the relationships between respiratory inhibition and perinatal factors and speculated on the cause of respiratory inhibition. The median gestational age, birth weight, Apgar score at 1 min, and Apgar score at 5 min of the subjects were 38.9 weeks, 2930 g, 8.0 points, and 9.0 points, respectively. Respiratory inhibition was observed in 422 infants. Lateral ventricle enlargement and increased echogenicity in the ganglionic eminence were observed in 417 and 516 infants, respectively. Respiratory inhibition was significantly correlated with shorter gestational periods, twin pregnancies, lateral ventricle enlargement, and increased echogenicity in the ganglionic eminence. We speculate that umbilical cord compression is a major cause of respiratory inhibition.

  10. Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Ying-Nan P.; LaMarche, Matthew J.; Chan, Ho Man; Fekkes, Peter; Garcia-Fortanet, Jorge; Acker, Michael G.; Antonakos, Brandon; Chen, Christine Hiu-Tung; Chen, Zhouliang; Cooke, Vesselina G.; Dobson, Jason R.; Deng, Zhan; Fei, Feng; Firestone, Brant; Fodor, Michelle; Fridrich, Cary; Gao, Hui; Grunenfelder, Denise; Hao, Huai-Xiang; Jacob, Jaison; Ho, Samuel; Hsiao, Kathy; Kang, Zhao B.; Karki, Rajesh; Kato, Mitsunori; Larrow, Jay; La Bonte, Laura R.; Lenoir, Francois; Liu, Gang; Liu, Shumei; Majumdar, Dyuti; Meyer, Matthew J.; Palermo, Mark; Perez, Lawrence; Pu, Minying; Price, Edmund; Quinn, Christopher; Shakya, Subarna; Shultz, Michael D.; Slisz, Joanna; Venkatesan, Kavitha; Wang, Ping; Warmuth, Markus; Williams, Sarah; Yang, Guizhi; Yuan, Jing; Zhang, Ji-Hu; Zhu, Ping; Ramsey, Timothy; Keen, Nicholas J.; Sellers, William R.; Stams, Travis; Fortin , Pascal D. (Novartis)

    2016-06-29

    The non-receptor protein tyrosine phosphatase SHP2, encoded by PTPN11, has an important role in signal transduction downstream of growth factor receptor signalling and was the first reported oncogenic tyrosine phosphatase1. Activating mutations of SHP2 have been associated with developmental pathologies such as Noonan syndrome and are found in multiple cancer types, including leukaemia, lung and breast cancer and neuroblastoma1, 2, 3, 4, 5. SHP2 is ubiquitously expressed and regulates cell survival and proliferation primarily through activation of the RAS–ERK signalling pathway2, 3. It is also a key mediator of the programmed cell death 1 (PD-1) and B- and T-lymphocyte attenuator (BTLA) immune checkpoint pathways6, 7. Reduction of SHP2 activity suppresses tumour cell growth and is a potential target of cancer therapy8, 9. Here we report the discovery of a highly potent (IC50 = 0.071 μM), selective and orally bioavailable small-molecule SHP2 inhibitor, SHP099, that stabilizes SHP2 in an auto-inhibited conformation. SHP099 concurrently binds to the interface of the N-terminal SH2, C-terminal SH2, and protein tyrosine phosphatase domains, thus inhibiting SHP2 activity through an allosteric mechanism. SHP099 suppresses RAS–ERK signalling to inhibit the proliferation of receptor-tyrosine-kinase-driven human cancer cells in vitro and is efficacious in mouse tumour xenograft models. Together, these data demonstrate that pharmacological inhibition of SHP2 is a valid therapeutic approach for the treatment of cancers.

  11. Arctigenin Inhibits Liver Cancer Tumorigenesis by Inhibiting Gankyrin Expression via C/EBPα and PPARα

    OpenAIRE

    Ying Sun; Ying Sun; Yu-jun Tan; Yu-jun Tan; Zhan-zhao Lu; Zhan-zhao Lu; Bing-bing Li; Bing-bing Li; Cheng-hong Sun; Cheng-hong Sun; Tao Li; Tao Li; Li-li Zhao; Li-li Zhao; Zhong Liu

    2018-01-01

    Burdock (Arctium lappa) is a popular vegetable in China and Japan that is consumed for its general health benefits. The principal active component of burdock is arctigenin, which shows a range of bioactivities in vivo and in vitro. Here, we investigated the potential anti-tumor effects of arctigenin using two human hepatocellular carcinoma (HCC) cell lines, HepG2 and Hep3B, and sought to elucidate its potential mechanisms of action. Our results showed that arctigenin treatment inhibited cell ...

  12. Glyphosate and AMPA inhibit cancer cell growth through inhibiting intracellular glycine synthesis

    Directory of Open Access Journals (Sweden)

    Li Q

    2013-07-01

    Full Text Available Qingli Li,1,2 Mark J Lambrechts,1 Qiuyang Zhang,1 Sen Liu,1 Dongxia Ge,1 Rutie Yin,2 Mingrong Xi,2 Zongbing You1 1Departments of Structural and Cellular Biology and Orthopaedic Surgery, Tulane Cancer Center and Louisiana Cancer Research Consortium, Tulane Center for Stem Cell Research and Regenerative Medicine, and Tulane Center for Aging, Tulane University Health Sciences Center, New Orleans, LA, USA; 2Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, People’s Republic of China Abstract: Glycine is a nonessential amino acid that is reversibly converted from serine intracellularly by serine hydroxymethyltransferase. Glyphosate and its degradation product, aminomethylphosphonic acid (AMPA, are analogs to glycine, thus they may inhibit serine hydroxymethyltransferase to decrease intracellular glycine synthesis. In this study, we found that glyphosate and AMPA inhibited cell growth in eight human cancer cell lines but not in two immortalized human normal prostatic epithelial cell lines. AMPA arrested C4-2B and PC-3 cancer cells in the G1/G0 phase and inhibited entry into the S phase of the cell cycle. AMPA also promoted apoptosis in C4-2B and PC-3 cancer cell lines. AMPA upregulated p53 and p21 protein levels as well as procaspase 9 protein levels in C4-2B cells, whereas it downregulated cyclin D3 protein levels. AMPA also activated caspase 3 and induced cleavage of poly (adenosine diphosphate [ADP]-ribose polymerase. This study provides the first evidence that glyphosate and AMPA can inhibit proliferation and promote apoptosis of cancer cells but not normal cells, suggesting that they have potentials to be developed into a new anticancer therapy. Keywords: serine hydroxymethyltransferase, prostate cancer, apoptosis

  13. Ketamine inhibits 45Ca influx and catecholamine secretion by inhibiting 22Na influx in cultured bovine adrenal medullary cells

    International Nuclear Information System (INIS)

    Takara, Hiroshi; Wada, Akihiko; Arita, Masahide; Izumi, Futoshi; Sumikawa, Koji

    1986-01-01

    The effects of ketamine, an intravenous anesthetic, on 22 Na influx, 45 Ca influx and catecholamine secretion were investigated in cultured bovine adrenal medullary cells. Ketamine inhibited carbachol-induced 45 Ca influx and catecholamine secretion in a concentration-dependent manner with a similar potency. Ketamine also reduced veratridine-induced 45 Ca influx and catecholamine secretion. The influx of 22 Na caused by carbachol or by veratridine was suppressed by ketamine with a concentration-inhibition curve similar to that of 45 Ca influx and catecholamine secretion. Inhibition by ketamine of the carbachol-induced influx of 22 Na, 45 Ca and secretion of catecholamines was not reversed by the increased concentrations of carbachol. These observations indicate that ketamine, at clinical concentrations, can inhibit nicotinic receptor-associated ionic channels and that the inhibition of Na influx via the receptor-associated ionic channels is responsible for the inhibition of carbachol-induced Ca influx and catecholamine secretion. (Auth.)

  14. Fluoxetine-induced inhibition of synaptosomal [3H]5-HT release: Possible Ca2+-channel inhibition

    International Nuclear Information System (INIS)

    Stauderman, K.A.; Gandhi, V.C.; Jones, D.J.

    1992-01-01

    Fluoxetine, a selective 5-Ht uptake inhibitor, inhibited 15 mM K + -induced [ 3 H]5-HT release from rat spinal cord and cortical synaptosomes at concentrations > 0.5 uM. This effect reflected a property shared by another selective 5-HT uptake inhibitor paroxetine but not by less selective uptake inhibitors such as amitriptyline, desipramine, imipramine or nortriptyline. Inhibition of release by fluoxetine was inversely related to both the concentration of K + used to depolarize the synaptosomes and the concentration of external Ca 2+ . Experiments aimed at determining a mechanism of action revealed that fluoxetine did not inhibit voltage-independent release of [ 3 H]5-HT release induced by the Ca 2+ -ionophore A 23187 or Ca 2+ -independent release induced by fenfluramine. Moreover the 5-HT autoreceptor antagonist methiothepin did not reverse the inhibitory actions of fluoxetine on K + -induced release. Further studies examined the effects of fluoxetine on voltage-dependent Ca 2+ channels and Ca 2+ entry

  15. Vitamin K3 (menadione) redox cycling inhibits cytochrome P450-mediated metabolism and inhibits parathion intoxication.

    Science.gov (United States)

    Jan, Yi-Hua; Richardson, Jason R; Baker, Angela A; Mishin, Vladimir; Heck, Diane E; Laskin, Debra L; Laskin, Jeffrey D

    2015-10-01

    Parathion, a widely used organophosphate insecticide, is considered a high priority chemical threat. Parathion toxicity is dependent on its metabolism by the cytochrome P450 system to paraoxon (diethyl 4-nitrophenyl phosphate), a cytotoxic metabolite. As an effective inhibitor of cholinesterases, paraoxon causes the accumulation of acetylcholine in synapses and overstimulation of nicotinic and muscarinic cholinergic receptors, leading to characteristic signs of organophosphate poisoning. Inhibition of parathion metabolism to paraoxon represents a potential approach to counter parathion toxicity. Herein, we demonstrate that menadione (methyl-1,4-naphthoquinone, vitamin K3) is a potent inhibitor of cytochrome P450-mediated metabolism of parathion. Menadione is active in redox cycling, a reaction mediated by NADPH-cytochrome P450 reductase that preferentially uses electrons from NADPH at the expense of their supply to the P450s. Using human recombinant CYP 1A2, 2B6, 3A4 and human liver microsomes, menadione was found to inhibit the formation of paraoxon from parathion. Administration of menadione bisulfite (40mg/kg, ip) to rats also reduced parathion-induced inhibition of brain cholinesterase activity, as well as parathion-induced tremors and the progression of other signs and symptoms of parathion poisoning. These data suggest that redox cycling compounds, such as menadione, have the potential to effectively mitigate the toxicity of organophosphorus pesticides including parathion which require cytochrome P450-mediated activation. Copyright © 2015 Elsevier Inc. All rights reserved.

  16. Inhibition of chrysin on xanthine oxidase activity and its inhibition mechanism.

    Science.gov (United States)

    Lin, Suyun; Zhang, Guowen; Liao, Yijing; Pan, Junhui

    2015-11-01

    Chrysin, a bioactive flavonoid, was investigated for its potential to inhibit the activity of xanthine oxidase (XO), a key enzyme catalyzing xanthine to uric acid and finally causing gout. The kinetic analysis showed that chrysin possessed a strong inhibition on XO ability in a reversible competitive manner with IC50 value of (1.26±0.04)×10(-6)molL(-1). The results of fluorescence titrations indicated that chrysin bound to XO with high affinity, and the interaction was predominately driven by hydrogen bonds and van der Waals forces. Analysis of circular dichroism demonstrated that chrysin induced the conformational change of XO with increases in α-helix and β-sheet and reductions in β-turn and random coil structures. Molecular simulation revealed that chrysin interacted with the amino acid residues Leu648, Phe649, Glu802, Leu873, Ser876, Glu879, Arg880, Phe1009, Thr1010, Val1011 and Phe1013 located within the active cavity of XO. The mechanism of chrysin on XO activity may be the insertion of chrysin into the active site occupying the catalytic center of XO to avoid the entrance of xanthine and causing conformational changes in XO. Furthermore, the interaction assays indicated that chrysin and its structural analog apigenin exhibited an additive effect on inhibition of XO. Copyright © 2015 Elsevier B.V. All rights reserved.

  17. Inhibition of lignin-derived phenolic compounds to cellulase.

    Science.gov (United States)

    Qin, Lei; Li, Wen-Chao; Liu, Li; Zhu, Jia-Qing; Li, Xia; Li, Bing-Zhi; Yuan, Ying-Jin

    2016-01-01

    Lignin-derived phenolic compounds are universal in the hydrolysate of pretreated lignocellulosic biomass. The phenolics reduce the efficiency of enzymatic hydrolysis and increase the cost of ethanol production. We investigated inhibition of phenolics on cellulase during enzymatic hydrolysis using vanillin as one of the typical lignin-derived phenolics and Avicel as cellulose substrate. As vanillin concentration increased from 0 to 10 mg/mL, cellulose conversion after 72-h enzymatic hydrolysis decreased from 53 to 26 %. Enzyme deactivation and precipitation were detected with the vanillin addition. The enzyme concentration and activity consecutively decreased during hydrolysis, but the inhibition degree, expressed as the ratio of the cellulose conversion without vanillin to the conversion with vanillin (A 0 /A), was almost independent on hydrolysis time. Inhibition can be mitigated by increasing cellulose loading or cellulase concentration. The inhibition degree showed linear relationship with the vanillin concentration and exponential relationship with the cellulose loading and the cellulase concentration. The addition of calcium chloride, BSA, and Tween 80 did not release the inhibition of vanillin significantly. pH and temperature for hydrolysis also showed no significant impact on inhibition degree. The presence of hydroxyl group, carbonyl group, and methoxy group in phenolics affected the inhibition degree. Besides phenolics concentration, other factors such as cellulose loading, enzyme concentration, and phenolic structure also affect the inhibition of cellulose conversion. Lignin-blocking agents have little effect on the inhibition effect of soluble phenolics, indicating that the inhibition mechanism of phenolics to enzyme is likely different from insoluble lignin. The inhibition of soluble phenolics can hardly be entirely removed by increasing enzyme concentration or adding blocking proteins due to the dispersity and multiple binding sites of phenolics

  18. Altered cortical processing of motor inhibition in schizophrenia.

    Science.gov (United States)

    Lindberg, Påvel G; Térémetz, Maxime; Charron, Sylvain; Kebir, Oussama; Saby, Agathe; Bendjemaa, Narjes; Lion, Stéphanie; Crépon, Benoît; Gaillard, Raphaël; Oppenheim, Catherine; Krebs, Marie-Odile; Amado, Isabelle

    2016-12-01

    Inhibition is considered a key mechanism in schizophrenia. Short-latency intracortical inhibition (SICI) in the motor cortex is reduced in schizophrenia and is considered to reflect locally deficient γ-aminobutyric acid (GABA)-ergic modulation. However, it remains unclear how SICI is modulated during motor inhibition and how it relates to neural processing in other cortical areas. Here we studied motor inhibition Stop signal task (SST) in stabilized patients with schizophrenia (N = 28), healthy siblings (N = 21) and healthy controls (n = 31) matched in general cognitive status and educational level. Transcranial magnetic stimulation (TMS) and functional magnetic resonance imaging (fMRI) were used to investigate neural correlates of motor inhibition. SST performance was similar in patients and controls. SICI was modulated by the task as expected in healthy controls and siblings but was reduced in patients with schizophrenia during inhibition despite equivalent motor inhibition performance. fMRI showed greater prefrontal and premotor activation during motor inhibition in schizophrenia. Task-related modulation of SICI was higher in subjects who showed less inhibition-related activity in pre-supplementary motor area (SMA) and cingulate motor area. An exploratory genetic analysis of selected markers of inhibition (GABRB2, GAD1, GRM1, and GRM3) did not explain task-related differences in SICI or cortical activation. In conclusion, this multimodal study provides direct evidence of a task-related deficiency in SICI modulation in schizophrenia likely reflecting deficient GABA-A related processing in motor cortex. Compensatory activation of premotor areas may explain similar motor inhibition in patients despite local deficits in intracortical processing. Task-related modulation of SICI may serve as a useful non-invasive GABAergic marker in development of therapeutic strategies in schizophrenia. Copyright © 2016 Elsevier Ltd. All rights reserved.

  19. Pharmacologic inhibition of lactate production prevents myofibroblast differentiation.

    Science.gov (United States)

    Kottmann, Robert Matthew; Trawick, Emma; Judge, Jennifer L; Wahl, Lindsay A; Epa, Amali P; Owens, Kristina M; Thatcher, Thomas H; Phipps, Richard P; Sime, Patricia J

    2015-12-01

    Myofibroblasts are one of the primary cell types responsible for the accumulation of extracellular matrix in fibrosing diseases, and targeting myofibroblast differentiation is an important therapeutic strategy for the treatment of pulmonary fibrosis. Transforming growth factor-β (TGF-β) has been shown to be an important inducer of myofibroblast differentiation. We previously demonstrated that lactate dehydrogenase and its metabolic product lactic acid are important mediators of myofibroblast differentiation, via acid-induced activation of latent TGF-β. Here we explore whether pharmacologic inhibition of LDH activity can prevent TGF-β-induced myofibroblast differentiation. Primary human lung fibroblasts from healthy patients and those with pulmonary fibrosis were treated with TGF-β and or gossypol, an LDH inhibitor. Protein and RNA were analyzed for markers of myofibroblast differentiation and extracellular matrix generation. Gossypol inhibited TGF-β-induced expression of the myofibroblast marker α-smooth muscle actin (α-SMA) in a dose-dependent manner in both healthy and fibrotic human lung fibroblasts. Gossypol also inhibited expression of collagen 1, collagen 3, and fibronectin. Gossypol inhibited LDH activity, the generation of extracellular lactic acid, and the rate of extracellular acidification in a dose-dependent manner. Furthermore, gossypol inhibited TGF-β bioactivity in a dose-dependent manner. Concurrent treatment with an LDH siRNA increased the ability of gossypol to inhibit TGF-β-induced myofibroblast differentiation. Gossypol inhibits TGF-β-induced myofibroblast differentiation through inhibition of LDH, inhibition of extracellular accumulation of lactic acid, and inhibition of TGF-β bioactivity. These data support the hypothesis that pharmacologic inhibition of LDH may play an important role in the treatment of pulmonary fibrosis. Copyright © 2015 the American Physiological Society.

  20. High outgroup entitativity can inhibit intergroup retribution.

    Science.gov (United States)

    Newheiser, Anna-Kaisa; Dovidio, John F

    2015-06-01

    Understanding the psychological processes that are involved in the perpetuation and escalation of intergroup conflict remains an important goal for intergroup relations research. In the present research, we examined perceived outgroup entitativity as a potential determinant of intergroup hostility. In intergroup conflict situations, high-entitative outgroups are perceived as particularly deserving of retribution; however, high-entitative outgroups are also perceived as efficacious and capable of retaliating successfully, suggesting that people may inhibit hostility against high-entitative (vs. low-entitative) outgroups that are in a position to retaliate. We tested this prediction in two studies. In Study 1, we manipulated intergroup provocation and outgroup entitativity, and found that higher negative mood predicted greater aggression against a low-entitative provoker outgroup, but failed to predict aggression against a high-entitative provoker outgroup that was plausibly in a position to retaliate. In Study 2, we held provocation constant while manipulating outgroup entitativity and the possibility of retaliation by the outgroup, and found that people acted in a retributive manner against a high-entitative provoker outgroup only when the outgroup was not in a position to retaliate. Implications for intergroup conflict are discussed. © 2014 The British Psychological Society.

  1. Poxviruses Utilize Multiple Strategies to Inhibit Apoptosis

    Science.gov (United States)

    Nichols, Daniel Brian; De Martini, William; Cottrell, Jessica

    2017-01-01

    Cells have multiple means to induce apoptosis in response to viral infection. Poxviruses must prevent activation of cellular apoptosis to ensure successful replication. These viruses devote a substantial portion of their genome to immune evasion. Many of these immune evasion products expressed during infection antagonize cellular apoptotic pathways. Poxvirus products target multiple points in both the extrinsic and intrinsic apoptotic pathways, thereby mitigating apoptosis during infection. Interestingly, recent evidence indicates that poxviruses also hijack cellular means of eliminating apoptotic bodies as a means to spread cell to cell through a process called apoptotic mimicry. Poxviruses are the causative agent of many human and veterinary diseases. Further, there is substantial interest in developing these viruses as vectors for a variety of uses including vaccine delivery and as oncolytic viruses to treat certain human cancers. Therefore, an understanding of the molecular mechanisms through which poxviruses regulate the cellular apoptotic pathways remains a top research priority. In this review, we consider anti-apoptotic strategies of poxviruses focusing on three relevant poxvirus genera: Orthopoxvirus, Molluscipoxvirus, and Leporipoxvirus. All three genera express multiple products to inhibit both extrinsic and intrinsic apoptotic pathways with many of these products required for virulence. PMID:28786952

  2. Inhibition of oxidation in nuclear graphite

    International Nuclear Information System (INIS)

    Winston, Philip L.; Sterbentz, James W.; Windes, William E.

    2015-01-01

    Graphite is a fundamental material of high-temperature gas-cooled nuclear reactors, providing both structure and neutron moderation. Its high thermal conductivity, chemical inertness, thermal heat capacity, and high thermal structural stability under normal and off-normal conditions contribute to the inherent safety of these reactor designs. One of the primary safety issues for a high-temperature graphite reactor core is the possibility of rapid oxidation of the carbon structure during an off-normal design basis event where an oxidising atmosphere (air ingress) can be introduced to the hot core. Although the current Generation IV high-temperature reactor designs attempt to mitigate any damage caused by a postulated air ingress event, the use of graphite components that inhibit oxidation is a logical step to increase the safety of these reactors. Recent experimental studies of graphite containing between 5.5 and 7 wt% boron carbide (B 4 C) indicate that oxidation is dramatically reduced even at prolonged exposures at temperatures up to 900 deg. C. The proposed addition of B 4 C to graphite components in the nuclear core would necessarily be enriched in B-11 isotope in order to minimise B-10 neutron absorption and graphite swelling. The enriched boron can be added to the graphite during billet fabrication. Experimental oxidation rate results and potential applications for borated graphite in nuclear reactor components will be discussed. (authors)

  3. Conditioned inhibition in the spatial domain.

    Science.gov (United States)

    Sansa, J; Rodrigo, T; Santamaría, J J; Manteiga, R D; Chamizo, V D

    2009-10-01

    Using a variation on the standard procedure of conditioned inhibition (Trials A+ and AX-), rats (Rattus norvegicus) in a circular pool were trained to find a hidden platform that was located in a specific spatial position in relation to 2 individual landmarks (Trials A --> platform and B --> platform; Experiments 1a and 1b) and to 2 configurations of landmarks (Trials ABC --> platform and FGH --> platform; Experiment 2a). The rats also underwent inhibitory trials (Experiment 1: Trials AZ --> no platform; Experiment 2a: Trials CDE --> no platform) interspersed with these excitatory trials. In both experiments, subsequent test trials without the platform showed both a summation effect and retardation of excitatory conditioning, and in Experiment 2a rats learned to avoid the CDE quadrant over the course of the experiment. Two further experiments established that these results could not be attributed to any difference in salience between the conditioned inhibitors and the control stimuli. All these results contribute to the growing body of evidence consistent with the idea that there is a general mechanism of learning that is associative in nature. PsycINFO Database Record (c) 2009 APA, all rights reserved.

  4. Inhibition of RAS in diabetic nephropathy

    Directory of Open Access Journals (Sweden)

    Yacoub R

    2015-04-01

    Full Text Available Rabi Yacoub, Kirk N Campbell Department of Medicine, Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY, USA Abstract: Diabetic kidney disease (DKD is a progressive proteinuric renal disorder in patients with type 1 or type 2 diabetes mellitus. It is a common cause of end-stage kidney disease worldwide, particularly in developed countries. Therapeutic targeting of the renin–angiotensin system (RAS is the most validated clinical strategy for slowing disease progression. DKD is paradoxically a low systematic renin state with an increased intrarenal RAS activity implicated in its pathogenesis. Angiotensin II (AngII, the main peptide of RAS, is not only a vasoactive peptide but functions as a growth factor, activating interstitial fibroblasts and mesangial and tubular cells, while promoting the synthesis of extracellular matrix proteins. AngII also promotes podocyte injury through increased calcium influx and the generation of reactive oxygen species. Blockade of the RAS using either angiotensin converting enzyme inhibitors, or angiotensin receptor blockers can attenuate progressive glomerulosclerosis in animal models, and slows disease progression in humans with DKD. In this review, we summarize the role of intrarenal RAS activation in the pathogenesis and progression of DKD and the rationale for RAS inhibition in this population. Keywords: renin–angiotensin system, diabetic kidney disease, angiotensin II, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers

  5. Insulin-Inducible SMILE Inhibits Hepatic Gluconeogenesis.

    Science.gov (United States)

    Lee, Ji-Min; Seo, Woo-Young; Han, Hye-Sook; Oh, Kyoung-Jin; Lee, Yong-Soo; Kim, Don-Kyu; Choi, Seri; Choi, Byeong Hun; Harris, Robert A; Lee, Chul-Ho; Koo, Seung-Hoi; Choi, Hueng-Sik

    2016-01-01

    The role of a glucagon/cAMP-dependent protein kinase-inducible coactivator PGC-1α signaling pathway is well characterized in hepatic gluconeogenesis. However, an opposing protein kinase B (PKB)/Akt-inducible corepressor signaling pathway is unknown. A previous report has demonstrated that small heterodimer partner-interacting leucine zipper protein (SMILE) regulates the nuclear receptors and transcriptional factors that control hepatic gluconeogenesis. Here, we show that hepatic SMILE expression was induced by feeding in normal mice but not in db/db and high-fat diet (HFD)-fed mice. Interestingly, SMILE expression was induced by insulin in mouse primary hepatocyte and liver. Hepatic SMILE expression was not altered by refeeding in liver-specific insulin receptor knockout (LIRKO) or PKB β-deficient (PKBβ(-/-)) mice. At the molecular level, SMILE inhibited hepatocyte nuclear factor 4-mediated transcriptional activity via direct competition with PGC-1α. Moreover, ablation of SMILE augmented gluconeogenesis and increased blood glucose levels in mice. Conversely, overexpression of SMILE reduced hepatic gluconeogenic gene expression and ameliorated hyperglycemia and glucose intolerance in db/db and HFD-fed mice. Therefore, SMILE is an insulin-inducible corepressor that suppresses hepatic gluconeogenesis. Small molecules that enhance SMILE expression would have potential for treating hyperglycemia in diabetes. © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

  6. Efficacy of ALK5 inhibition in myelofibrosis

    Science.gov (United States)

    Zhao, Wanke; Ho, Wanting Tina; Han, Ying; Murdun, Cem; Mailloux, Adam W.; Zhang, Ling; Wang, Xuefeng; Budhathoki, Anjali; Pradhan, Kith; Rapaport, Franck; Wang, Huaquan; Shao, Zonghong; Ren, Xiubao; Steidl, Ulrich; Levine, Ross L.; Zhao, Zhizhuang Joe; Verma, Amit; Epling-Burnette, Pearlie K.

    2017-01-01

    Myelofibrosis (MF) is a bone marrow disorder characterized by clonal myeloproliferation, aberrant cytokine production, extramedullary hematopoiesis, and bone marrow fibrosis. Although somatic mutations in JAK2, MPL, and CALR have been identified in the pathogenesis of these diseases, inhibitors of the Jak2 pathway have not demonstrated efficacy in ameliorating MF in patients. TGF-β family members are profibrotic cytokines and we observed significant TGF-β1 isoform overexpression in a large cohort of primary MF patient samples. Significant overexpression of TGF-β1 was also observed in murine clonal MPLW515L megakaryocytic cells. TGF-β1 stimulated the deposition of excessive collagen by mesenchymal stromal cells (MSCs) by activating the TGF-β receptor I kinase (ALK5)/Smad3 pathway. MSCs derived from MPLW515L mice demonstrated sustained overproduction of both collagen I and collagen III, effects that were abrogated by ALK5 inhibition in vitro and in vivo. Importantly, use of galunisertib, a clinically active ALK5 inhibitor, significantly improved MF in both MPLW515L and JAK2V617F mouse models. These data demonstrate the role of malignant hematopoietic stem cell (HSC)/TGF-β/MSC axis in the pathogenesis of MF, and provide a preclinical rationale for ALK5 blockade as a therapeutic strategy in MF. PMID:28405618

  7. Inhibition of lignifying processes by sulfur dioxide

    International Nuclear Information System (INIS)

    Pfanz, H.; Oppmann, B.

    1991-01-01

    Intercellular washing fluids (IWF) from spruce needles (Picea abies L. Karst.) contain peroxidases 1-2% of total IWF protein. These apoplastic enzymes show the ability to polymerize monophenols or phenylpropanes to form lignin precursors in vitro. In the presence of potentially acidic air pollutants like NO 2 , HF(20 mM of salts in solution), and in the presence of Pb-, Cd- (0.5 mM) or Al-salts (8 mM) no inhibitory effect on the polymerization reactions examined was detectable. In contrast, the anions of SO 2 (sulfite and bisulfite) revealed a strong inhibition on the dimerization of ferulic and caffeic acid (Ki ca. 1 mM), and on the dehydration of syringaldazine (Ki ca. 8 μM). Polymerization of coniferyl alcohol, on the other hand, seemed to be enhanced. Maier-Maercker and Koch (1986) demonstrated that the cell walls of guard cells from undamaged spruce needles are properly lignified, whereas those of damaged needles seem to be affected. It is therefore assumed that cell wall lignification, and concomitantly stomatal regulation of coniferous needles are disturbed in regions with high atmospheric SO 2 pollution (e.g. Ore Mountains in CSFR)

  8. Bioelectronic sniffer for nicotine using enzyme inhibition.

    Science.gov (United States)

    Mitsubayashi, Kohji; Nakayama, Kazumi; Taniguchi, Midori; Saito, Hirokazu; Otsuka, Kimio; Kudo, Hiroyuki

    2006-07-28

    A novel bioelectronic sniffer for nicotine in the gas phase was developed with enzyme inhibition principle to butyrylcholinesterase activity. The bioelectronic devices for nicotine in the gas and liquid phases were constructed using a Clark-type dissolved oxygen electrode and a membrane immobilized butyrylcholinesterase and choline oxidase. After the assessment of the sensor performances to choline and butyrylcholine as pre-examinations, the characteristics of the biosensor and bio-sniffer for nicotine were evaluated in the liquid and gas phases, respectively. The sensor signal of the bio-devices with 300 micromol l(-1) of butyrylcholine decreased quickly following application of nicotine and reached to the steady-state current, thus relating the concentration of nicotine in the liquid and gas phases. The biosensor was used to measure nicotine solution from 10 to 300 micromol l(-1). In the gas-phase experiment, the current signal of the bio-sniffer was also found to be linearly to the nicotine concentration over the range of 10.0-1000 ppb including 75.0 ppb as threshold limit value (TLV) by American Conference of Governmental Industrial Hygienists (ACGIH).

  9. Radiation metagenesis and inhibition of DNA synthesis

    International Nuclear Information System (INIS)

    Dubinina, L.G.; Sergievskaya, S.P.; Kurashova, Z.I.; Dubinin, N.P.

    1983-01-01

    The study of modification of radiation mutagenesis and inhibition of the DNA synthesis by means of 1-β-D arabinofuranosylcytosine (ara-C) is carried out. It is shown that ara-C-acting on chromosomes in the G 1 phase and G 2 phase does not cause mutations in the C capillaris cells. The modification by means of ara-C radiation effect in the G 1 phase and G 2 phase correlates with duration and time of administering ara-C before and after irradiation. A new form of ara-C DNA synthesis inhibitor interaction with mutation processes has been found out. Protective effect of the DNA synthesis inhibitor (ara-C) from mutageneous radiation effect is stressed. Sensibilization of the radiation mutagenesis during cell treafment by the DNA synthesis inhibitor (ara-C) is shown. It is pointed out that emergence of sensibilization or protective effect, i. e. antimutagenesis phenomenon depends on conditions under which the synthesis inhibitor acted in G 1 and G 2 phases

  10. Lycopene Inhibits Propagation of Chlamydia Infection

    Directory of Open Access Journals (Sweden)

    Naylia A. Zigangirova

    2017-01-01

    Full Text Available Chlamydiaceae is a family of obligate intracellular pathogenic bacteria with similar developmental cycles and cell biology responsible for a wide range of diseases in different hosts including genital and eye inflammatory diseases, arthritis, and inflammatory diseases of the respiratory and cardiovascular systems. In the present paper, we report that lycopene, one of the main dietary carotenoids, which is present in tomato and some other fruits, has a strong inhibitory effect on C. trachomatis and C. pneumoniae infections in alveolar macrophages. This finding was documented by both immunofluorescence analysis and electron microscopy. It was noted that lycopene treatment inhibited intracellular phase of the chlamydial developmental cycle and resulted in a significant loss of infectious progeny. The antichlamydial effect of lycopene was also confirmed in a clinical setting. There was a significant reduction of IgG antibodies against C. pneumoniae in the serum of volunteers treated for a month with oral ingestion of 7 mg of lycopene. Additional studies are needed to further explore the antichlamydial activity of lycopene and its possible effect on C. pneumoniae in relation to antichlamydial activity of lycopene to mechanisms of atherosclerosis.

  11. Clofilium inhibits Slick and Slack potassium channels.

    Science.gov (United States)

    de Los Angeles Tejada, Maria; Stolpe, Kathleen; Meinild, Anne-Kristine; Klaerke, Dan A

    2012-01-01

    Slick and Slack high-conductance potassium channels have been recently discovered, and are found in the central nervous system and in the heart. Both channels are activated by Na(+) and Cl(-), and Slick channels are also inhibited by adenosine triphospate (ATP). An important role of setting the resting membrane potential and controlling the basal excitability of neurons has been suggested for these channels. In addition, no specific blockers for these channels are known up to the present. With the purpose of studying the pharmacological characteristics of Slick and Slack channels, the effects of exposure to the antiarrhythmic compound clofilium were evaluated. Clofilium was able to modulate the activity of Slick and Slack channels effectively, with a stronger effect on Slack than Slick channels. In order to evaluate the pharmacological behavior of Slick and Slack channels further, 38 commonly used potassium channel blockers were tested. Screening of these compounds did not reveal any modulators of Slick and Slack channels, except for clofilium. The present study provides a first approach towards elucidating the pharmacological characteristics of Slick and Slack channels and could be the basis for future studies aimed at developing potent and specific blockers and activators for these channels.

  12. Linking algal growth inhibition to chemical activity

    DEFF Research Database (Denmark)

    Schmidt, Stine N.; Mayer, Philipp

    Unitless chemical activity, expressing the energetic level of a compound relative to its energetic level in pure liquid [0-1], has proven useful to quantify the effective exposure to hydrophobic organic compounds through both aerial and aqueous media. Several studies have linked toxicity to chemi......Unitless chemical activity, expressing the energetic level of a compound relative to its energetic level in pure liquid [0-1], has proven useful to quantify the effective exposure to hydrophobic organic compounds through both aerial and aqueous media. Several studies have linked toxicity...... to chemical activity, as opposed to e.g. the total concentration. Baseline toxicity (narcosis) for neutral hydrophobic organic compounds has been shown to initiate in the narrow chemical activity range of 0.01 to 0.1. This presentation focuses on linking algal growth inhibition to chemical activity......-polar liquids were applied to challenge the chemical activity range for baseline toxicity. For each compound, the effective activity (Ea50) was estimated as the ratio of the effective concentration (EC50) and water solubility. Of these ratios, 90% were within the expected chemical activity range of 0.01 to 0...

  13. Peliminary examination of herbal extracts on the inhibition of ...

    African Journals Online (AJOL)

    Methods: The activity was quantitatively assessed on the basis of the inhibition zone, and their activity index was also calculated along with the MIC method. Results: All the plants demonstrated antimicrobial activity against H. pylori with zone of inhibition diameters ranging from 0 - 30 mm and minimum inhibitory ...

  14. Attention Inhibition Training Can Reduce Betel-Nut Chewing Time

    Directory of Open Access Journals (Sweden)

    Ming-Chou Ho

    2011-05-01

    Full Text Available Betel nut (or areca is the fourth most commonly used drug worldwide after tobacco, alcohol, and caffeine. Many chemical ingredients of betel nut are carcinogenic. We examined whether the manipulation of attentional inhibition toward the areca-related stimuli could affect betel-nut chewing time. Three matched groups of habitual chewers were recruited: inhibit-areca, inhibit-non-areca, and control. This study consisted of a Go/No-Go task for inhibition training, followed by a taste test for observing chewing behavior. The Go/No-Go task constituted three phases (pretest, training and posttest. In the taste test, the habitual chewers were asked to rate the flavors of one betel nut and one gum. The purpose (blind to the chewers of this taste test was to observe whether their picking order and chewing time were affected by experimental manipulation. Results from the Go/No-Go task showed successful training. Further, the training groups (the inhibit-areca and inhibit-non-areca groups showed a significant reduction in betel nut chewing time, in comparison to the control group. Since both training groups showed reduced chewing time, the inhibition training may affect general control ability, in regardless of the stimulus (areca or not to be inhibited. Reduced chewing time is important for reducing areca-related diseases.

  15. Cohort-Sequential Study of Conflict Inhibition during Middle Childhood

    Science.gov (United States)

    Rollins, Leslie; Riggins, Tracy

    2017-01-01

    This longitudinal study examined developmental changes in conflict inhibition and error correction in three cohorts of children (5, 7, and 9 years of age). At each point of assessment, children completed three levels of Luria's tapping task (1980), which requires the inhibition of a dominant response and maintenance of task rules in working…

  16. Optogenetic inhibition of chemically induced hypersynchronized bursting in mice

    DEFF Research Database (Denmark)

    Berglind, Fredrik; Ledri, Marco; Sørensen, Andreas Toft

    2014-01-01

    hyperpolarization and thereby inactivation of a principal neuronal population in the hippocampus is effectively attenuating seizure activity caused by disconnected network inhibition both in vitro and in vivo. Our data suggest that epileptiform activity in the hippocampus caused by impaired inhibition may...

  17. The role of non-CRF inhibition in contour detection

    NARCIS (Netherlands)

    Grigorescu, C.; Petkov, N.; Westenberg, M.A.

    2003-01-01

    We propose a biologically motivated computational step, called non-classical receptive field (non-CRF) inhibition, to improve the performance of contour detectors. Non-CRF inhibition is exhibited by 80% of the orientation selective neurons in the primary visual cortex of macaque monkeys and has been

  18. Pseudomonas aeruginosa inhibits the growth of Cryptococcus species.

    Science.gov (United States)

    Rella, Antonella; Yang, Mo Wei; Gruber, Jordon; Montagna, Maria Teresa; Luberto, Chiara; Zhang, Yong-Mei; Del Poeta, Maurizio

    2012-06-01

    Pseudomonas aeruginosa is a ubiquitous and opportunistic bacterium that inhibits the growth of different microorganisms, including Gram-positive bacteria and fungi such as Candida spp. and Aspergillus fumigatus. In this study, we investigated the interaction between P. aeruginosa and Cryptococcus spp. We found that P. aeruginosa PA14 and, to a lesser extent, PAO1 significantly inhibited the growth of Cryptococcus spp. The inhibition of growth was observed on solid medium by the visualization of a zone of inhibition of yeast growth and in liquid culture by viable cell counting. Interestingly, such inhibition was only observed when P. aeruginosa and Cryptococcus were co-cultured. Minimal inhibition was observed when cell-cell contact was prevented using a separation membrane, suggesting that cell contact is required for inhibition. Using mutant strains of Pseudomonas quinoline signaling, we showed that P. aeruginosa inhibited the growth of Cryptococcus spp. by producing antifungal molecules pyocyanin, a redox-active phenazine, and 2-heptyl-3,4-dihydroxyquinoline (PQS), an extracellular quorum-sensing signal. Because both P. aeruginosa and Cryptococcus neoformans are commonly found in lung infections of immunocompromised patients, this study may have important implication for the interaction of these microbes in both an ecological and a clinical point of view.

  19. Stuttering Inhibition via Altered Auditory Feedback during Scripted Telephone Conversations

    Science.gov (United States)

    Hudock, Daniel; Kalinowski, Joseph

    2014-01-01

    Background: Overt stuttering is inhibited by approximately 80% when people who stutter read aloud as they hear an altered form of their speech feedback to them. However, levels of stuttering inhibition vary from 60% to 100% depending on speaking situation and signal presentation. For example, binaural presentations of delayed auditory feedback…

  20. Menadione inhibits MIBG uptake in two neuroendocrine cell lines

    NARCIS (Netherlands)

    Cornelissen, J.; Tytgat, G. A.; van den Brug, M.; van Kuilenburg, A. B.; Voûte, P. A.; van Gennip, A. H.

    1997-01-01

    In this paper we report on our studies of the effect of menadione on the uptake of MIBG in the neuroendocrine cell lines PC12 and SK-N-SH. Menadione inhibits the uptake of MIBG in both cell lines in a dose-dependent manner. Inhibition of MIBG uptake is most pronounced in the PC12 cell line.

  1. Methanol Extract of Hydroclathrus clathratus Inhibits Production of ...

    African Journals Online (AJOL)

    Methanol Extract of Hydroclathrus clathratus Inhibits Production of Nitric Oxide, Prostaglandin E2 and Tumor Necrosis Factor-α in Lipopolysaccharidestimulated BV2 Microglial Cells via Inhibition of NF-κB Activity. RGPT Jayasooriya, D-O Moon, YH Chol, C-H Yoon, G-Y Kim ...

  2. Trichilia monadelpha Bark Extracts Inhibit Carrageenan-Induced ...

    African Journals Online (AJOL)

    The present study was undertaken to evaluate the anti-inflammatory properties of aqueous (TWE), alcoholic (TAE) and petroleum ether extract (TPEE) of T. ... The reference anti-inflammatory drugs (diclofenac and dexamethasone) inhibited the chick-carrageenan-induced footpad oedema, with maximal inhibitions of ...

  3. Social inhibition sense of belonging and vulnerability to internalizing problems

    NARCIS (Netherlands)

    de Moor, E.L.; Denollet, J.; Laceulle, O.M.

    2018-01-01

    Background The aim of this study was to provide a conceptual test of how social inhibition, sense of belonging and internalizing problems are related, and whether sense of belonging moderates or mediates the relation between social inhibition and internalizing problems. Methods Data were used from

  4. The Affective Consequences of Cognitive Inhibition: Devaluation or Neutralization?

    Science.gov (United States)

    Frischen, Alexandra; Ferrey, Anne E.; Burt, Dustin H. R.; Pistchik, Meghan; Fenske, Mark J.

    2012-01-01

    Affective evaluations of previously ignored visual stimuli are more negative than those of novel items or prior targets of attention or response. This has been taken as evidence that inhibition has negative affective consequences. But inhibition could act instead to attenuate or "neutralize" preexisting affective salience, predicting opposite…

  5. Distractor Inhibition: Principles of Operation during Selective Attention

    Science.gov (United States)

    Wyatt, Natalie; Machado, Liana

    2013-01-01

    Research suggests that although target amplification acts as the main determinant of the efficacy of selective attention, distractor inhibition contributes under some circumstances. Here we aimed to gain insight into the operating principles that regulate the use of distractor inhibition during selective attention. The results suggest that, in…

  6. Study of electroplated silver-palladium biofouling inhibiting coating

    DEFF Research Database (Denmark)

    Chiang, Wen-Chi; Hilbert, Lisbeth Rischel; Schroll, Casper

    2008-01-01

    Biofouling can cause many undesirable effects in industrial and medical settings. In this study, a new biofouling inhibiting Ag-Pd surface was designed to form an inhibiting effect by itself. This design was based on silver combined with nobler palladium, both with catalytic properties. Owing to ...

  7. Corrosion Inhibition of Aluminium by Capparis deciduas in Acidic Media

    Directory of Open Access Journals (Sweden)

    P. Arora

    2007-01-01

    Full Text Available The inhibition efficiency of ethanolic extract of different parts of Capparis deciduas (Ker in acidic medium has been evaluated by mass loss and thermometric methods. Values of inhibition efficiency obtained from the two methods are in good agreement and are dependent upon the concentration of inhibitor and acid.

  8. Corrosion Inhibition of Aluminium by Capparis deciduas in Acidic Media

    OpenAIRE

    P. Arora; S. Kumar; M. K. Sharma; S. P. Mathur

    2007-01-01

    The inhibition efficiency of ethanolic extract of different parts of Capparis deciduas (Ker) in acidic medium has been evaluated by mass loss and thermometric methods. Values of inhibition efficiency obtained from the two methods are in good agreement and are dependent upon the concentration of inhibitor and acid.

  9. Experimental and quantum chemical studies on corrosion inhibition ...

    Indian Academy of Sciences (India)

    Abstract. The corrosion inhibition effect of fluconazole (FLU) was investigated on steel in 1 M hydrochloric acid solution. Weight loss measurements and atomic force microscope analysis were utilized to investigate the corrosion inhibition properties and film formation behaviour of FLU. Quantum chemical approach was also ...

  10. Belief Inhibition in Children's Reasoning: Memory-Based Evidence

    Science.gov (United States)

    Steegen, Sara; Neys, Wim De

    2012-01-01

    Adult reasoning has been shown as mediated by the inhibition of intuitive beliefs that are in conflict with logic. The current study introduces a classic procedure from the memory field to investigate belief inhibition in 12- to 17-year-old reasoners. A lexical decision task was used to probe the memory accessibility of beliefs that were cued…

  11. Inhibition of Snl6 expression for biofuel production

    Science.gov (United States)

    Bart, Rebecca; Chern, Mawsheng; Ronald, Pamela; Vega-Sanchez, Miguel

    2018-04-03

    The invention provides compositions and methods for inhibiting the expression of the gene Snl6 in plants. Plants with inhibited expression of Snl6 have use in biofuel production, e.g., by increasing the amount of soluble sugar that can be extracted from the plant.

  12. Apigenin inhibits proliferation and migratory properties of Barrett's ...

    African Journals Online (AJOL)

    dependent fashion, with an IC50 of 75 µM, after 72 h of incubation, and also induced apoptosis, with modulation of pro- and anti-apoptotic genes. Furthermore, apigenin inhibited the motility of OE33 by targeting PI3K/Akt/mTOR signaling. Conclusion: Apigenin effectively inhibits the oncogenicity of OE33 cells by targeting ...

  13. Cognitive Inhibition in Students with and without Dyslexia and Dyscalculia

    Science.gov (United States)

    Wang, Li-Chih; Tasi, Hung-Ju; Yang, Hsien-Ming

    2012-01-01

    The present study presents a comparison of the cognitive inhibition abilities of dyslexic, dyscalculic, and control students. The participants were 45 dyslexic students, 45 dyscalculic students, and 45 age-, gender-, and IQ-matched control students. The major evaluation tools included six cognitive inhibition tasks which were restructured during…

  14. Inhibition of autophagy initiation potentiates chemosensitivity in mesothelioma.

    Science.gov (United States)

    Follo, Carlo; Cheng, Yao; Richards, William G; Bueno, Raphael; Broaddus, Virginia Courtney

    2018-03-01

    The benefits of inhibiting autophagy in cancer are still controversial, with differences in outcome based on the type of tumor, the context and the particular stage of inhibition. Here, we investigated the impact of inhibiting autophagy at different stages on chemosensitivity using 3-dimensional (3D) models of mesothelioma, including ex vivo human tumor fragment spheroids. As shown by LC3B accumulation, we successfully inhibited autophagy using either an early stage ULK1/2 inhibitor (MRT 68921) or a late stage inhibitor (hydroxychloroquine). We found that inhibition of autophagy at the early stage, but not at late stage, potentiated chemosensitivity. This effect was seen only in those spheroids with high autophagy and active initiation at steady state. Inhibition of autophagy alone, at either early or late stage, did not cause cell death, showing that the inhibitors were non-toxic and that mesothelioma did not depend on autophagy at baseline, at least over 24 h. Using ATG13 puncta analysis, we found that autophagy initiation identified tumors that are more chemosensitive at baseline and after autophagy inhibition. Our results highlight a potential role of autophagy initiation in supporting mesothelioma cells during chemotherapy. Our work also highlights the importance of testing the inhibition of different stages in order to uncover the role of autophagy and the potential of its modulation in the treatment of cancer. © 2017 Wiley Periodicals, Inc.

  15. Experimental and quantum chemical studies on corrosion inhibition

    Indian Academy of Sciences (India)

    The corrosion inhibition effect of fluconazole (FLU) was investigated on steel in 1 M hydrochloric acid solution. Weight loss measurements and atomic force microscope analysis were utilized to investigate the corrosion inhibition properties and film formation behaviour of FLU. Quantum chemical approach was also used to ...

  16. Probe substrate and enzyme source-dependent inhibition of UDP ...

    African Journals Online (AJOL)

    Background: Drug-metabolizing enzymes (DMEs) inhibition based drug-drug interaction and herb-drug interaction severely challenge the R&D process of drugs or herbal ingredients. Objective: To evaluate the inhibition potential of wogonin (an important flavonoid isolated from the root of Scutellaria baicalensis) towards ...

  17. Sulindac Sulfide, but Not Sulindac Sulfone, Inhibits Colorectal Cancer Growth

    Directory of Open Access Journals (Sweden)

    Christopher S. Williams

    1999-06-01

    Full Text Available Sulindac sulfide, a metabolite of the nonsteroidal antiinflammatory drug (NSAID sulindac sulfoxide, is effective at reducing tumor burden in both familial adenomatous polyposis patients and in animals with colorectal cancer. Another sulindac sulfoxide metabolite, sulindac sulfone, has been reported to have antitumor properties without inhibiting cyclooxygenase activity. Here we report the effect of sulindac sulfone treatment on the growth of colorectal carcinoma cells. We observed that sulindac sulfide or sulfone treatment of HCA-7 cells led to inhibition of prostaglandin E2 production. Both sulindac sulfide and sulfone inhibited HCA-7 and HCT-116 cell growth in vitro. Sulindac sulfone had no effect on the growth of either HCA-7 or HCT-116 xenografts, whereas the sulfide derivative inhibited HCA-7 growth in vivo. Both sulindac sulfide and sulfone inhibited colon carcinoma cell growth and prostaglandin production in vitro, but sulindac sulfone had no effect on the growth of colon cancer cell xenografts in nude mice.

  18. Feedforward somatosensory inhibition is normal in cervical dystonia.

    Science.gov (United States)

    Ferrè, Elisa R; Ganos, Christos; Bhatia, Kailash P; Haggard, Patrick

    2015-03-01

    Insufficient cortical inhibition is a key pathophysiological finding in dystonia. Subliminal sensory stimuli were reported to transiently inhibit somatosensory processing. Here we investigated whether such subliminal feedforward inhibition is reduced in patients with cervical dystonia. Sixteen cervical dystonia patients and 16 matched healthy controls performed a somatosensory detection task. We measured the drop in sensitivity to detect a threshold-level digital nerve shock when it was preceded by a subliminal conditioning shock, compared to when it was not. Subliminal conditioning shocks reduced sensitivity to threshold stimuli to a similar extent in both patients and controls, suggesting that somatosensory subliminal feedforward inhibition is normal in cervical dystonia. Somatosensory feedforward inhibition was normal in this group of cervical dystonia patients. Our results qualify previous concepts of a general dystonic deficit in sensorimotor inhibitory processing. Copyright © 2015 Elsevier Ltd. All rights reserved.

  19. Effect of overall feedback inhibition in unbranched biosynthetic pathways.

    Science.gov (United States)

    Alves, R; Savageau, M A

    2000-11-01

    We have determined the effects of control by overall feedback inhibition on the systemic behavior of unbranched metabolic pathways with an arbitrary pattern of other feedback inhibitions by using a recently developed numerical generalization of Mathematically Controlled Comparisons, a method for comparing the function of alternative molecular designs. This method allows the rigorous determination of the changes in systemic properties that can be exclusively attributed to overall feedback inhibition. Analytical results show that the unbranched pathway can achieve the same steady-state flux, concentrations, and logarithmic gains with respect to changes in substrate, with or without overall feedback inhibition. The analytical approach also shows that control by overall feedback inhibition amplifies the regulation of flux by the demand for end product while attenuating the sensitivity of the concentrations to the same demand. This approach does not provide a clear answer regarding the effect of overall feedback inhibition on the robustness, stability, and transient time of the pathway. However, the generalized numerical method we have used does clarify the answers to these questions. On average, an unbranched pathway with control by overall feedback inhibition is less sensitive to perturbations in the values of the parameters that define the system. The difference in robustness can range from a few percent to fifty percent or more, depending on the length of the pathway and on the metabolite one considers. On average, overall feedback inhibition decreases the stability margins by a minimal amount (typically less than 5%). Finally, and again on average, stable systems with overall feedback inhibition respond faster to fluctuations in the metabolite concentrations. Taken together, these results show that control by overall feedback inhibition confers several functional advantages upon unbranched pathways. These advantages provide a rationale for the prevalence of this

  20. Targeting fibroblast growth factor receptor signaling inhibits prostate cancer progression.

    Science.gov (United States)

    Feng, Shu; Shao, Longjiang; Yu, Wendong; Gavine, Paul; Ittmann, Michael

    2012-07-15

    Extensive correlative studies in human prostate cancer as well as studies in vitro and in mouse models indicate that fibroblast growth factor receptor (FGFR) signaling plays an important role in prostate cancer progression. In this study, we used a probe compound for an FGFR inhibitor, which potently inhibits FGFR-1-3 and significantly inhibits FGFR-4. The purpose of this study is to determine whether targeting FGFR signaling from all four FGFRs will have in vitro activities consistent with inhibition of tumor progression and will inhibit tumor progression in vivo. Effects of AZ8010 on FGFR signaling and invasion were analyzed using immortalized normal prostate epithelial (PNT1a) cells and PNT1a overexpressing FGFR-1 or FGFR-4. The effect of AZ8010 on invasion and proliferation in vitro was also evaluated in prostate cancer cell lines. Finally, the impact of AZ8010 on tumor progression in vivo was evaluated using a VCaP xenograft model. AZ8010 completely inhibits FGFR-1 and significantly inhibits FGFR-4 signaling at 100 nmol/L, which is an achievable in vivo concentration. This results in marked inhibition of extracellular signal-regulated kinase (ERK) phosphorylation and invasion in PNT1a cells expressing FGFR-1 and FGFR-4 and all prostate cancer cell lines tested. Treatment in vivo completely inhibited VCaP tumor growth and significantly inhibited angiogenesis and proliferation and increased cell death in treated tumors. This was associated with marked inhibition of ERK phosphorylation in treated tumors. Targeting FGFR signaling is a promising new approach to treating aggressive prostate cancer.

  1. Magnolol Inhibits the Growth of Non-Small Cell Lung Cancer via Inhibiting Microtubule Polymerization

    Directory of Open Access Journals (Sweden)

    Jia Shen

    2017-07-01

    Full Text Available Background: The tubulin/microtubule system, which is an integral component of the cytoskeleton, plays an essential role in mitosis. Targeting mitotic progression by disturbing microtubule dynamics is a rational strategy for cancer treatment. Methods: Microtubule polymerization assay was performed to examine the effect of Magnolol (a novel natural phenolic compound isolated from Magnolia obovata on cellular microtubule polymerization in human non-small cell lung cancer (NSCLC cells. Cell cycle analysis, mitotic index assay, cell proliferation assay, colony formation assay, western blotting analysis of cell cycle regulators, Annexin V-FITC/PI staining, and live/dead viability staining were carried out to investigate the Magnolol’s inhibitory effect on proliferation and viability of NSCLS cells in vitro. Xenograft model of human A549 NSCLC tumor was used to determine the Magnolol’s efficacy in vivo. Results: Magnolol treatment effectively inhibited cell proliferation and colony formation of NSCLC cells. Further study proved that Magnolol induced the mitotic phase arrest and inhibited G2/M progression in a dose-dependent manner, which were mechanistically associated with expression alteration of a series of cell cycle regulators. Furthermore, Magnolol treatment disrupted the cellular microtubule organization via inhibiting the polymerization of microtubule. We also found treatment with NSCLC cells with Magnolol resulted in apoptosis activation through a p53-independent pathway, and autophgy induction via down-regulation of the Akt/mTOR pathway. Finally, Magnolol treatment significantly suppressed the NSCLC tumor growth in mouse xenograft model in vivo. Conclusion: These findings identify Magnolol as a promising candidate with anti-microtubule polymerization activity for NSCLC treatment.

  2. Global inhibition of reactive oxygen species (ROS inhibits paclitaxel-induced painful peripheral neuropathy.

    Directory of Open Access Journals (Sweden)

    Mehmet Fidanboylu

    Full Text Available Paclitaxel (Taxol® is a widely used chemotherapeutic agent that has a major dose limiting side-effect of painful peripheral neuropathy. Currently there is no effective therapy for the prevention or treatment of chemotherapy-induced painful peripheral neuropathies. Evidence for mitochondrial dysfunction during paclitaxel-induced pain was previously indicated with the presence of swollen and vacuolated neuronal mitochondria. As mitochondria are a major source of reactive oxygen species (ROS, the aim of this study was to examine whether pharmacological inhibition of ROS could reverse established paclitaxel-induced pain or prevent the development of paclitaxel-induced pain. Using a rat model of paclitaxel-induced pain (intraperitoneal 2 mg/kg paclitaxel on days 0, 2, 4 & 6, the effects of a non-specific ROS scavenger, N-tert-Butyl-α-phenylnitrone (PBN and a superoxide selective scavenger, 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPOL were compared. Systemic 100 mg/kg PBN administration markedly inhibited established paclitaxel-induced mechanical hypersensitivity to von Frey 8 g and 15 g stimulation and cold hypersensitivity to plantar acetone application. Daily systemic administration of 50 mg/kg PBN (days -1 to 13 completely prevented mechanical hypersensitivity to von Frey 4 g and 8 g stimulation and significantly attenuated mechanical hypersensitivity to von Frey 15 g. Systemic 100 mg/kg TEMPOL had no effect on established paclitaxel-induced mechanical or cold hypersensitivity. High dose (250 mg/kg systemic TEMPOL significantly inhibited mechanical hypersensitivity to von Frey 8 g & 15 g, but to a lesser extent than PBN. Daily systemic administration of 100 mg/kg TEMPOL (day -1 to 12 did not affect the development of paclitaxel-induced mechanical hypersensitivity. These data suggest that ROS play a causal role in the development and maintenance of paclitaxel-induced pain, but such effects cannot be attributed to superoxide radicals

  3. Combined Angiotensin Receptor Antagonism and Neprilysin Inhibition

    Science.gov (United States)

    Hubers, Scott A.; Brown, Nancy J.

    2016-01-01

    Heart failure affects approximately 5.7 million people in the United States alone. Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, and aldosterone antagonists have improved mortality in patients with heart failure and reduced ejection fraction, but mortality remains high. In July 2015, the FDA approved the first of a new class of drugs for the treatment of heart failure; valsartan/sacubitril (formerly known as LCZ696 and currently marketed by Novartis as Entresto) combines the angiotensin receptor blocker valsartan and the neprilysin inhibitor prodrug sacubitril in a 1:1 ratio in a sodium supramolecular complex. Sacubitril is converted by esterases to LBQ657, which inhibits neprilysin, the enzyme responsible for the degradation of the natriuretic peptides and many other vasoactive peptides. Thus, this combined angiotensin receptor antagonist and neprilysin inhibitor addresses two of the pathophysiologic mechanisms of heart failure - activation of the renin-angiotensin-aldosterone system and decreased sensitivity to natriuretic peptides. In the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure (PARADIGM-HF) trial, valsartan/sacubitril significantly reduced mortality and hospitalization for heart failure, as well as blood pressure, compared to enalapril in patients with heart failure, reduced ejection fraction, and an elevated circulating level of brain natriuretic peptide or N-terminal pro-brain natriuretic peptide. Ongoing clinical trials are evaluating the role of valsartan/sacubitril in the treatment of heart failure with preserved ejection fraction and hypertension. We review here the mechanisms of action of valsartan/sacubitril, the pharmacologic properties of the drug, and its efficacy and safety in the treatment of heart failure and hypertension. PMID:26976916

  4. Iron inhibits hydroxyapatite crystal growth in vitro.

    Science.gov (United States)

    Guggenbuhl, Pascal; Filmon, Robert; Mabilleau, Guillaume; Baslé, Michel F; Chappard, Daniel

    2008-07-01

    Hemochromatosis is a known cause of osteoporosis in which the pathophysiology of bone loss is largely unknown and the role of iron remains questionable. We have investigated the effects of iron on the growth of hydroxyapatite crystals in vitro on carboxymethylated poly(2-hydroxyethyl methacrylate) pellets. This noncellular and enzyme-independent model mimics the calcification of woven bone (composed of calcospherites made of hydroxyapatite crystals). Polymer pellets were incubated with body fluid containing iron at increasing concentrations (20, 40, 60 micromol/L). Hydroxyapatite growth was studied by chemical analysis, scanning electron microscopy, and Raman microscopy. When incubated in body fluid containing iron, significant differences were observed with control pellets. Iron was detected at a concentration of 5.41- to 7.16-fold that of controls. In pellets incubated with iron, there was a approximately 3- to 4-fold decrease of Ca and P and a approximately 1.3- to 1.4-fold increase in the Ca/P ratio. There was no significant difference among the iron groups of pellets, but a trend to a decrease of Ca with the increase of iron concentration was noted. Calcospherite diameters were significantly lower on pellets incubated with iron. Raman microspectroscopy showed a decrease in crystallinity (measured by the full width of the half height of the 960 Deltacm(-1) band) with a significant increase in carbonate substitution (measured by the intensity ratio of 1071 to 960 Deltacm(-1) band). Energy dispersive x-ray analysis identified iron in the calcospherites. In vitro, iron is capable to inhibit bone crystal growth with significant changes in crystallinity and carbonate substitution.

  5. Adrenergic manipulation inhibits pavlovian conditioned approach behaviors.

    Science.gov (United States)

    Pasquariello, Kyle Z; Han, Marina; Unal, Cagla; Meyer, Paul J

    2018-02-26

    Environmental rewards and Pavlovian reward cues can acquire incentive salience, thereby eliciting incentive motivational states and instigate reward-seeking. In rats, the incentive salience of food cues can be measured during a Pavlovian conditioned approach paradigm, in which rats engage in cue-directed approach ("sign-tracking") or approach the food delivery location ("goal-tracking"). While it has been shown that dopamine signaling is necessary for sign-tracking, some studies have suggested that norepinephrine is involved in learning to sign-track as well. Thus, in order to investigate the influence of norepinephrine in Pavlovian conditioned approach, we administered three adrenergic drugs while rats learned that a food cue (an illuminated, retractable lever) preceded the delivery of banana-flavored food pellets into a food-cup. We found that pre-session injections of disulfiram (a dopamine-β-hydroxylase inhibitor) inhibited the development of sign-tracking, but goal-tracking was only affected at the high dose. In one experiment, post-session injections of disulfiram blocked the development of sign-tracking, although this effect was not replicated in a separate set of rats. Post-session injections of prazosin (an α1-adrenergic receptor antagonist) and propranolol (a β-adrenergic receptor antagonist) also blocked the development of sign-tracking but not goal-tracking. Taken together, these results suggest that adrenergic transmission mediates the acquisition of sign-tracking but not goal-tracking, and thus plays a selective role in the attribution of incentive salience food cues. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. Reactor design for minimizing product inhibition during enzymatic lignocellulose hydrolysis II. Quantification of inhibition and suitability of membrane reactors

    DEFF Research Database (Denmark)

    Andric, Pavle; Meyer, Anne S.; Jensen, Peter Arendt

    2010-01-01

    conversion are required for alleviation of glucose product inhibition. Supported by numerous calculations this review assesses the quantitative aspects of glucose product inhibition on enzyme-catalyzed cellulose degradation rates. The significance of glucose product inhibition on dimensioning of different......Product inhibition of cellulolytic enzymes affects the efficiency of the biocatalytic conversion of lignocellulosic biomass to ethanol and other valuable products. New strategies that focus on reactor designs encompassing product removal, notably glucose removal, during enzymatic cellulose...... reactor features, including system set-up, dilution rate, glucose output profile, and the problem of cellobiose are examined to illustrate the quantitative significance of the glucose product inhibition and the total glucose concentration on the cellulolytic conversion rate. Comprehensive overviews...

  7. Neural correlates of central inhibition during physical fatigue.

    Directory of Open Access Journals (Sweden)

    Masaaki Tanaka

    Full Text Available Central inhibition plays a pivotal role in determining physical performance during physical fatigue. Classical conditioning of central inhibition is believed to be associated with the pathophysiology of chronic fatigue. We tried to determine whether classical conditioning of central inhibition can really occur and to clarify the neural mechanisms of central inhibition related to classical conditioning during physical fatigue using magnetoencephalography (MEG. Eight right-handed volunteers participated in this study. We used metronome sounds as conditioned stimuli and maximum handgrip trials as unconditioned stimuli to cause central inhibition. Participants underwent MEG recording during imagery of maximum grips of the right hand guided by metronome sounds for 10 min. Thereafter, fatigue-inducing maximum handgrip trials were performed for 10 min; the metronome sounds were started 5 min after the beginning of the handgrip trials. The next day, neural activities during imagery of maximum grips of the right hand guided by metronome sounds were measured for 10 min. Levels of fatigue sensation and sympathetic nerve activity on the second day were significantly higher relative to those of the first day. Equivalent current dipoles (ECDs in the posterior cingulated cortex (PCC, with latencies of approximately 460 ms, were observed in all the participants on the second day, although ECDs were not identified in any of the participants on the first day. We demonstrated that classical conditioning of central inhibition can occur and that the PCC is involved in the neural substrates of central inhibition related to classical conditioning during physical fatigue.

  8. The somatotopy of tic inhibition: Where and how much?

    Science.gov (United States)

    Ganos, Christos; Bongert, Jens; Asmuss, Luisa; Martino, Davide; Haggard, Patrick; Münchau, Alexander

    2015-08-01

    Tics are the hallmark feature of Tourette syndrome. The basic phenomenological and neurophysiological characteristics of tics have been widely investigated. Interestingly, the spatial distribution of tics across different body parts has received little attention. No previous study has investigated whether the capacity for voluntary tic inhibition also varies across body parts. We analyzed video sequences of 26 adolescents with Tourette syndrome in a "tic freely" condition, and in a "voluntary tic inhibition" condition, to obtain absolute tic counts for different body parts. Two measures of the spatial distribution of tics were then analyzed. Linear regression analyses were employed to investigate the relation between the contribution of each body part to overall tic behavior and the ability to inhibit tics in that body part, averaged over our patient group. Tic distribution across patients showed a characteristic somatotopic pattern, with the face most strongly represented. A significant negative relation was found between the ability to inhibit tics and pooled tic frequency across body parts. The body parts that exhibited the fewest tics were the ones for which tic inhibition was most effective. Our data are consistent with the idea that tic recruitment order reflects a "tic generator" spreading across a somatotopic map in the brain. Voluntary tic inhibition did not simply cause a proportional reduction of tics in each body part. Rather, the least affected body parts showed most effective voluntary tic inhibition. The results are discussed in terms of signal and noise within cortical-subcortical motor loops. © 2015 International Parkinson and Movement Disorder Society.

  9. Harmane inhibits serotonergic dorsal raphe neurons in the rat.

    Science.gov (United States)

    Touiki, Khalid; Rat, Pascal; Molimard, Robert; Chait, Abderrahman; de Beaurepaire, Renaud

    2005-11-01

    Harmane and norharmane (two beta-carbolines) are tobacco components or products. The effects of harmane and norharmane on serotonergic raphe neurons remain unknown. Harmane and norharmane are inhibitors of the monoamine oxidases A (MAO-A) and B (MAO-B), respectively. To study the effects of harmane, norharmane, befloxatone (MAOI-A), and selegiline (MAOI-B) on the firing of serotonergic neurons. To compare the effects of these compounds to those of nicotine (whose inhibitory action on serotonergic neurons has been previously described). The effects of cotinine, a metabolite of nicotine known to interact with serotonergic systems, are also tested. In vivo electrophysiological recordings of serotonergic dorsal raphe neurons in the anaesthetized rat. Nicotine, harmane, and befloxatone inhibited serotonergic dorsal raphe neurons. The other compounds had no effects. The inhibitory effect of harmane (rapid and long-lasting inhibition) differed from that of nicotine (short and rapidly reversed inhibition) and from that of befloxatone (slow, progressive, and long-lasting inhibition). The inhibitory effects of harmane and befloxatone were reversed by the 5-HT1A antagonist WAY 100 635. Pretreatment of animals with p-chlorophenylalanine abolished the inhibitory effect of befloxatone, but not that of harmane. Nicotine, harmane, and befloxatone inhibit the activity of raphe serotonergic neurons. Therefore, at least two tobacco compounds, nicotine and harmane, inhibit the activity of serotonergic neurons. The mechanism by which harmane inhibits serotonergic dorsal raphe neurons is likely unrelated to a MAO-A inhibitory effect.

  10. Australine, a pyrrolizidine alkaloid that inhibits amyloglucosidase and glycoprotein processing

    Energy Technology Data Exchange (ETDEWEB)

    Tropea, J.E.; Molyneux, R.J.; Kaushal, G.P.; Pan, Y.T.; Mitchell, M.; Elbein, A.D. (Univ. of Texas Health Science Center, San Antonio (USA))

    1989-03-07

    Australine is a polyhydroxylated pyrrolizidine alkaloid that was isolated from the seeds of the Australian tree Castanospermum australe and characterized by NMR and X-ray diffraction analysis. Since swainsonine and catanospermine are polyhydroxylated indolizidine alkaloids that inhibit specific glycosidases, the authors tested australine against a variety of exoglycosidases to determine whether it would inhibit any of these enzymes. This alkaloid proved to be a good inhibitor of the {alpha}-glucosidase amyloglucosidase (50% inhibition at 5.8 {mu}M), but it did not inhibit {beta}-glucosidase, {alpha}- or {beta}-mannosidase, or {alpha}- or {beta}-galactosidase. The inhibition of amyloglucosidase was of a competitive nature. Australine also inhibited the glycoprotein processing enzyme glucosidase I, but had only slight activity toward glucosidase II. When incubated with cultured cells, this alkaloid inhibited glycoprotein processing at the glucosidase I step and caused the accumulation of glycoproteins with Glc{sub 3}Man{sub 7-9}(GlcNAc){sub 2}-oligosaccharides.

  11. The development of children's inhibition: does parenting matter?

    Science.gov (United States)

    Roskam, Isabelle; Stievenart, Marie; Meunier, Jean-Christophe; Noël, Marie-Pascale

    2014-06-01

    Whereas a large body of research has investigated the maturation of inhibition in relation to the prefrontal cortex, far less research has been devoted to environmental factors that could contribute to inhibition improvement. The aim of the current study was to test whether and to what extent parenting matters for inhibition development from 2 to 8years of age. Data were collected from 421 families, with 348 mother-child dyads and 342 father-child dyads participating. Children's inhibition capacities and parenting behaviors were assessed in a three-wave longitudinal data collection. The main analyses examined the impact of parenting on the development of children's inhibition capacities. They were conducted using a multilevel modeling (MLM) framework. The results lead to the conclusion that both mothers and fathers contribute through their child-rearing behavior to their children's executive functioning, even when controlling for age-related improvement (maturation) and important covariates such as gender, verbal IQ, and place of enrollment. More significant relations between children's inhibition development and parenting were displayed for mothers than for fathers. More precisely, parenting behaviors that involve higher monitoring, lower discipline, inconsistency and negative controlling, and a positive parenting style are associated with good development of inhibition capacities in children. Copyright © 2014 Elsevier Inc. All rights reserved.

  12. Andrographolide inhibits multiple myeloma cells by inhibiting the TLR4/NF-κB signaling pathway.

    Science.gov (United States)

    Gao, Hui; Wang, Jianrong

    2016-02-01

    Andrographolide is an active component from the extract of Andrographis paniculata [(Burm.f) Nees], a medicinal plant from the Acanthaceae family. Pharmacological studies have revealed that andrographolide possesses anti-bacterial, anti-inflammatory, anti-viral, immune regulatory and hepatoprotective properties, and is efficacious in the treatment of cardiovascular diseases, while exhibiting low toxicity and low cost. The present study aimed to determine the inhibitory effects of andrographolide on the growth of multiple myeloma (MM) cells and its possible impact on the Toll-like receptor (TLR)4/nuclear factor (NF)-κB signaling pathway. Cell proliferation was detected using an MTT assay, cellular apoptosis was measured using flow cytometry, and caspase-9/3 activation were assessed using colorimetric assay kits. Furthermore, TLR4 and NF-κB protein expression was determined by western blot analysis. The results revealed that andrographolide reduced the proliferation, while increasing cellular apoptosis and caspase-9/3 activation of MM cells, in addition to downregulating the expression of TLR4 and NF-κB protein. Of note, TLR4- or NF-κB-targeting small-interfering (si)RNA enhanced the andrographolide-induced inhibition of cell proliferation and induction of apoptosis of MM cells. The results of the present study therefore suggested that andrographolide inhibited multiple myeloma cells via the TLR4/NF-κB signaling pathway.

  13. BET bromodomain inhibition promotes neurogenesis while inhibiting gliogenesis in neural progenitor cells

    Directory of Open Access Journals (Sweden)

    Jingjun Li

    2016-09-01

    Full Text Available Neural stem cells and progenitor cells (NPCs are increasingly appreciated to hold great promise for regenerative medicine to treat CNS injuries and neurodegenerative diseases. However, evidence for effective stimulation of neuronal production from endogenous or transplanted NPCs for neuron replacement with small molecules remains limited. To identify novel chemical entities/targets for neurogenesis, we had established a NPC phenotypic screen assay and validated it using known small-molecule neurogenesis inducers. Through screening small molecule libraries with annotated targets, we identified BET bromodomain inhibition as a novel mechanism for enhancing neurogenesis. BET bromodomain proteins, Brd2, Brd3, and Brd4 were found to be downregulated in NPCs upon differentiation, while their levels remain unaltered in proliferating NPCs. Consistent with the pharmacological study using bromodomain selective inhibitor (+-JQ-1, knockdown of each BET protein resulted in an increase in the number of neurons with simultaneous reduction in both astrocytes and oligodendrocytes. Gene expression profiling analysis demonstrated that BET bromodomain inhibition induced a broad but specific transcription program enhancing directed differentiation of NPCs into neurons while suppressing cell cycle progression and gliogenesis. Together, these results highlight a crucial role of BET proteins as epigenetic regulators in NPC development and suggest a therapeutic potential of BET inhibitors in treating brain injuries and neurodegenerative diseases.

  14. Sex differences in emotional contexts modulation on response inhibition.

    Science.gov (United States)

    Ramos-Loyo, Julieta; Angulo-Chavira, Armando; Llamas-Alonso, Luis A; González-Garrido, Andrés A

    2016-10-01

    The aim of the present study was to explore sex differences in the effects that emotional contexts exert on the temporal course of response inhibition using event-related potentials (ERP). Participants performed a Go-NoGo response inhibition task under 3 context conditions: with 1) neutral background stimuli, and 2) pleasant, and 3) unpleasant emotional contexts. No sex differences were found in relation to accuracy. Women showed higher N2NoGo amplitudes than men in both emotional contexts; whereas during inhibition men tended to show higher P3NoGo amplitudes than women in the unpleasant context. Both groups experienced a relevant effect of the presence of the unpleasant context during inhibition processing, as shown by the enhancement of the N2NoGo amplitudes in frontal regions compared to results from the neutral and pleasant conditions. In addition, women showed differences between the pleasant and unpleasant contexts, with the latter inducing higher amplitude values. Only in men did inhibition accuracy correlate with higher N2NoGo and lower P3NoGo amplitudes in the emotional context conditions. These findings suggest that when an inhibition task is performed in an emotionally-neutral background context no sex differences are observed in either accuracy or ERP components. However, when the emotional context was introduced -especially the unpleasant one- some gender differences did become evident. The higher N2NoGo amplitude at the presence of the unpleasant context may reflect an effect on attention and conflict monitoring. In addition, results suggest that during earlier processing stages, women invested more resources to process inhibition than men. Furthermore, men who invested more neural resources during earlier stages showed better response inhibition than those who did it during later processing stages, more closely-related to cognitive and motor inhibition processes. Copyright © 2016 Elsevier Ltd. All rights reserved.

  15. Lactate dehydrogenase activity is inhibited by methylmalonate in vitro.

    Science.gov (United States)

    Saad, Laura O; Mirandola, Sandra R; Maciel, Evelise N; Castilho, Roger F

    2006-04-01

    Methylmalonic acidemia (MMAemia) is an inherited metabolic disorder of branched amino acid and odd-chain fatty acid metabolism, involving a defect in the conversion of methylmalonyl-coenzyme A to succinyl-coenzyme A. Systemic and neurological manifestations in this disease are thought to be associated with the accumulation of methylmalonate (MMA) in tissues and biological fluids with consequent impairment of energy metabolism and oxidative stress. In the present work we studied the effect of MMA and two other inhibitors of mitochondrial respiratory chain complex II (malonate and 3-nitropropionate) on the activity of lactate dehydrogenase (LDH) in tissue homogenates from adult rats. MMA potently inhibited LDH-catalyzed conversion of lactate to pyruvate in liver and brain homogenates as well as in a purified bovine heart LDH preparation. LDH was about one order of magnitude less sensitive to inhibition by MMA when catalyzing the conversion of pyruvate to lactate. Kinetic studies on the inhibition of brain LDH indicated that MMA inhibits this enzyme competitively with lactate as a substrate (K (i)=3.02+/-0.59 mM). Malonate and 3-nitropropionate also strongly inhibited LDH-catalyzed conversion of lactate to pyruvate in brain homogenates, while no inhibition was observed by succinate or propionate, when present in concentrations of up to 25 mM. We propose that inhibition of the lactate/pyruvate conversion by MMA contributes to lactate accumulation in blood, metabolic acidemia and inhibition of gluconeogenesis observed in patients with MMAemia. Moreover, the inhibition of LDH in the central nervous system may also impair the lactate shuttle between astrocytes and neurons, compromising neuronal energy metabolism.

  16. Metalloproteinase inhibition prevents acute respiratory distress syndrome.

    Science.gov (United States)

    Carney, D E; McCann, U G; Schiller, H J; Gatto, L A; Steinberg, J; Picone, A L; Nieman, G F

    2001-08-01

    -3 prevented lung injury in our model of endotoxin-induced ARDS. The proposed mechanism of COL-3 is a synergistic inhibition of the terminal neutrophil effectors MMPs and NE. Similar to the universal practice of prophylaxis against gastric stress ulceration and deep venous thromboses in trauma patients, chemically modified tetracyclines may likewise be administered to prevent acute lung injury in critically injured patients at risk of developing ARDS. Copyright 2001 Academic Press.

  17. Curcumin inhibits amygdaloid kindled seizures in rats.

    Science.gov (United States)

    DU, Peng; Li, Xin; Lin, Hao-Jie; Peng, Wei-Feng; Liu, Jian-Ying; Ma, Yu; Fan, Wei; Wang, Xin

    2009-06-20

    Curcumin can reduce the severity of seizures induced by kainate acid (KA), but the role of curcumin in amygdaloid kindled models is still unknown. This study aimed to explore the effect of curcumin on the development of kindling in amygdaloid kindled rats. With an amygdaloid kindled Sprague-Dawley (SD) rat model and an electrophysiological method, different doses of curcumin (10 mgxkg(-1)xd(-1) and 30 mgxkg(-1)xd(-1) as low dose groups, 100 mgxkg(-1)xd(-1) and 300 mgxkg(-1)xd(-1) as high dose groups) were administrated intraperitoneally during the whole kindling days, by comparison with the course of kindling, afterdischarge (AD) thresholds and the number of ADs to reach the stages of class I to V seizures in the rats between control and experimental groups. One-way or two-way ANOVA and Fisher's least significant difference post hoc test were used for statistical analyses. Curcumin (both 100 mgxkg(-1)xd(-1) and 300 mgxkg(-1)xd(-1)) significantly inhibited the behavioral seizure development in the (19.80 +/- 2.25) and (21.70 +/- 2.21) stimulations respectively required to reach the kindled state. Rats treated with 100 mgxkg(-1)xd(-1) curcumin 30 minutes before kindling stimulation showed an obvious increase in the stimulation current intensity required to evoke AD from (703.3 +/- 85.9) microA to (960.0 +/- 116.5) microA during the progression to class V seizures. Rats treated with 300 mgxkg(-1)xd(-1) curcumin showed a significant increase in the stimulation current intensity required to evoke AD from (735.0 +/- 65.2) microA to (867.0 +/- 93.4) microA during the progression to class V seizures. Rats treated with 300 mgxkg(-1)xd(-1) curcumin required much more evoked ADs to reach the stage of class both IV (as (199.83 +/- 12.47) seconds) and V seizures (as (210.66 +/- 10.68) seconds). Rats treated with 100 mgxkg(-1)xd(-1) curcumin required much more evoked ADs to reach the stage of class V seizures (as (219.56 +/- 18.24) seconds). Our study suggests that curcumin has

  18. Inhibition of PTEN and activation of Akt by menadione

    OpenAIRE

    Yoshikawa, Kyoko; Nigorikawa, Kiyomi; Tsukamoto, Mariko; Tamura, Namiko; Hazeki, Kaoru; Hazeki, Osamu

    2007-01-01

    Menadione (vitamin K3) has been shown to activate Erk in several cell lines. This effect has been shown to be due to the activation of EGF receptors (EGFR) as a result of inhibition of some protein tyrosine phosphatases. In the present study, we examined the effects of menadione on Akt in Chinese hamster ovary cells. The phosphorylation of Akt by menadione was not inhibited by AG1478, an inhibitor of EGFR. Menadione inhibited the lipid phosphatase activity of PTEN in a cell-free system. In an...

  19. Agnus castus extracts inhibit prolactin secretion of rat pituitary cells.

    Science.gov (United States)

    Sliutz, G; Speiser, P; Schultz, A M; Spona, J; Zeillinger, R

    1993-05-01

    In our studies on prolactin inhibition by plant extracts we focused on the effects of extracts of Vitex agnus castus and its preparations on rat pituitary cells under basal and stimulated conditions in primary cell culture. Both extracts from Vitex agnus castus as well as synthetic dopamine agonists (Lisuride) significantly inhibit basal as well as TRH-stimulated prolactin secretion of rat pituitary cells in vitro and as a consequence inhibition of prolactin secretion could be blocked by adding a dopamine receptor blocker. Therefore because of its dopaminergic effect Agnus castus could be considered as an efficient alternative phytotherapeutic drug in the treatment of slight hyperprolactinaemia.

  20. Measuring Feedforward Inhibition and Its Impact on Local Circuit Function.

    Science.gov (United States)

    Hull, Court

    2017-05-01

    This protocol describes a series of approaches to measure feedforward inhibition in acute brain slices from the cerebellar cortex. Using whole-cell voltage and current clamp recordings from Purkinje cells in conjunction with electrical stimulation of the parallel fibers, these methods demonstrate how to measure the relationship between excitation and inhibition in a feedforward circuit. This protocol also describes how to measure the impact of feedforward inhibition on Purkinje cell excitability, with an emphasis on spike timing. © 2017 Cold Spring Harbor Laboratory Press.

  1. Spike propagation in driven chain networks with dominant global inhibition

    International Nuclear Information System (INIS)

    Chang Wonil; Jin, Dezhe Z.

    2009-01-01

    Spike propagation in chain networks is usually studied in the synfire regime, in which successive groups of neurons are synaptically activated sequentially through the unidirectional excitatory connections. Here we study the dynamics of chain networks with dominant global feedback inhibition that prevents the synfire activity. Neural activity is driven by suprathreshold external inputs. We analytically and numerically demonstrate that spike propagation along the chain is a unique dynamical attractor in a wide parameter regime. The strong inhibition permits a robust winner-take-all propagation in the case of multiple chains competing via the inhibition.

  2. Inhibition of hepatic lipogenesis by 2-tetradecylglycidic acid.

    Science.gov (United States)

    McCune, S A; Nomura, T; Harris, R A

    1979-10-01

    2-Tetradecylglycidic acid (TDGA), a hypoglycemic agent, has been found to be a very effective inhibitor of de novo fatty acid synthesis by isolated hepatocytes. A comparison was made between the effectiveness of TDGA and 5-(tetradecyloxy)-2-furoic acid (TOFA), a hypolipidemic agent, on the metabolic processes of isolated hepatocytes. These compounds are structurally related and both inhibit fatty acid synthesis; however, they have opposite effects from each other on the oxidation and esterification of fatty acids. TDGA inhibits whereas TOFA stimulates fatty acid oxidation. TDGA stimulates whereas TOFA inhibits fatty acid esterification.

  3. Dicumarol inhibition of NADPH:quinone oxidoreductase induces growth inhibition of pancreatic cancer via a superoxide-mediated mechanism.

    Science.gov (United States)

    Cullen, Joseph J; Hinkhouse, Marilyn M; Grady, Matthew; Gaut, Andrew W; Liu, Jingru; Zhang, Yu Ping; Weydert, Christine J Darby; Domann, Frederick E; Oberley, Larry W

    2003-09-01

    NADPH:quinone oxidoreductase (NQO(1)), a homodimeric, ubiquitous, flavoprotein, catalyzes the two-electron reduction of quinones to hydroquinones. This reaction prevents the one-electron reduction of quinones by cytochrome P450 reductase and other flavoproteins that would result in oxidative cycling with generation of superoxide (O(2)(.-)). NQO(1) gene regulation may be up-regulated in some tumors to accommodate the needs of rapidly metabolizing cells to regenerate NAD(+). We hypothesized that pancreatic cancer cells would exhibit high levels of this enzyme, and inhibiting it would suppress the malignant phenotype. Reverse transcription-PCR, Western blots, and activity assays demonstrated that NQO(1) was up-regulated in the pancreatic cancer cell lines tested but present in very low amounts in the normal human pancreas. To determine whether inhibition of NQO(1) would alter the malignant phenotype, MIA PaCa-2 pancreatic cancer cells were treated with a selective inhibitor of NQO(1), dicumarol. Dicumarol increased intracellular production of O(2)(.-), as measured by hydroethidine staining, and inhibited cell growth. Both of these effects were blunted with infection of an adenoviral vector containing the cDNA for manganese superoxide dismutase. Dicumarol also inhibited cell growth, plating efficiency, and growth in soft agar. We conclude that inhibition of NQO(1) increases intracellular O(2)(.-) production and inhibits the in vitro malignant phenotype of pancreatic cancer. These mechanisms suggest that altering the intracellular redox environment of pancreatic cancer cells may inhibit growth and delineate a potential strategy directed against pancreatic cancer.

  4. Inhibiting prenylation augments chemotherapy efficacy in renal cell carcinoma through dual inhibition on mitochondrial respiration and glycolysis.

    Science.gov (United States)

    Huang, Jiangrong; Yang, Xiaoyu; Peng, Xiaochun; Huang, Wei

    2017-11-18

    Prenylation is a posttranslational lipid modification required for the proper functions of a number of proteins involved in cell regulation. Here, we show that prenylation inhibition is important for renal cell carcinoma (RCC) growth, survival and response to chemotherapy, and its underlying mechanism may be contributed to mitochondrial dysfunction. We first demonstrated that a HMG-CoA reductase inhibitor pitavastatin inhibited mevalonate pathway and thereby prenylation in RCC cells. In addition, pitavastatin is effective in inhibiting growth and inducing apoptosis in a panel of RCC cell lines. Combination of pitavastatin and paclitaxel is significantly more effective than pitavastatin or paclitaxel alone as shown by both in vitro cell culture system and in vivo RCC xenograft model. Importantly, pitavastatin treatment inhibits mitochondrial respiration via suppressing mitochondrial complex I and II enzyme activities. Interestingly, different from mitochondrial inhibitor phenformin that inhibits mitochondrial respiration but activates glycolytic rate in RCC cells, pitavastatin significantly decreases glycolytic rate. The dual inhibitory action of pitavastatin on mitochondrial respiration and glycolysis results in remarkable energy depletion and oxidative stress in RCC cells. In addition, inhibition of prenylation by depleting Isoprenylcysteine carboxylmethyltransferase (Icmt) also mimics the inhibitory effects of pitavastatin in RCC cells. Our work demonstrates the previously unappreciated association between prenylation inhibition and energy metabolism in RCC, which can be therapeutically exploited, likely in tumors that largely rely on energy metabolism. Copyright © 2017 Elsevier Inc. All rights reserved.

  5. Control of CA3 output by feedforward inhibition despite developmental changes in the excitation-inhibition balance.

    Science.gov (United States)

    Torborg, Christine L; Nakashiba, Toshiaki; Tonegawa, Susumu; McBain, Chris J

    2010-11-17

    In somatosensory cortex, the relative balance of excitation and inhibition determines how effectively feedforward inhibition enforces the temporal fidelity of action potentials. Within the CA3 region of the hippocampus, glutamatergic mossy fiber (MF) synapses onto CA3 pyramidal cells (PCs) provide strong monosynaptic excitation that exhibit prominent facilitation during repetitive activity. We demonstrate in the juvenile CA3 that MF-driven polysynaptic IPSCs facilitate to maintain a fixed EPSC-IPSC ratio during short-term plasticity. In contrast, in young adult mice this MF-driven polysynaptic inhibitory input can facilitate or depress in response to short trains of activity. Transgenic mice lacking the feedback inhibitory loop continue to exhibit both facilitating and depressing polysynaptic IPSCs, indicating that this robust inhibition is not caused by the secondary engagement of feedback inhibition. Surprisingly, eliminating MF-driven inhibition onto CA3 pyramidal cells by blockade of GABA(A) receptors did not lead to a loss of temporal precision of the first action potential observed after a stimulus but triggered in many cases a long excitatory plateau potential capable of triggering repetitive action potential firing. These observations indicate that, unlike other regions of the brain, the temporal precision of single MF-driven action potentials is dictated primarily by the kinetics of MF EPSPs, not feedforward inhibition. Instead, feedforward inhibition provides a robust regulation of CA3 PC excitability across development to prevent excessive depolarization by the monosynaptic EPSP and multiple action potential firings.

  6. Irreversible inhibition of RANK expression as a possible mechanism for IL-3 inhibition of RANKL-induced osteoclastogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Khapli, Shruti M.; Tomar, Geetanjali B.; Barhanpurkar, Amruta P.; Gupta, Navita; Yogesha, S.D.; Pote, Satish T. [National Center for Cell Science, University of Pune Campus, Pune 411 007 (India); Wani, Mohan R., E-mail: mohanwani@nccs.res.in [National Center for Cell Science, University of Pune Campus, Pune 411 007 (India)

    2010-09-03

    Research highlights: {yields} IL-3 inhibits receptor activator of NF-{kappa}B ligand (RANKL)-induced osteoclastogenesis. {yields} IL-3 inhibits RANKL-induced JNK activation. {yields} IL-3 down-regulates expression of c-Fos and NFATc1 transcription factors. {yields} IL-3 down-regulates RANK expression posttranscriptionally and irreversibly. {yields} IL-3 inhibits in vivo RANK expression. -- Abstract: IL-3, a cytokine secreted by activated T lymphocytes, stimulates the proliferation, differentiation and survival of pluripotent hematopoietic stem cells. In this study, we investigated the mechanism of inhibitory action of IL-3 on osteoclast differentiation. We show here that IL-3 significantly inhibits receptor activator of NF-{kappa}B (RANK) ligand (RANKL)-induced activation of c-Jun N-terminal kinase (JNK). IL-3 down-regulates expression of c-Fos and nuclear factor of activated T cells (NFATc1) transcription factors. In addition, IL-3 down-regulates RANK expression posttranscriptionally in both purified osteoclast precursors and whole bone marrow cells. Furthermore, the inhibitory effect of IL-3 on RANK expression was irreversible. Interestingly, IL-3 inhibits in vivo RANK expression in mice. Thus, we provide the first evidence that IL-3 irreversibly inhibits RANK expression that results in inhibition of important signaling molecules induced by RANKL.

  7. Irreversible inhibition of RANK expression as a possible mechanism for IL-3 inhibition of RANKL-induced osteoclastogenesis

    International Nuclear Information System (INIS)

    Khapli, Shruti M.; Tomar, Geetanjali B.; Barhanpurkar, Amruta P.; Gupta, Navita; Yogesha, S.D.; Pote, Satish T.; Wani, Mohan R.

    2010-01-01

    Research highlights: → IL-3 inhibits receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis. → IL-3 inhibits RANKL-induced JNK activation. → IL-3 down-regulates expression of c-Fos and NFATc1 transcription factors. → IL-3 down-regulates RANK expression posttranscriptionally and irreversibly. → IL-3 inhibits in vivo RANK expression. -- Abstract: IL-3, a cytokine secreted by activated T lymphocytes, stimulates the proliferation, differentiation and survival of pluripotent hematopoietic stem cells. In this study, we investigated the mechanism of inhibitory action of IL-3 on osteoclast differentiation. We show here that IL-3 significantly inhibits receptor activator of NF-κB (RANK) ligand (RANKL)-induced activation of c-Jun N-terminal kinase (JNK). IL-3 down-regulates expression of c-Fos and nuclear factor of activated T cells (NFATc1) transcription factors. In addition, IL-3 down-regulates RANK expression posttranscriptionally in both purified osteoclast precursors and whole bone marrow cells. Furthermore, the inhibitory effect of IL-3 on RANK expression was irreversible. Interestingly, IL-3 inhibits in vivo RANK expression in mice. Thus, we provide the first evidence that IL-3 irreversibly inhibits RANK expression that results in inhibition of important signaling molecules induced by RANKL.

  8. Arctigenin Inhibits Liver Cancer Tumorigenesis by Inhibiting Gankyrin Expression via C/EBPα and PPARα

    Science.gov (United States)

    Sun, Ying; Tan, Yu-jun; Lu, Zhan-zhao; Li, Bing-bing; Sun, Cheng-hong; Li, Tao; Zhao, Li-li; Liu, Zhong; Zhang, Gui-min; Yao, Jing-chun; Li, Jie

    2018-01-01

    Burdock (Arctium lappa) is a popular vegetable in China and Japan that is consumed for its general health benefits. The principal active component of burdock is arctigenin, which shows a range of bioactivities in vivo and in vitro. Here, we investigated the potential anti-tumor effects of arctigenin using two human hepatocellular carcinoma (HCC) cell lines, HepG2 and Hep3B, and sought to elucidate its potential mechanisms of action. Our results showed that arctigenin treatment inhibited cell growth in both HepG2 and Hep3B cell lines (IC50 of 4.74 nM for HepG2 cells, and of 59.27 nM for Hep3B cells). In addition, migration, invasion, and colony formation by HepG2 cells were significantly inhibited by arctigenin. By contrast, treatment of Hep3B cells with arctigenin did not alter these parameters. Arctigenin also significantly reduced the levels of gankyrin mRNA and protein in HepG2 cells, but not in Hep3B cells. A luciferase assay indicated that arctigenin targeted the -450 to -400 region of the gankyrin promoter. This region is also the potential binding site for both C/EBPα and PPARα, as predicted and confirmed by an online software analysis and ChIP assay. Additionally, a co-immunoprecipitation (Co-IP) assay showed that binding between C/EBPα and PPARα was increased in the presence of arctigenin. However, arctigenin did not increase the expression of C/EBPα or PPARα protein. A binding screening assay and liquid chromatography–mass spectrometry (LC–MS) were performed to identify the mechanisms by which arctigenin regulates gankyrin expression. The results suggested that arctigenin could directly increase C/EBPα binding to the gankyrin promoter (-432 to -422 region), but did not affect PPARα binding. Expression of gankyrin, C/EBPα, and PPARα were analyzed in tumor tissues of patients using real-time PCR. Both C/EBPα and PPARα showed negative correlations with gankyrin. In tumor-bearing mice, arctigenin had a significant inhibitory effect on HCC

  9. Arctigenin Inhibits Liver Cancer Tumorigenesis by Inhibiting Gankyrin Expression via C/EBPα and PPARα

    Directory of Open Access Journals (Sweden)

    Ying Sun

    2018-03-01

    Full Text Available Burdock (Arctium lappa is a popular vegetable in China and Japan that is consumed for its general health benefits. The principal active component of burdock is arctigenin, which shows a range of bioactivities in vivo and in vitro. Here, we investigated the potential anti-tumor effects of arctigenin using two human hepatocellular carcinoma (HCC cell lines, HepG2 and Hep3B, and sought to elucidate its potential mechanisms of action. Our results showed that arctigenin treatment inhibited cell growth in both HepG2 and Hep3B cell lines (IC50 of 4.74 nM for HepG2 cells, and of 59.27 nM for Hep3B cells. In addition, migration, invasion, and colony formation by HepG2 cells were significantly inhibited by arctigenin. By contrast, treatment of Hep3B cells with arctigenin did not alter these parameters. Arctigenin also significantly reduced the levels of gankyrin mRNA and protein in HepG2 cells, but not in Hep3B cells. A luciferase assay indicated that arctigenin targeted the -450 to -400 region of the gankyrin promoter. This region is also the potential binding site for both C/EBPα and PPARα, as predicted and confirmed by an online software analysis and ChIP assay. Additionally, a co-immunoprecipitation (Co-IP assay showed that binding between C/EBPα and PPARα was increased in the presence of arctigenin. However, arctigenin did not increase the expression of C/EBPα or PPARα protein. A binding screening assay and liquid chromatography–mass spectrometry (LC–MS were performed to identify the mechanisms by which arctigenin regulates gankyrin expression. The results suggested that arctigenin could directly increase C/EBPα binding to the gankyrin promoter (-432 to -422 region, but did not affect PPARα binding. Expression of gankyrin, C/EBPα, and PPARα were analyzed in tumor tissues of patients using real-time PCR. Both C/EBPα and PPARα showed negative correlations with gankyrin. In tumor-bearing mice, arctigenin had a significant inhibitory

  10. Arctigenin Inhibits Liver Cancer Tumorigenesis by Inhibiting Gankyrin Expression via C/EBPα and PPARα.

    Science.gov (United States)

    Sun, Ying; Tan, Yu-Jun; Lu, Zhan-Zhao; Li, Bing-Bing; Sun, Cheng-Hong; Li, Tao; Zhao, Li-Li; Liu, Zhong; Zhang, Gui-Min; Yao, Jing-Chun; Li, Jie

    2018-01-01

    Burdock ( Arctium lappa ) is a popular vegetable in China and Japan that is consumed for its general health benefits. The principal active component of burdock is arctigenin, which shows a range of bioactivities in vivo and in vitro . Here, we investigated the potential anti-tumor effects of arctigenin using two human hepatocellular carcinoma (HCC) cell lines, HepG2 and Hep3B, and sought to elucidate its potential mechanisms of action. Our results showed that arctigenin treatment inhibited cell growth in both HepG2 and Hep3B cell lines (IC 50 of 4.74 nM for HepG2 cells, and of 59.27 nM for Hep3B cells). In addition, migration, invasion, and colony formation by HepG2 cells were significantly inhibited by arctigenin. By contrast, treatment of Hep3B cells with arctigenin did not alter these parameters. Arctigenin also significantly reduced the levels of gankyrin mRNA and protein in HepG2 cells, but not in Hep3B cells. A luciferase assay indicated that arctigenin targeted the -450 to -400 region of the gankyrin promoter. This region is also the potential binding site for both C/EBPα and PPARα, as predicted and confirmed by an online software analysis and ChIP assay. Additionally, a co-immunoprecipitation (Co-IP) assay showed that binding between C/EBPα and PPARα was increased in the presence of arctigenin. However, arctigenin did not increase the expression of C/EBPα or PPARα protein. A binding screening assay and liquid chromatography-mass spectrometry (LC-MS) were performed to identify the mechanisms by which arctigenin regulates gankyrin expression. The results suggested that arctigenin could directly increase C/EBPα binding to the gankyrin promoter (-432 to -422 region), but did not affect PPARα binding. Expression of gankyrin, C/EBPα , and PPARα were analyzed in tumor tissues of patients using real-time PCR. Both C/EBPα and PPARα showed negative correlations with gankyrin. In tumor-bearing mice, arctigenin had a significant inhibitory effect on HCC

  11. Pathological histone acetylation in Parkinson's disease: Neuroprotection and inhibition of microglial activation through SIRT 2 inhibition.

    Science.gov (United States)

    Harrison, Ian F; Smith, Andrew D; Dexter, David T

    2018-02-14

    Parkinson's disease (PD) is associated with degeneration of nigrostriatal neurons due to intracytoplasmic inclusions composed predominantly of a synaptic protein called α-synuclein. Accumulations of α-synuclein are thought to 'mask' acetylation sites on histone proteins, inhibiting the action of histone acetyltransferase (HAT) enzymes in their equilibrium with histone deacetylases (HDACs), thus deregulating the dynamic control of gene transcription. It is therefore hypothesised that the misbalance in the actions of HATs/HDACs in neurodegeneration can be rectified with the use of HDAC inhibitors, limiting the deregulation of transcription and aiding neuronal homeostasis and neuroprotection in disorders such as PD. Here we quantify histone acetylation in the Substantia Nigra pars compacta (SNpc) in the brains of control, early and late stage PD cases to determine if histone acetylation is a function of disease progression. PD development is associated with Braak-dependent increases in histone acetylation. Concurrently, we show that as expected disease progression is associated with reduced markers of dopaminergic neurons and increased markers of activated microglia. We go on to demonstrate that in vitro, degenerating dopaminergic neurons exhibit histone hypoacetylation whereas activated microglia exhibit histone hyperacetylation. This suggests that the disease-dependent increase in histone acetylation observed in human PD cases is likely a combination of the contributions of both degenerating dopaminergic neurons and infiltrating activated microglia. The HDAC SIRT 2 has become increasingly implicated as a novel target for mediation of neuroprotection in PD: the neuronal and microglial specific effects of its inhibition however remain unclear. We demonstrate that SIRT 2 expression in the SNpc of PD brains remains relatively unchanged from controls and that SIRT 2 inhibition, via AGK2 treatment of neuronal and microglial cultures, results in neuroprotection of

  12. Inhibition Effect of Deanol on Mild Steel Corrosion in Dilute ...

    African Journals Online (AJOL)

    NICOLAAS

    2014-06-23

    Jun 23, 2014 ... allows for extensive use as the material of construction in petro- leum industries .... steel specimens was investigated after mass-loss analysis ..... Ogbuliec, Inhibition of pseudo-anaerobic corrosion of oil pipeline steel in ...

  13. Melanogenesis inhibition activity of floralginsenoside A from Panax ginseng berry

    Directory of Open Access Journals (Sweden)

    Dae Young Lee

    2017-10-01

    Conclusion: FGA showed the most potent inhibition of melanogenesis in both in vitro and in vivo studies. This study suggests that FGA purified from P. ginseng may be an effective melanogenesis inhibitor.

  14. Automatic motion inhibit system for a nuclear power generating system

    International Nuclear Information System (INIS)

    Musick, C.R.; Torres, J.M.

    1977-01-01

    Disclosed is an automatic motion inhibit system for a nuclear power generating system for inhibiting automatic motion of the control elements to reduce reactor power in response to a turbine load reduction. The system generates a final reactor power level setpoint signal which is continuously compared with a reactor power signal. The final reactor power level setpoint is a setpoint within the capacity of the bypass valves to bypass steam which in no event is lower in value than the lower limit of automatic control of the reactor. If the final reactor power level setpoint is greater than the reactor power, an inhibit signal is generated to inhibit automatic control of the reactor. 6 claims, 5 figures

  15. Noninvasive optical inhibition with a red-shifted microbial rhodopsin

    DEFF Research Database (Denmark)

    Chuong, Amy S; Miri, Mitra L; Busskamp, Volker

    2014-01-01

    Optogenetic inhibition of the electrical activity of neurons enables the causal assessment of their contributions to brain functions. Red light penetrates deeper into tissue than other visible wavelengths. We present a red-shifted cruxhalorhodopsin, Jaws, derived from Haloarcula (Halobacterium......) salinarum (strain Shark) and engineered to result in red light-induced photocurrents three times those of earlier silencers. Jaws exhibits robust inhibition of sensory-evoked neural activity in the cortex and results in strong light responses when used in retinas of retinitis pigmentosa model mice. We also...... demonstrate that Jaws can noninvasively mediate transcranial optical inhibition of neurons deep in the brains of awake mice. The noninvasive optogenetic inhibition opened up by Jaws enables a variety of important neuroscience experiments and offers a powerful general-use chloride pump for basic and applied...

  16. Inhibition of Nitric Oxide and Prostaglandin E 2 Expression by ...

    African Journals Online (AJOL)

    Inhibition of Nitric Oxide and Prostaglandin E 2 Expression by Methanol Extract of Polyopes affinis in Lipopolysaccharide-stimulated BV2 Microglial Cells through Suppression of Akt-dependent NF-kB Activity and MAPK Pathway.

  17. Functional inhibition of UQCRB suppresses angiogenesis in zebrafish

    Energy Technology Data Exchange (ETDEWEB)

    Cho, Yoon Sun; Jung, Hye Jin [Chemical Genomics National Research Laboratory, Department of Biotechnology, Translational Research Center for Protein Function Control, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749 (Korea, Republic of); Seok, Seung Hyeok [Department of Microbiology and Immunology, Institute for Experimental Animals, Seoul National University College of Medicine, Seoul 110-799 (Korea, Republic of); Payumo, Alexander Y.; Chen, James K. [Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305 (United States); Kwon, Ho Jeong, E-mail: kwonhj@yonsei.ac.kr [Chemical Genomics National Research Laboratory, Department of Biotechnology, Translational Research Center for Protein Function Control, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749 (Korea, Republic of)

    2013-04-19

    Highlights: ► This is the first functional characterization of UQCRB in vivo model. ► Angiogenesis is inhibited with UQCRB loss of function in zebrafish. ► UQCRB is introduced as a prognostic marker for mitochondria- and angiogenesis-related diseases. -- Abstract: As a subunit of mitochondrial complex III, UQCRB plays an important role in complex III stability, electron transport, and cellular oxygen sensing. Herein, we report UQCRB function regarding angiogenesis in vivo with the zebrafish (Danio rerio). UQCRB knockdown inhibited angiogenesis in zebrafish leading to the suppression of VEGF expression. Moreover, the UQCRB-targeting small molecule terpestacin also inhibited angiogenesis and VEGF levels in zebrafish, supporting the role of UQCRB in angiogenesis. Collectively, UQCRB loss of function by either genetic and pharmacological means inhibited angiogenesis, indicating that UQCRB plays a key role in this process and can be a prognostic marker of angiogenesis- and mitochondria-related diseases.

  18. Inhibiting DNA Polymerases as a Therapeutic Intervention against Cancer

    Directory of Open Access Journals (Sweden)

    Anthony J. Berdis

    2017-11-01

    Full Text Available Inhibiting DNA synthesis is an important therapeutic strategy that is widely used to treat a number of hyperproliferative diseases including viral infections, autoimmune disorders, and cancer. This chapter describes two major categories of therapeutic agents used to inhibit DNA synthesis. The first category includes purine and pyrmidine nucleoside analogs that directly inhibit DNA polymerase activity. The second category includes DNA damaging agents including cisplatin and chlorambucil that modify the composition and structure of the nucleic acid substrate to indirectly inhibit DNA synthesis. Special emphasis is placed on describing the molecular mechanisms of these inhibitory effects against chromosomal and mitochondrial DNA polymerases. Discussions are also provided on the mechanisms associated with resistance to these therapeutic agents. A primary focus is toward understanding the roles of specialized DNA polymerases that by-pass DNA lesions produced by DNA damaging agents. Finally, a section is provided that describes emerging areas in developing new therapeutic strategies targeting specialized DNA polymerases.

  19. Inhibition of trypsin by condensed tannins and wine.

    Science.gov (United States)

    Gonçalves, Rui; Soares, Susana; Mateus, Nuno; de Freitas, Victor

    2007-09-05

    Phenolic compounds are abundant vegetable secondary metabolites in the human diet. The ability of procyanidin oligomers and wine polyphenols to inhibit trypsin activity was studied using a versatile and reliable in vitro method. The hydrolysis of the chromogenic substrate N-benzoyl-d,l-arginine-p-nitroanilide (BApNA) by trypsin was followed by spectrophotometry in the presence and absence of condensed tannins and wine. A clear relationship between the degree of polymerization of procyanidins and enzymatic inhibition was observed. Trypsin activity inhibition was also detected in several types of wine. In general, the inhibition increased with the concentration of phenolic compounds in wines. These results may be relevant when considering these compounds as antinutritional factors, thereby contributing to a reduced absorption of nutrients.

  20. Ginsenoside Rb1 Reduces Nitric Oxide Production via Inhibition of ...

    African Journals Online (AJOL)

    Inhibition of Nuclear Factor-κB Activation in Interleukin-1β- ... 20, 40, 80 µM ginsenoside Rb1. NO concentration was assessed by the Griess reaction. ... International Pharmaceutical Abstract, Chemical Abstracts, Embase, Index Copernicus, ...

  1. Transcriptome dynamics of the microRNA inhibition response

    DEFF Research Database (Denmark)

    Wen, Jiayu; Leucci, Elenora; Vendramin, Roberto

    2015-01-01

    We report a high-resolution time series study of transcriptome dynamics following antimiR-mediated inhibition of miR-9 in a Hodgkin lymphoma cell-line-the first such dynamic study of the microRNA inhibition response-revealing both general and specific aspects of the physiological response. We show...... validate the key observations with independent time series qPCR and we experimentally validate key predicted miR-9 targets. Methodologically, we developed sensitive functional data analytic predictive methods to analyse the weak response inherent in microRNA inhibition experiments. The methods...... of this study will be applicable to similar high-resolution time series transcriptome analyses and provides the context for more accurate experimental design and interpretation of future microRNA inhibition studies....

  2. Inhibition of human lung adenocarcinoma growth using survivint34a ...

    Indian Academy of Sciences (India)

    Prakash

    knockdown, survivin-directed vaccines (Pisarev et al. 2003), ... Endotoxin levels of the plasmid DNA prepared were determined by .... power fields/slide). ... inhibition of angiogenesis and directly increase apoptosis of .... α-induced apoptosis.

  3. Functional inhibition of UQCRB suppresses angiogenesis in zebrafish

    International Nuclear Information System (INIS)

    Cho, Yoon Sun; Jung, Hye Jin; Seok, Seung Hyeok; Payumo, Alexander Y.; Chen, James K.; Kwon, Ho Jeong

    2013-01-01

    Highlights: ► This is the first functional characterization of UQCRB in vivo model. ► Angiogenesis is inhibited with UQCRB loss of function in zebrafish. ► UQCRB is introduced as a prognostic marker for mitochondria- and angiogenesis-related diseases. -- Abstract: As a subunit of mitochondrial complex III, UQCRB plays an important role in complex III stability, electron transport, and cellular oxygen sensing. Herein, we report UQCRB function regarding angiogenesis in vivo with the zebrafish (Danio rerio). UQCRB knockdown inhibited angiogenesis in zebrafish leading to the suppression of VEGF expression. Moreover, the UQCRB-targeting small molecule terpestacin also inhibited angiogenesis and VEGF levels in zebrafish, supporting the role of UQCRB in angiogenesis. Collectively, UQCRB loss of function by either genetic and pharmacological means inhibited angiogenesis, indicating that UQCRB plays a key role in this process and can be a prognostic marker of angiogenesis- and mitochondria-related diseases

  4. Nitric oxide inhibits glycogen synthesis in isolated rat hepatocytes

    NARCIS (Netherlands)

    Sprangers, F.; Sauerwein, H. P.; Romijn, J. A.; van Woerkom, G. M.; Meijer, A. J.

    1998-01-01

    There is increasing evidence for the existence of intrahepatic regulation of glucose metabolism by Kupffer cell products. Nitric oxide (NO) is known to inhibit gluconeogenic flux through pyruvate carboxylase and phosphoenolpyruvate carboxykinase. However, NO may also influence glucose metabolism at

  5. Inhibition of glutathione S-transferases (GSTs) activity from cowpea ...

    African Journals Online (AJOL)

    STORAGESEVER

    2009-10-19

    Oct 19, 2009 ... Inhibition effect of the plant extracts on the GST was studied by spectrophotometric method. The ... of assuring food security in developing countries like ..... studies on African cat fish (Clarias gariepinus) liver glutathione s-.

  6. Impaired face recognition is associated with social inhibition.

    Science.gov (United States)

    Avery, Suzanne N; VanDerKlok, Ross M; Heckers, Stephan; Blackford, Jennifer U

    2016-02-28

    Face recognition is fundamental to successful social interaction. Individuals with deficits in face recognition are likely to have social functioning impairments that may lead to heightened risk for social anxiety. A critical component of social interaction is how quickly a face is learned during initial exposure to a new individual. Here, we used a novel Repeated Faces task to assess how quickly memory for faces is established. Face recognition was measured over multiple exposures in 52 young adults ranging from low to high in social inhibition, a core dimension of social anxiety. High social inhibition was associated with a smaller slope of change in recognition memory over repeated face exposure, indicating participants with higher social inhibition showed smaller improvements in recognition memory after seeing faces multiple times. We propose that impaired face learning is an important mechanism underlying social inhibition and may contribute to, or maintain, social anxiety. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  7. IN VITRO STUDY ON INHIBITION OF GLYCOSYLATION OF ...

    African Journals Online (AJOL)

    Administrator

    complications of diabetes mellitus (Makita et al., 1991). Apart from protein ... enzymes; inhibition of regulatory molecule binding; crosslinking of glycosylated .... further investigation specific bio active compound responsible for such activities.

  8. Hyperoxia Inhibits T Cell Activation in Mice

    Science.gov (United States)

    Hughes-Fulford, M.; Meissler, J.; Aguayo, E. T.; Globus, R.; Aguado, J.; Candelario, T.

    2013-02-01

    , spleens were removed and the splenocytes were isolated and kept as individual biological samples. We have also examined transcription factors (JASPAR) and pathways of the immune system to help us understand the mechanism of regulation. Results: Our recent mouse immunology experiment aboard STS-131 suggests that the early T cell immune response was inhibited in animals that have been exposed to spaceflight, even 24 hours after return to earth. Moreover, recent experiments in hyperoxic mice show that many of the same genes involved in early T cell activation were altered. Specifically, expression of IL-2Rα, Cxcl2, TNFα, FGF2, LTA and BCL2 genes are dysregulated in mice exposed to hyperoxia. Conclusions: If these hyperoxia-induced changes of gene expression in early T cell activation are additive to the changes seen in the microgravity of spaceflight, there could be an increased infection risk to EVA astronauts, which should be addressed prior to conducting a Mars or other long-term mission.

  9. Study of oxygen inhibition effect on radiation curing

    International Nuclear Information System (INIS)

    Xiao Bin; Yang Xuemei; Zhao Pengji; Zeng Shuqing; Jiang Bo; Zhou Yong; Huang Wei; Zhou Youyi

    1995-01-01

    Michacl addition reaction product was used in the research of oxygen inhibition effect of radiation curing. The experimental results was measured by the content of gel and percentage of double bonds. It was proved that 9% of Michacl addition product could speed up 1.2 times of the radiation curing rate at 30 kGy of EB irradiation. This kind of formulation can withstand oxygen inhibition effect obviously, so it was the foundation of application for radiation curing in atmospheric condition

  10. Antiangiogenic and Antitumor Effects of Src Inhibition in Ovarian Carcinoma

    Science.gov (United States)

    Han, Liz Y.; Landen, Charles N.; Trevino, Jose G.; Halder, Jyotsnabaran; Lin, Yvonne G.; Kamat, Aparna A.; Kim, Tae-Jin; Merritt, William M.; Coleman, Robert L.; Gershenson, David M.; Shakespeare, William C.; Wang, Yihan; Sundaramoorth, Raji; Metcalf, Chester A.; Dalgarno, David C.; Sawyer, Tomi K.; Gallick, Gary E.; Sood, Anil K.

    2011-01-01

    Src, a nonreceptor tyrosine kinase, is a key mediator for multiple signaling pathways that regulate critical cellular functions and is often aberrantly activated in a number of solid tumors, including ovarian carcinoma. The purpose of this study was to determine the role of activated Src inhibition on tumor growth in an orthotopic murine model of ovarian carcinoma. In vitro studies on HeyA8 and SKOV3ip1 cell lines revealed that Src inhibition by the Src-selective inhibitor, AP23846, occurred within 1 hour and responded in a dose-dependent manner. Furthermore, Src inhibition enhanced the cytotoxicity of docetaxel in both chemosensitive and chemoresistant ovarian cancer cell lines, HeyA8 and HeyA8-MDR, respectively. In vivo, Src inhibition by AP23994, an orally bioavailable analogue of AP23846, significantly decreased tumor burden in HeyA8 (P = 0.02), SKOV3ip1 (P = 0.01), as well as HeyA8-MDR (P < 0.03) relative to the untreated controls. However, the greatest effect on tumor reduction was observed in combination therapy with docetaxel (P < 0.001, P = 0.002, and P = 0.01, for the above models, respectively). Proliferating cell nuclear antigen staining showed that Src inhibition alone (P = 0.02) and in combination with docetaxel (P = 0.007) significantly reduced tumor proliferation. In addition, Src inhibition alone and in combination with docetaxel significantly down-regulated tumoral production of vascular endothelial growth factor and interleukin 8, whereas combination therapy decreased the microvessel density (P = 0.02) and significantly affected vascular permeability (P < 0.05). In summary, Src inhibition with AP23994 has potent antiangiogenic effects and significantly reduces tumor burden in preclinical ovarian cancer models. Thus, Src inhibition may be an attractive therapeutic approach for patients with ovarian carcinoma. PMID:16951177

  11. Hili Inhibits HIV Replication in Activated T Cells.

    Science.gov (United States)

    Peterlin, B Matija; Liu, Pingyang; Wang, Xiaoyun; Cary, Daniele; Shao, Wei; Leoz, Marie; Hong, Tian; Pan, Tao; Fujinaga, Koh

    2017-06-01

    P-element-induced wimpy-like (Piwil) proteins restrict the replication of mobile genetic elements in the germ line. They are also expressed in many transformed cell lines. In this study, we discovered that the human Piwil 2 (Hili) protein can also inhibit HIV replication, especially in activated CD4 + T cells that are the preferred target cells for this virus in the infected host. Although resting cells did not express Hili, its expression was rapidly induced following T cell activation. In these cells and transformed cell lines, depletion of Hili increased levels of viral proteins and new viral particles. Further studies revealed that Hili binds to tRNA. Some of the tRNAs represent rare tRNA species, whose codons are overrepresented in the viral genome. Targeting tRNA Arg (UCU) with an antisense oligonucleotide replicated effects of Hili and also inhibited HIV replication. Finally, Hili also inhibited the retrotransposition of the endogenous intracysternal A particle (IAP) by a similar mechanism. Thus, Hili joins a list of host proteins that inhibit the replication of HIV and other mobile genetic elements. IMPORTANCE Piwil proteins inhibit the movement of mobile genetic elements in the germ line. In their absence, sperm does not form and male mice are sterile. This inhibition is thought to occur via small Piwi-interacting RNAs (piRNAs). However, in some species and in human somatic cells, Piwil proteins bind primarily to tRNA. In this report, we demonstrate that human Piwil proteins, especially Hili, not only bind to select tRNA species, including rare tRNAs, but also inhibit HIV replication. Importantly, T cell activation induces the expression of Hili in CD4 + T cells. Since Hili also inhibited the movement of an endogenous retrovirus (IAP), our finding shed new light on this intracellular resistance to exogenous and endogenous retroviruses as well as other mobile genetic elements. Copyright © 2017 American Society for Microbiology.

  12. Novel Antimicrobial Peptides That Inhibit Gram Positive Bacterial Exotoxin Synthesis

    Science.gov (United States)

    Merriman, Joseph A.; Nemeth, Kimberly A.; Schlievert, Patrick M.

    2014-01-01

    Gram-positive bacteria, such as Staphylococcus aureus, cause serious human illnesses through combinations of surface virulence factors and secretion of exotoxins. Our prior studies using the protein synthesis inhibitor clindamycin and signal transduction inhibitors glycerol monolaurate and α-globin and β-globin chains of hemoglobin indicate that their abilities to inhibit exotoxin production by S. aureus are separable from abilities to inhibit growth of the organism. Additionally, our previous studies suggest that inhibition of exotoxin production, in absence of ability to kill S. aureus and normal flora lactobacilli, will prevent colonization by pathogenic S. aureus, while not interfering with lactobacilli colonization. These disparate activities may be important in development of novel anti-infective agents that do not alter normal flora. We initiated studies to explore the exotoxin-synthesis-inhibition activity of hemoglobin peptides further to develop potential agents to prevent S. aureus infections. We tested synthesized α-globin chain peptides, synthetic variants of α-globin chain peptides, and two human defensins for ability to inhibit exotoxin production without significantly inhibiting S. aureus growth. All of these peptides were weakly or not inhibitory to bacterial growth. However, the peptides were inhibitory to exotoxin production with increasing activity dependent on increasing numbers of positively-charged amino acids. Additionally, the peptides could be immobilized on agarose beads or have amino acid sequences scrambled and still retain exotoxin-synthesis-inhibition. The peptides are not toxic to human vaginal epithelial cells and do not inhibit growth of normal flora L. crispatus. These peptides may interfere with plasma membrane signal transduction in S. aureus due to their positive charges. PMID:24748386

  13. The contribution of forward masking to saccadic inhibition of return.

    Science.gov (United States)

    Souto, David; Born, Sabine; Kerzel, Dirk

    2018-03-08

    Inhibition of return is the name typically given to the prolonged latency of motor responses directed to a previously cued target location. There is intense debate about the origins of this effect and its function, but most take for granted (despite lack of evidence) that it depends little on forward masking. Therefore, we re-examined the role of forward masking in inhibition of return. Forward masking was indexed by slower saccadic reaction times (SRTs) when the target orientation repeated the cue orientation at the same location. We confirmed effects of orientation repetition in the absence of an attentional bias when cues were presented on both sides of fixation (bilateral presentation). The effect of orientation repetition was reduced with high target contrast, consistent with a low-level origin such as contrast gain control in early visual areas. When presenting cues on only one side of fixation (unilateral presentation), we obtained inhibition of return with longer cue-target intervals and facilitation with targets presented shortly after the cue. The effect of orientation repetition was reduced when facilitation was observed, but was as strong as with bilateral cues when inhibition of return was observed. Therefore, forward masking may contribute to the inhibition of return effect by delaying reaction times to repeated features at the same location, but is not a principal cause of inhibition of return; in agreement with previous views. The saccadic inhibition of return effect is a reaction-time cost when responding to a pre-cued location. Additional object updating costs are typically invoked to explain reaction-time costs observed when cue and target have the same shape. Yet, lower-level, forward masking of the target by the cue can not be ruled out. Importantly, we show an effect of orientation repetition that is consistent with low-level forward masking rather than object updating costs and that does not interact with inhibition of return.

  14. Buprofezin inhibits acetylcholinesterase activity in B-biotype Bemisia tabaci.

    Science.gov (United States)

    Cottage, Emma L A; Gunning, Robin V

    2006-01-01

    B-biotype Bemisia tabaci is a severe insect pest worldwide in many ornamental, agricultural, and horticultural industries. Control of this insect is hampered by resistance to many acetylcholinesterase (AChE)-inhibiting insecticides, such as organophosphates and carbamates. Consequently, insect growth regulators such as buprofezin, which act by inhibiting chitin synthesis, are being investigated for use against B-biotype B. tabaci in Australia. This study discusses the effects of buprofezin on B. tabaciAChE.

  15. Influence of norepinephrine transporter inhibition on hemodynamic response to hypergravitation

    OpenAIRE

    Strempel, Sebastian

    2011-01-01

    Background: Sympathetically-mediated tachycardia and vasoconstriction maintain blood pressure during hypergravitational stress, thereby preventing gravitation-induced loss of consciousness (g-LOC). Norepinephrine transporter (NET) inhibition prevents neurally-mediated (pre)syncope during gravitational stress imposed by head-up tilt testing. Thus, it seems reasonable that NET inhibition could increase tolerance to hypergravitational stress. Methods. We performed a double-blind, randomized...

  16. Cantharidin biosynthesis in a blister beetle: inhibition by 6-fluoromevalonate causes chemical disarmament.

    Science.gov (United States)

    Carrel, J E; Doom, J P; McCormick, J P

    1986-07-15

    Biosynthesis of cantharidin in a blister beetle, Lytta polita, is effectively inhibited by 6-fluoromevalonate. Inhibition is attributed specifically to the fluorine substituent. Biochemical inhibition has not been demonstrated previously for an arthropod's defensive substance.

  17. Prepotent response inhibition predicts treatment outcome in attention deficit/hyperactivity disorder

    NARCIS (Netherlands)

    van der Oord, S.; Geurts, H.M.; Prins, P.J.M.; Emmelkamp, P.M.G.; Oosterlaan, J.

    2012-01-01

    Objective: Inhibition deficits, including deficits in prepotent response inhibition and interference control, are core deficits in ADHD. The predictive value of prepotent response inhibition and interference control was assessed for outcome in a 10-week treatment trial with methylphenidate. Methods:

  18. Substrate and product inhibition of hydrogen production by the extreme thermophile, Caldicellulosiruptor saccharolyticus

    NARCIS (Netherlands)

    Niel, van E.W.J.; Claassen, P.A.M.; Stams, A.J.M.

    2003-01-01

    Substrate and product inhibition of hydrogen production during sucrose fermentation by the extremely thermophilic bacterium Caldicellulosiruptor saccharolyticus was studied. The inhibition kinetics were analyzed with a noncompetitive, nonlinear inhibition model. Hydrogen was the most severe

  19. Beyond Behavioral Inhibition: A Computer Avatar Task Designed to Assess Behavioral Inhibition Extends to Harm Avoidance

    Directory of Open Access Journals (Sweden)

    Michael Todd Allen

    2017-09-01

    Full Text Available Personality factors such as behavioral inhibition (BI, a temperamental tendency for avoidance in the face of unfamiliar situations, have been identified as risk factors for anxiety disorders. Personality factors are generally identified through self-report inventories. However, this tendency to avoid may affect the accuracy of these self-report inventories. Previously, a computer based task was developed in which the participant guides an on-screen “avatar” through a series of onscreen events; performance on the task could accurately predict participants’ BI, measured by a standard paper and pencil questionnaire (Adult Measure of Behavioral Inhibition, or AMBI. Here, we sought to replicate this finding as well as compare performance on the avatar task to another measure related to BI, the harm avoidance (HA scale of the Tridimensional Personality Questionnaire (TPQ. The TPQ includes HA scales as well as scales assessing reward dependence (RD, novelty seeking (NS and persistence. One hundred and one undergraduates voluntarily completed the avatar task and the paper and pencil inventories in a counter-balanced order. Scores on the avatar task were strongly correlated with BI assessed via the AMBI questionnaire, which replicates prior findings. Females exhibited higher HA scores than males, but did not differ on scores on the avatar task. There was a strong positive relationship between scores on the avatar task and HA scores. One aspect of HA, fear of uncertainty was found to moderately mediate the relationship between AMBI scores and avatar scores. NS had a strong negative relationship with scores on the avatar task, but there was no significant relationship between RD and scores on the avatar task. These findings indicate the effectiveness of the avatar task as a behavioral alternative to self-report measures to assess avoidance. In addition, the use of computer based behavioral tasks are a viable alternative to paper and pencil self

  20. DMSO inhibits human platelet activation through cyclooxygenase-1 inhibition. A novel agent for drug eluting stents?

    International Nuclear Information System (INIS)

    Asmis, Lars; Tanner, Felix C.; Sudano, Isabella; Luescher, Thomas F.; Camici, Giovanni G.

    2010-01-01

    Background: DMSO is routinely infused together with hematopoietic cells in patients undergoing myeloablative therapy and was recently found to inhibit smooth muscle cells proliferation and arterial thrombus formation in the mouse by preventing tissue factor (TF), a key activator of the coagulation cascade. This study was designed to investigate whether DMSO prevents platelet activation and thus, whether it may represent an interesting agent to be used on drug eluting stents. Methods and results: Human venous blood from healthy volunteers was collected in citrated tubes and platelet activation was studied by cone and platelet analyzer (CPA) and rapid-platelet-function-assay (RPFA). CPA analysis showed that DMSO-treated platelets exhibit a lower adherence in response to shear stress (-15.54 ± 0.9427%, n = 5, P < 0.0001 versus control). Additionally, aggregometry studies revealed that DMSO-treated, arachidonate-stimulated platelets had an increased lag phase (18.0% ± 4.031, n = 9, P = 0.0004 versus control) as well as a decreased maximal aggregation (-6.388 ± 2.212%, n = 6, P = 0.0162 versus control). Inhibitory action of DMSO could be rescued by exogenous thromboxane A2 and was mediated, at least in part, by COX-1 inhibition. Conclusions: Clinically relevant concentrations of DMSO impair platelet activation by a thromboxane A2-dependent, COX-1-mediated effect. This finding may be crucial for the previously reported anti-thrombotic property displayed by DMSO. Our findings support a role for DMSO as a novel drug to prevent not only proliferation, but also thrombotic complications of drug eluting stents.

  1. SGLT2 inhibition in the diabetic kidney – an update

    Science.gov (United States)

    Novikov, Aleksandra; Vallon, Volker

    2016-01-01

    Purpose of review The sodium glucose cotransporter SGLT2 reabsorbs most of the glucose filtered by the kidneys. SGLT2 inhibitors reduce glucose reabsorption thereby lowering blood glucose levels and have been approved as new anti-hyperglycemic drugs. While the therapeutic strategy is very promising, many questions remain. Recent findings Using validated antibodies SGLT2 expression was localized to the brush border of the early proximal tubule in human kidney and was found upregulated in genetic murine models of type 1 and 2 diabetes. SGLT2 may functionally interact with the Na/H exchanger NHE3 in the proximal tubule. SGLT1-mediated reabsorption explains the fractional glucose reabsorption of 40–50% during SGLT2 inhibition. SGLT2 is expressed on pancreatic alpha cells where its inhibition induces glucagon secretion. SGLT2 inhibition lowers GFR in hyperfiltering diabetic patients consistent with the tubular hypothesis of diabetic hyperfiltration. New data indicate a potential of SGLT2 inhibition for renal medullary hypoxia and ketoacidosis, but also for blood glucose effect-dependent and independent nephroprotective actions, renal gluconeogenesis inhibition, reduction in cardiovascular mortality, and cancer therapy. Summary The findings expand and refine our understanding of SGLT2 and its inhibition, have relevance for clinical practice, and will help interpret ongoing clinical trials on the long-term safety and cardiovascular effects of SGLT2 inhibitors. PMID:26575393

  2. Acrolein in cigarette smoke inhibits T-cell responses.

    Science.gov (United States)

    Lambert, Cherie; McCue, Jesica; Portas, Mary; Ouyang, Yanli; Li, JiMei; Rosano, Thomas G; Lazis, Alexander; Freed, Brian M

    2005-10-01

    Cigarette smoking inhibits T-cell responses in the lungs, but the immunosuppressive compounds have not been fully identified. Cigarette smoke extracts inhibit IL-2, IFN-gamma, and TNF-alpha production in stimulated lymphocytes obtained from peripheral blood, even when the extracts were diluted 100-fold to 1000-fold. The objective of these studies was to identify the immunosuppressive compounds found in cigarette smoke. Gas chromatography/mass spectroscopy and HPLC were used to identify and quantitate volatile compounds found in cigarette smoke extracts. Bioactivity was measured by viability and production of cytokine mRNA and protein levels in treated human lymphocytes. The vapor phase of the cigarette smoke extract inhibited cytokine production, indicating that the immunosuppressive compounds were volatile. Among the volatile compounds identified in cigarette smoke extracts, only the alpha,beta-unsaturated aldehydes, acrolein (inhibitory concentration of 50% [IC50] = 3 micromol/L) and crotonaldehyde (IC50 = 6 micromol/L), exhibited significant inhibition of cytokine production. Although the levels of aldehydes varied 10-fold between high-tar (Camel) and ultralow-tar (Carlton) extracts, even ultralow-tar cigarettes produced sufficient levels of acrolein (34 micromol/L) to suppress cytokine production by >95%. We determined that the cigarette smoke extract inhibited transcription of cytokine genes. The inhibitory effects of acrolein could be blocked with the thiol compound N-acetylcysteine. The vapor phase from cigarette smoke extracts potently suppresses cytokine production. The compound responsible for this inhibition appears to be acrolein.

  3. Palmitoylethanolamide Inhibits Glutamate Release in Rat Cerebrocortical Nerve Terminals

    Directory of Open Access Journals (Sweden)

    Tzu-Yu Lin

    2015-03-01

    Full Text Available The effect of palmitoylethanolamide (PEA, an endogenous fatty acid amide displaying neuroprotective actions, on glutamate release from rat cerebrocortical nerve terminals (synaptosomes was investigated. PEA inhibited the Ca2+-dependent release of glutamate, which was triggered by exposing synaptosomes to the potassium channel blocker 4-aminopyridine. This release inhibition was concentration dependent, associated with a reduction in cytosolic Ca2+ concentration, and not due to a change in synaptosomal membrane potential. The glutamate release-inhibiting effect of PEA was prevented by the Cav2.1 (P/Q-type channel blocker ω-agatoxin IVA or the protein kinase A inhibitor H89, not affected by the intracellular Ca2+ release inhibitors dantrolene and CGP37157, and partially antagonized by the cannabinoid CB1 receptor antagonist AM281. Based on these results, we suggest that PEA exerts its presynaptic inhibition, likely through a reduction in the Ca2+ influx mediated by Cav2.1 (P/Q-type channels, thereby inhibiting the release of glutamate from rat cortical nerve terminals. This release inhibition might be linked to the activation of presynaptic cannabinoid CB1 receptors and the suppression of the protein kinase A pathway.

  4. Response inhibition under alcohol: effects of cognitive and motivational conflict.

    Science.gov (United States)

    Fillmore, M T; Vogel-Sprott, M

    2000-03-01

    This experiment tested the effect of cognitive and motivational conflict on response inhibition under alcohol. Fifty-six male social drinkers were randomly assigned to one of eight groups (n = 8). Four pairs of groups received 0.62 g/kg of alcohol, or a placebo, and each pair performed a go/stop choice reaction time task under one of four conflict conditions. One condition (C) produced cognitive conflict by presenting "go" and "stop" signals in the task. Another condition (IR) added motivational conflict by administering an equal monetary reward for inhibiting responses to stop-signals, and for responding to go-signals. The remaining two conditions resolved the motivational conflict by administering the monetary reward only for inhibitions (I), or only for responses (R). Compared with placebo, alcohol reduced inhibitions (i.e., impaired inhibitory control) under cognitive conflict (C; p = .041) and under motivational conflict (IR; p = .012). No significant effect of alcohol on inhibitions was observed in conditions where conflict was resolved (i.e., I and R). The study shows that alcohol can reduce the ability to inhibit a response. However, impaired inhibitory control is not an inevitable outcome of the drug action, because it can be counteracted by the consequences of behavior in the situation.

  5. Inhibition of PTEN and activation of Akt by menadione.

    Science.gov (United States)

    Yoshikawa, Kyoko; Nigorikawa, Kiyomi; Tsukamoto, Mariko; Tamura, Namiko; Hazeki, Kaoru; Hazeki, Osamu

    2007-04-01

    Menadione (vitamin K(3)) has been shown to activate Erk in several cell lines. This effect has been shown to be due to the activation of EGF receptors (EGFR) as a result of inhibition of some protein tyrosine phosphatases. In the present study, we examined the effects of menadione on Akt in Chinese hamster ovary cells. The phosphorylation of Akt by menadione was not inhibited by AG1478, an inhibitor of EGFR. Menadione inhibited the lipid phosphatase activity of PTEN in a cell-free system. In an intact cell system, menadione inhibited the effect of transfected PTEN on Akt. Thus, one mechanism of its action was considered the accelerated activation of Akt through inhibition of PTEN. This was not the sole mechanism responsible for the EGFR-independent activation of Akt, because menadione attenuated the rate of Akt dephosphorylation even in PTEN-null PC3 cells. The decelerated inactivation of Akt, probably through inhibition of some tyrosine phosphatases, was considered another mechanism of its action.

  6. Lipid-Lowering Pharmaceutical Clofibrate Inhibits Human Sweet Taste

    Science.gov (United States)

    Kochem, Matthew

    2017-01-01

    T1R2-T1R3 is a heteromeric receptor that binds sugars, high potency sweeteners, and sweet taste blockers. In rodents, T1R2-T1R3 is largely responsible for transducing sweet taste perception. T1R2-T1R3 is also expressed in non-taste tissues, and a growing body of evidence suggests that it helps regulate glucose and lipid metabolism. It was previously shown that clofibric acid, a blood lipid-lowering drug, binds T1R2-T1R3 and inhibits its activity in vitro. The purpose of this study was to determine whether clofibric acid inhibits sweetness perception in humans and is, therefore, a T1R2-T1R3 antagonist in vivo. Fourteen participants rated the sweetness intensity of 4 sweeteners (sucrose, sucralose, Na cyclamate, acesulfame K) across a broad range of concentrations. Each sweetener was prepared in solution neat and in mixture with either clofibric acid or lactisole. Clofibric acid inhibited sweetness of every sweetener. Consistent with competitive binding, inhibition by clofibric acid was diminished with increasing sweetener concentration. This study provides in vivo evidence that the lipid-lowering drug clofibric acid inhibits sweetness perception and is, therefore, a T1R carbohydrate receptor inhibitor. Our results are consistent with previous in vitro findings. Given that T1R2-T1R3 may in part regulate glucose and lipid metabolism, future studies should investigate the metabolic effects of T1R inhibition. PMID:27742692

  7. Iron chelators ICL670 and 311 inhibit HIV-1 transcription

    International Nuclear Information System (INIS)

    Debebe, Zufan; Ammosova, Tatyana; Jerebtsova, Marina; Kurantsin-Mills, Joseph; Niu, Xiaomei; Charles, Sharroya; Richardson, Des R.; Ray, Patricio E.; Gordeuk, Victor R.; Nekhai, Sergei

    2007-01-01

    HIV-1 replication is induced by an excess of iron and iron chelation by desferrioxamine (DFO) inhibits viral replication by reducing proliferation of infected cells. Treatment of cells with DFO and 2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone (311) inhibit expression of proteins that regulate cell-cycle progression, including cycle-dependent kinase 2 (CDK2). Our recent studies showed that CDK2 participates in HIV-1 transcription and viral replication suggesting that inhibition of CDK2 by iron chelators might also affect HIV-1 transcription. Here we evaluated the effect of a clinically approved orally effective iron chelator, 4-[3,5-bis-(hydroxyphenyl)-1,2,4-triazol-1-yl]-benzoic acid (ICL670) and 311 on HIV-1 transcription. Both ICL670 and 311 inhibited Tat-induced HIV-1 transcription in CEM-T cells, 293T and HeLa cells. Neither ICL670 nor 311 induced cytotoxicity at concentrations that inhibited HIV-1 transcription. The chelators decreased cellular activity of CDK2 and reduced HIV-1 Tat phosphorylation by CDK2. Neither ICL670A or 311 decreased CDK9 protein level but significantly reduced association of CDK9 with cyclin T1 and reduced phosphorylation of Ser-2 residues of RNA polymerase II C-terminal domain. In conclusion, our findings add to the evidence that iron chelators can inhibit HIV-1 transcription by deregulating CDK2 and CDK9. Further consideration should be given to the development of iron chelators for future anti-retroviral therapeutics

  8. Inhibition of AMPK catabolic action by GSK3

    Science.gov (United States)

    Suzuki, Tsukasa; Bridges, Dave; Nakada, Daisuke; Skiniotis, Georgios; Morrison, Sean J.; Lin, Jiandie; Saltiel, Alan R.; Inoki, Ken

    2013-01-01

    SUMMARY AMP-activated protein kinase (AMPK) regulates cellular energy homeostasis by inhibiting anabolic and activating catabolic processes. While AMPK activation has been extensively studied, mechanisms that inhibit AMPK remain elusive. Here we report that glycogen synthase kinase 3 (GSK3) inhibits AMPK function. GSK3 forms a stable complex with AMPK through interactions with the AMPK β regulatory subunit and phosphorylates the AMPK α catalytic subunit. This phosphorylation enhances the accessibility of the activation loop of the α subunit to phosphatases, thereby inhibiting AMPK kinase activity. Surprisingly, PI3K-Akt signaling, which is a major anabolic signaling and normally inhibits GSK3 activity, promotes GSK3 phosphorylation and inhibition of AMPK, thus revealing how AMPK senses anabolic environments in addition to cellular energy levels. Consistently, disrupting GSK3 function within the AMPK complex sustains higher AMPK activity and cellular catabolic processes even under anabolic conditions, indicating that GSK3 acts as a critical sensor for anabolic signaling to regulate AMPK. PMID:23623684

  9. Gingival tissue-produced inhibition of platelet aggregation and the loss of inhibition in streptozotocin-induced diabetic rats

    Energy Technology Data Exchange (ETDEWEB)

    Kawamura, Keiichiroh; Tamai, Kazuharu; Shirakawa, Masaharu; Okamoto, Hiroshi; Dohi, Toshihiro; Tsujimoto, Akira

    1988-01-01

    Addition of medium incubated with normal rat gingival tissue to platelet-rich plasma inhibited ADP-induced platelet aggregation. The ability of rat gingiva to produce activity inhibiting platelet aggregation was enhanced by the addition of arachidonic acid. Diabetic rat gingiva failed to inhibit platelet aggregation but did produce the anti-platelet aggregating activity in the presence of arachidonic acid. Indomethacin blocked the production of anti-platelet aggregating activity. There was no difference in conversion of (1-/sup 14/C)arachidonic acid to prostaglandins by normal and diabetic rat gingiva. These results suggest that an arachidonic acid metabolite released from gingiva during incubation inhibits platelet aggregation, and the synthesis of the metabolite is impaired in diabetic rat gingiva. A decrease in availability of arachidonic acid may be a causal factor of the defect in diabetic rat gingiva.

  10. Gingival tissue-produced inhibition of platelet aggregation and the loss of inhibition in streptozotocin-induced diabetic rats

    International Nuclear Information System (INIS)

    Kawamura, Keiichiroh; Tamai, Kazuharu; Shirakawa, Masaharu; Okamoto, Hiroshi; Dohi, Toshihiro; Tsujimoto, Akira

    1988-01-01

    Addition of medium incubated with normal rat gingival tissue to platelet-rich plasma inhibited ADP-induced platelet aggregation. The ability of rat gingiva to produce activity inhibiting platelet aggregation was enhanced by the addition of arachidonic acid. Diabetic rat gingiva failed to inhibit platelet aggregation but did produce the anti-platelet aggregating activity in the presence of arachidonic acid. Indomethacin blocked the production of anti-platelet aggregating activity. There was no difference in conversion of [1- 14 C]arachidonic acid to prostaglandins by normal and diabetic rat gingiva. These results suggest that an arachidonic acid metabolite released from gingiva during incubation inhibits platelet aggregation, and the synthesis of the metabolite is impaired in diabetic rat gingiva. A decrease in availability of arachidonic acid may be a causal factor of the defect in diabetic rat gingiva. (author)

  11. Allosteric Inhibition of Factor XIIIa. Non-Saccharide Glycosaminoglycan Mimetics, but Not Glycosaminoglycans, Exhibit Promising Inhibition Profile.

    Directory of Open Access Journals (Sweden)

    Rami A Al-Horani

    Full Text Available Factor XIIIa (FXIIIa is a transglutaminase that catalyzes the last step in the coagulation process. Orthostery is the only approach that has been exploited to design FXIIIa inhibitors. Yet, allosteric inhibition of FXIIIa is a paradigm that may offer a key advantage of controlled inhibition over orthosteric inhibition. Such an approach is likely to lead to novel FXIIIa inhibitors that do not carry bleeding risks. We reasoned that targeting a collection of basic amino acid residues distant from FXIIIa's active site by using sulfated glycosaminoglycans (GAGs or non-saccharide GAG mimetics (NSGMs would lead to the discovery of the first allosteric FXIIIa inhibitors. We tested a library of 22 variably sulfated GAGs and NSGMs against human FXIIIa to discover promising hits. Interestingly, although some GAGs bound to FXIIIa better than NSGMs, no GAG displayed any inhibition. An undecasulfated quercetin analog was found to inhibit FXIIIa with reasonable potency (efficacy of 98%. Michaelis-Menten kinetic studies revealed an allosteric mechanism of inhibition. Fluorescence studies confirmed close correspondence between binding affinity and inhibition potency, as expected for an allosteric process. The inhibitor was reversible and at least 9-fold- and 26-fold selective over two GAG-binding proteins factor Xa (efficacy of 71% and thrombin, respectively, and at least 27-fold selective over a cysteine protease papain. The inhibitor also inhibited the FXIIIa-mediated polymerization of fibrin in vitro. Overall, our work presents the proof-of-principle that FXIIIa can be allosterically modulated by sulfated non-saccharide agents much smaller than GAGs, which should enable the design of selective and safe anticoagulants.

  12. A rhodanine derivative CCR-11 inhibits bacterial proliferation by inhibiting the assembly and GTPase activity of FtsZ.

    Science.gov (United States)

    Singh, Parminder; Jindal, Bhavya; Surolia, Avadhesha; Panda, Dulal

    2012-07-10

    A perturbation of FtsZ assembly dynamics has been shown to inhibit bacterial cytokinesis. In this study, the antibacterial activity of 151 rhodanine compounds was assayed using Bacillus subtilis cells. Of 151 compounds, eight strongly inhibited bacterial proliferation at 2 μM. Subsequently, we used the elongation of B. subtilis cells as a secondary screen to identify potential FtsZ-targeted antibacterial agents. We found that three compounds significantly increased bacterial cell length. One of the three compounds, namely, CCR-11 [(E)-2-thioxo-5-({[3-(trifluoromethyl)phenyl]furan-2-yl}methylene)thiazolidin-4-one], inhibited the assembly and GTPase activity of FtsZ in vitro. CCR-11 bound to FtsZ with a dissociation constant of 1.5 ± 0.3 μM. A docking analysis indicated that CCR-11 may bind to FtsZ in a cavity adjacent to the T7 loop and that short halogen-oxygen, H-bonding, and hydrophobic interactions might be important for the binding of CCR-11 with FtsZ. CCR-11 inhibited the proliferation of B. subtilis cells with a half-maximal inhibitory concentration (IC(50)) of 1.2 ± 0.2 μM and a minimal inhibitory concentration of 3 μM. It also potently inhibited proliferation of Mycobacterium smegmatis cells. Further, CCR-11 perturbed Z-ring formation in B. subtilis cells; however, it neither visibly affected nucleoid segregation nor altered the membrane integrity of the cells. CCR-11 inhibited HeLa cell proliferation with an IC(50) value of 18.1 ± 0.2 μM (∼15 × IC(50) of B. subtilis cell proliferation). The results suggested that CCR-11 inhibits bacterial cytokinesis by inhibiting FtsZ assembly, and it can be used as a lead molecule to develop FtsZ-targeted antibacterial agents.

  13. CORROSION INHIBITION OF ALUMINUM ALLOY 3SR IN HCl BY POLYVINYLPYRROLIDONE AND POLYACRYLAMIDE: EFFECT OF MOLECULAR STRUCTURE ON INHIBITION EFFICIENCY

    OpenAIRE

    S. A. UMOREN

    2009-01-01

    The inhibitive performance of two water soluble polymers–polyacrylamide (PA) and polyvinylpyrrolidone (PVP) on the corrosion behavior of aluminum alloy 3SR in HCl solution was investigated using weight loss, hydrogen evolution, and thermometric methods at 30–60°C. Results obtained indicate that both polymers inhibited acid-induced corrosion of aluminum at the temperatures studied. PVP was found to be a better corrosion inhibitor than PA. All measurements from the three techniques show that in...

  14. Method of inhibiting the onset of acute radiation syndrome and also inhibiting the onset of septicemia and a composition therefor

    Energy Technology Data Exchange (ETDEWEB)

    Ribi, E E

    1986-01-14

    A method is described for inhibiting the onset of acute radiation syndrome caused by the exposure of warm-blooded animals to a whole body dose of at least 100 rads of x-radiation. Also described is a method for inhibiting the onset of septicemia. The methods comprise administering to a warm-blooded animal an effective amount of a pharmaceutical preparation containing refined detoxified endotoxin in combination with a pharmaceutically acceptable carrier.

  15. Inhibition of carbachol-induced formation of inositolphosphates in isolated pancreatic islets

    DEFF Research Database (Denmark)

    Kardasz, A.M.J.; Capito, Kirsten; Hansen, Svend Erik

    1991-01-01

    Medicinsk biokemi, feed-back inhibition, phospholipase C, pancreatic islets, Calcium, proteinkinase C......Medicinsk biokemi, feed-back inhibition, phospholipase C, pancreatic islets, Calcium, proteinkinase C...

  16. Chlorpromazine inhibits tumour necrosis factor synthesis and cytotoxicity in vitro.

    Science.gov (United States)

    Zinetti, M; Galli, G; Demitri, M T; Fantuzzi, G; Minto, M; Ghezzi, P; Alzani, R; Cozzi, E; Fratelli, M

    1995-11-01

    Chlorpromazine (CPZ) has been previously shown to protect against endotoxin [lipopolysaccharide (LPS)] lethality and inhibit the release of tumour necrosis factor in vivo. We investigated at the cellular level whether this was due to direct inhibition of tumour necrosis factor-alpha (TNF-alpha) synthesis, using LPS-stimulated THP-1 human monocytic leukemia cells. We also studied the effect of CPZ on human TNF-alpha action by assessing TNF-alpha cytotoxicity on mouse fibrosarcoma L929 cells. CPZ (1-100 microM) inhibited TNF-alpha production in THP-1 cells in a dose dependent manner by a maximum of 80%. This effect was comparable to that of two well-known inhibitory drugs, dexamethasone and cyclicAMP. Inhibition was also evident at the mRNA level. On the other hand CPZ (10-25 microM) also inhibited TNF-alpha activity: in fact it reduced the cytotoxicity of TNF-alpha on L929 cells (EC50 was increased four times) and could provide protection even as a post-treatment. CPZ inhibited TNF-induced apoptosis in L929 cells, as detected by analysis of nuclear morphology. However, since we showed that apoptosis was very limited, and was not the main mode of cell death in our conditions, this could not explain the overall protection. Since CPZ did not interfere with either the oligomerization state of TNF-alpha or its receptor binding, our data suggest that it reduced cytotoxicity by inhibiting some steps in the TNF-alpha signalling pathways.

  17. High Concentrations of Tranexamic Acid Inhibit Ionotropic Glutamate Receptors.

    Science.gov (United States)

    Lecker, Irene; Wang, Dian-Shi; Kaneshwaran, Kirusanthy; Mazer, C David; Orser, Beverley A

    2017-07-01

    The antifibrinolytic drug tranexamic acid is structurally similar to the amino acid glycine and may cause seizures and myoclonus by acting as a competitive antagonist of glycine receptors. Glycine is an obligatory co-agonist of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors. Thus, it is plausible that tranexamic acid inhibits NMDA receptors by acting as a competitive antagonist at the glycine binding site. The aim of this study was to determine whether tranexamic acid inhibits NMDA receptors, as well as α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and kainate subtypes of ionotropic glutamate receptors. Tranexamic acid modulation of NMDA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, and kainate receptors was studied using whole cell voltage-clamp recordings of current from cultured mouse hippocampal neurons. Tranexamic acid rapidly and reversibly inhibited NMDA receptors (half maximal inhibitory concentration = 241 ± 45 mM, mean ± SD; 95% CI, 200 to 281; n = 5) and shifted the glycine concentration-response curve for NMDA-evoked current to the right. Tranexamic acid also inhibited α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (half maximal inhibitory concentration = 231 ± 91 mM; 95% CI, 148 to 314; n = 5 to 6) and kainate receptors (half maximal inhibitory concentration = 90 ± 24 mM; 95% CI, 68 to 112; n = 5). Tranexamic acid inhibits NMDA receptors likely by reducing the binding of the co-agonist glycine and also inhibits α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and kainate receptors. Receptor blockade occurs at high millimolar concentrations of tranexamic acid, similar to the concentrations that occur after topical application to peripheral tissues. Glutamate receptors in tissues including bone, heart, and nerves play various physiologic roles, and tranexamic acid inhibition of these receptors may contribute to adverse drug effects.

  18. Digestion products of the PH20 hyaluronidase inhibit remyelination.

    Science.gov (United States)

    Preston, Marnie; Gong, Xi; Su, Weiping; Matsumoto, Steven G; Banine, Fatima; Winkler, Clayton; Foster, Scott; Xing, Rubing; Struve, Jaime; Dean, Justin; Baggenstoss, Bruce; Weigel, Paul H; Montine, Thomas J; Back, Stephen A; Sherman, Larry S

    2013-02-01

    Oligodendrocyte progenitor cells (OPCs) recruited to demyelinating lesions often fail to mature into oligodendrocytes (OLs) that remyelinate spared axons. The glycosaminoglycan hyaluronan (HA) accumulates in demyelinating lesions and has been implicated in the failure of OPC maturation and remyelination. We tested the hypothesis that OPCs in demyelinating lesions express a specific hyaluronidase, and that digestion products of this enzyme inhibit OPC maturation. Mouse OPCs grown in vitro were analyzed for hyaluronidase expression and activity. Gain of function studies were used to define the hyaluronidases that blocked OPC maturation. Mouse and human demyelinating lesions were assessed for hyaluronidase expression. Digestion products from different hyaluronidases and a hyaluronidase inhibitor were tested for their effects on OPC maturation and functional remyelination in vivo. OPCs demonstrated hyaluronidase activity in vitro and expressed multiple hyaluronidases, including HYAL1, HYAL2, and PH20. HA digestion by PH20 but not other hyaluronidases inhibited OPC maturation into OLs. In contrast, inhibiting HA synthesis did not influence OPC maturation. PH20 expression was elevated in OPCs and reactive astrocytes in both rodent and human demyelinating lesions. HA digestion products generated by the PH20 hyaluronidase but not another hyaluronidase inhibited remyelination following lysolecithin-induced demyelination. Inhibition of hyaluronidase activity lead to increased OPC maturation and promoted increased conduction velocities through lesions. We determined that PH20 is elevated in demyelinating lesions and that increased PH20 expression is sufficient to inhibit OPC maturation and remyelination. Pharmacological inhibition of PH20 may therefore be an effective way to promote remyelination in multiple sclerosis and related conditions. Copyright © 2012 American Neurological Association.

  19. Mechanisms of caffeine-induced inhibition of UVB carcinogenesis

    Directory of Open Access Journals (Sweden)

    Allan H Conney

    2013-06-01

    Full Text Available Sunlight-induced nonmelanoma skin cancer is the most prevalent cancer in the United States with more than 2 million cases per year. Several studies have shown an inhibitory effect of caffeine administration on UVB-induced skin cancer in mice, and these studies are paralleled by epidemiology studies that indicate an inhibitory effect of coffee drinking on nonmelanoma skin cancer in humans. Strikingly, decaffeinated coffee consumption had no such inhibitory effect.Mechanism studies indicate that caffeine has a sunscreen effect that inhibits UVB-induced formation of thymine dimers and sunburn lesions in the epidermis of mice. In addition, caffeine administration has a biological effect that enhances UVB-induced apoptosis thereby enhancing the elimination of damaged precancerous cells, and caffeine administration also enhances apoptosis in tumors. Caffeine administration enhances UVB-induced apoptosis by p53-dependent and p53-independent mechanisms. Exploration of the p53-independent effect indicated that caffeine administration enhanced UVB-induced apoptosis by inhibiting the UVB-induced increase in ATR-mediated formation of phospho-Chk1 (Ser345 and abolishing the UVB-induced decrease in cyclin B1 which resulted in caffeine-induced premature and lethal mitosis in mouse skin. In studies with cultured primary human keratinocytes, inhibition of ATR with siRNA against ATR inhibited Chk1 phosphorylation and enhanced UVB-induced apoptosis. Transgenic mice with decreased epidermal ATR function that were irradiated chronically with UVB had 69% fewer tumors at the end of the study compared with irradiated littermate controls with normal ATR function. These results, which indicate that genetic inhibition of ATR (like pharmacologic inhibition of ATR via caffeine inhibits UVB-induced carcinogenesis and supports the concept that ATR-mediated phosphorylation of Chk1 is an important target for caffeine’s inhibitory effect on UVB-induced carcinogenesis.

  20. Metformin and Its Sulfenamide Prodrugs Inhibit Human Cholinesterase Activity

    Directory of Open Access Journals (Sweden)

    Magdalena Markowicz-Piasecka

    2017-01-01

    Full Text Available The results of epidemiological and pathophysiological studies suggest that type 2 diabetes mellitus (T2DM may predispose to Alzheimer’s disease (AD. The two conditions present similar glucose levels, insulin resistance, and biochemical etiologies such as inflammation and oxidative stress. The diabetic state also contributes to increased acetylcholinesterase (AChE activity, which is one of the factors leading to neurodegeneration in AD. The aim of this study was to assess in vitro the effects of metformin, phenformin, and metformin sulfenamide prodrugs on the activity of human AChE and butyrylcholinesterase (BuChE and establish the type of inhibition. Metformin inhibited 50% of the AChE activity at micromolar concentrations (2.35 μmol/mL, mixed type of inhibition and seemed to be selective towards AChE since it presented low anti-BuChE activity. The tested metformin prodrugs inhibited cholinesterases (ChE at nanomolar range and thus were more active than metformin or phenformin. The cyclohexyl sulfenamide prodrug demonstrated the highest activity towards both AChE (IC50 = 890 nmol/mL, noncompetitive inhibition and BuChE (IC50 = 28 nmol/mL, mixed type inhibition, while the octyl sulfenamide prodrug did not present anti-AChE activity, but exhibited mixed inhibition towards BuChE (IC50 = 184 nmol/mL. Therefore, these two bulkier prodrugs were concluded to be the most selective compounds for BuChE over AChE. In conclusion, it was demonstrated that biguanides present a novel class of inhibitors for AChE and BuChE and encourages further studies of these compounds for developing both selective and nonselective inhibitors of ChEs in the future.