scholarly journals GATA4 Is a Critical Regulator of Gonadectomy-Induced Adrenocortical Tumorigenesis in Mice

Endocrinology ◽  
2012 ◽  
Vol 153 (6) ◽  
pp. 2599-2611 ◽  
Author(s):  
Justyna Krachulec ◽  
Melanie Vetter ◽  
Anja Schrade ◽  
Ann-Kathrin Löbs ◽  
Malgorzata Bielinska ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Adrenal Glands ◽  
Inbred Mouse ◽  
Mouse Strains ◽  
Dependent Manner ◽  
Loss Of Function ◽  
Estrogen Production ◽  
Steroidogenic Cell ◽  
Steroidogenic Cells ◽  
Dose Dependent

In response to gonadectomy certain inbred mouse strains develop sex steroidogenic adrenocortical neoplasms. One of the hallmarks of neoplastic transformation is expression of GATA4, a transcription factor normally present in gonadal but not adrenal steroidogenic cells of the adult mouse. To show that GATA4 directly modulates adrenocortical tumorigenesis and is not merely a marker of gonadal-like differentiation in the neoplasms, we studied mice with germline or conditional loss-of-function mutations in the Gata4 gene. Germline Gata4 haploinsufficiency was associated with attenuated tumor growth and reduced expression of sex steroidogenic genes in the adrenal glands of ovariectomized B6D2F1 and B6AF1 mice. At 12 months after ovariectomy, wild-type B6D2F1 mice had biochemical and histological evidence of adrenocortical estrogen production, whereas Gata4+/− B6D2F1 mice did not. Germline Gata4 haploinsufficiency exacerbated the secondary phenotype of postovariectomy obesity in B6D2F1 mice, presumably by limiting ectopic estrogen production in the adrenal glands. Amhr2-cre-mediated deletion of floxed Gata4 (Gata4F) in nascent adrenocortical neoplasms of ovariectomized B6.129 mice reduced tumor growth and the expression of gonadal-like markers in a Gata4F dose-dependent manner. We conclude that GATA4 is a key modifier of gonadectomy-induced adrenocortical neoplasia, postovariectomy obesity, and sex steroidogenic cell differentiation.

A Cuticle Collagen Encoded by the lon-3 Gene May Be a Target of TGF-β Signaling in Determining Caenorhabditis elegans Body Shape

Genetics ◽  
2002 ◽  
Vol 162 (4) ◽  
pp. 1631-1639
Author(s):  
Yo Suzuki ◽  
Gail A Morris ◽  
Min Han ◽  
William B Wood
Keyword(s):  
Caenorhabditis Elegans ◽  
Body Shape ◽  
Small Body ◽  
Dependent Manner ◽  
Loss Of Function ◽  
Cellular Mechanisms ◽  
C Elegans ◽  
Gene Expression Analyses ◽  
Dose Dependent

Abstract The signaling pathway initiated by the TGF-β family member DBL-1 in Caenorhabditis elegans controls body shape in a dose-dependent manner. Loss-of-function (lf) mutations in the dbl-1 gene cause a short, small body (Sma phenotype), whereas overexpression of dbl-1 causes a long body (Lon phenotype). To understand the cellular mechanisms underlying these phenotypes, we have isolated suppressors of the Sma phenotype resulting from a dbl-1(lf) mutation. Two of these suppressors are mutations in the lon-3 gene, of which four additional alleles are known. We show that lon-3 encodes a collagen that is a component of the C. elegans cuticle. Genetic and reporter-gene expression analyses suggest that lon-3 is involved in determination of body shape and is post-transcriptionally regulated by the dbl-1 pathway. These results support the possibility that TGF-β signaling controls C. elegans body shape by regulating cuticle composition.

scholarly journals N-Acetyl Cysteine Overdose Inducing Hepatic Steatosis and Systemic Inflammation in Both Propacetamol-Induced Hepatotoxic and Normal Mice

Antioxidants ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 442
Author(s):  
Gunn-Guang Liou ◽  
Cheng-Chi Hsieh ◽  
Yi-Ju Lee ◽  
Pin-Hung Li ◽  
Ming-Shiun Tsai ◽  
...  
Keyword(s):  
Inbred Mouse ◽  
Serum Triglyceride ◽  
Mouse Strains ◽  
High Dose ◽  
Therapeutic Effects ◽  
Protein Nitration ◽  
Cholesterol Levels ◽  
Antioxidative Enzyme Activities ◽  
Acetyl Cysteine ◽  
Dose Dependent

Acetaminophen (APAP) overdose induces acute liver damage and even death. The standard therapeutic dose of N-acetyl cysteine (NAC) cannot be applied to every patient, especially those with high-dose APAP poisoning. There is insufficient evidence to prove that increasing NAC dose can treat patients who failed in standard treatment. This study explores the toxicity of NAC overdose in both APAP poisoning and normal mice. Two inbred mouse strains with different sensitivities to propacetamol-induced hepatotoxicity (PIH) were treated with different NAC doses. NAC therapy decreased PIH by reducing lipid oxidation, protein nitration and inflammation, and increasing glutathione (GSH) levels and antioxidative enzyme activities. However, the therapeutic effects of NAC on PIH were dose-dependent from 125 (N125) to 275 mg/kg (N275). Elevated doses of NAC (400 and 800 mg/kg, N400 and N800) caused additional deaths in both propacetamol-treated and normal mice. N800 treatments significantly decreased hepatic GSH levels and induced inflammatory cytokines and hepatic microvesicular steatosis in both propacetamol-treated and normal mice. Furthermore, both N275 and N400 treatments decreased serum triglyceride (TG) and induced hepatic TG, whereas N800 treatment significantly increased interleukin-6, hepatic TG, and total cholesterol levels. In conclusion, NAC overdose induces hepatic and systemic inflammations and interferes with fatty acid metabolism.

scholarly journals Identification of Wild-Derived Inbred Mouse Strains Highly Susceptible to Monkeypox Virus Infection for Use as Small Animal Models

2010 ◽  
Vol 84 (16) ◽  
pp. 8172-8180 ◽  
Author(s):  
Jeffrey L. Americo ◽  
Bernard Moss ◽  
Patricia L. Earl
Keyword(s):  
Animal Models ◽  
B Lymphocyte ◽  
Inbred Mouse ◽  
Lethal Dose ◽  
Small Animal ◽  
Congo Basin ◽  
Mouse Strains ◽  
Dependent Manner ◽  
Inbred Mouse Strains ◽  
Monkeypox Virus

ABSTRACT Infection with monkeypox virus (MPXV) causes disease manifestations in humans that are similar, although usually less severe, than those of smallpox. Since routine vaccination for smallpox ceased more than 30 years ago, there is concern that MPXV could be used for bioterrorism. Thus, there is a need to develop animal models to study MPXV infection. Accordingly, we screened 38 inbred mouse strains for susceptibility to MPXV. Three highly susceptible wild-derived inbred strains were identified, of which CAST/EiJ was further developed as a model. Using an intranasal route of infection with an isolate of the Congo Basin clade of MPXV, CAST/EiJ mice exhibited weight loss, morbidity, and death in a dose-dependent manner with a calculated 50% lethal dose (LD50) of 680 PFU, whereas there were no deaths of BALB/c mice at a 10,000-fold higher dose. CAST/EiJ mice exhibited greater MPXV sensitivity when infected via the intraperitoneal route, with an LD50 of 14 PFU. Both routes resulted in MPXV replication in the lung, spleen, and liver. Intranasal infection with an isolate of the less-pathogenic West African clade yielded an LD50 of 7,600 PFU. The immune competence of CAST/EiJ mice was established by immunization with vaccinia virus, which induced antigen-specific T- and B-lymphocyte responses and fully protected mice from lethal doses of MPXV. The new mouse model has the following advantages for studying pathogenesis of MPXV, as well as for evaluation of potential vaccines and therapeutics: relative sensitivity to MPXV through multiple routes, genetic homogeneity, available immunological reagents, and commercial production.

scholarly journals PK11195 Effect on Steroidogenesis Is Not Mediated Through the Translocator Protein (TSPO)

Endocrinology ◽  
2015 ◽  
Vol 156 (3) ◽  
pp. 1033-1039 ◽  
Author(s):  
Lan N. Tu ◽  
Amy H. Zhao ◽  
Douglas M. Stocco ◽  
Vimal Selvaraj
Keyword(s):  
Translocator Protein ◽  
Mitochondrial Outer Membrane ◽  
Dependent Manner ◽  
Tumor Cell Lines ◽  
Dibutyryl Camp ◽  
Progesterone Production ◽  
Similar Dose ◽  
Leydig Tumor Cells ◽  
Steroidogenic Cells ◽  
Dose Dependent

Abstract Translocator protein (TSPO) is a mitochondrial outer membrane protein of unknown function with high physiological expression in steroidogenic cells. Using TSPO gene–deleted mice, we recently demonstrated that TSPO function is not essential for steroidogenesis. The first link between TSPO and steroidogenesis was established in studies showing modest increases in progesterone production by adrenocortical and Leydig tumor cell lines after treatment with PK11195. To reconcile discrepancies between physiological and pharmacological interpretations of TSPO function, we generated TSPO-knockout MA-10 mouse Leydig tumor cells (MA-10:TspoΔ/Δ) and examined their steroidogenic potential after exposure to either dibutyryl-cAMP or PK11195. Progesterone production in MA-10:TspoΔ/Δ after dibutyryl-cAMP was not different from control MA-10:Tspo+/+ cells, confirming that TSPO function is not essential for steroidogenesis. Interestingly, when treated with increasing concentrations of PK11195, both control MA-10:Tspo+/+ cells and MA-10:TspoΔ/Δ cells responded in a similar dose-dependent manner showing increases in progesterone production. These results show that the pharmacological effect of PK11195 on steroidogenesis is not mediated through TSPO.

scholarly journals Dysregulated Inflammatory Response to Candida albicans in a C5-Deficient Mouse Strain

2004 ◽  
Vol 72 (10) ◽  
pp. 5868-5876 ◽  
Author(s):  
Alaka Mullick ◽  
Miria Elias ◽  
Serge Picard ◽  
Lucie Bourget ◽  
Orce Jovcevski ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Inflammatory Response ◽  
Mouse Strain ◽  
Host Response ◽  
Inbred Mouse ◽  
Differential Susceptibility ◽  
Mouse Strains ◽  
Causative Role ◽  
Loss Of Function ◽  
Necrosis Factor Alpha

ABSTRACT Experimental infection of inbred mouse strains with Candida albicans provides a good model system to identify host genetic determinants that regulate onset of, response to, and ultimate outcome of disseminated candidiasis. The A/J mouse strain is exquisitely sensitive to infection with C. albicans, while the C57BL/6J strain is relatively resistant, as measured by survival following intravenous injection of Candida blastospores. This differential susceptibility is caused by an A/J-specific loss-of-function mutation in the C5 component of the complement pathway. C5 plays several critical roles in host response to infection, including target lysis and phagocyte recruitment. Therefore, to determine which of its functions were required for host resistance to candidiasis, a detailed comparative analysis of pathophysiology and host response to acute C. albicans infection was conducted in A/J and C57BL/6J mice. C5-sufficient C57BL/6J mice were found to succumb late in infection due to severe kidney pathology, typified by fungal replication and robust neutrophil-based inflammatory response associated with extensive tissue damage. In contrast, A/J mice were moribund within 24 h postinfection but displayed little if any kidney damage despite an inability to mobilize granulocytes and a high fungal load in the kidney. Rather, C5 deficiency in A/J mice was associated with higher levels of circulating cytokines tumor necrosis factor alpha, interleukin-6, monocyte chemotactic protein 1 (MCP-1), MCP-5, and eotaxin in response to C. albicans. Transfer of the C5-defective allele from A/J onto a C57BL/6J genetic background in recombinant congenic strain BcA17 recapitulated the phenotypic aspects of the susceptibility of A/J mice to C. albicans, confirming the causative role of C5 deficiency in the dysregulated cytokine response.

GFI1 Is a Tumor Suppressor in Myeloid Progenitors

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2942-2942
Author(s):  
Aditya Chaubey ◽  
Shane Hormon ◽  
Chinavenmeni S. Velu ◽  
Tristan Bourdeau ◽  
Jinfang Zhu ◽  
...  
Keyword(s):  
Dna Sequences ◽  
Myeloid Leukemia ◽  
Dependent Manner ◽  
Loss Of Function ◽  
Increased Risk ◽  
Myeloid Leukemias ◽  
Dose Dependent ◽  
Anterior Posterior

Abstract In severe congenital neutropenia (SCN) patients and mice with Growth factor independent-1 (Gfi1) loss of function, arrested progenitors are suspended in a hyperproliferative state while terminal granulpoiesis is blocked. SCN patients are at increased risk for the development of acute myeloid leukemia. We demonstrate that Gfi1 directly targets HoxA9, Pbx1 and Meis1 during normal myelopoiesis. Gfi1−/− progenitors exhibit elevated levels of HoxA9, Pbx1 and Meis1, exaggerated HoxA9-Pbx1-Meis1 activity, and increased persistence in vivo and in vitro. Limiting HoxA9 alleles corrects, in a dose dependent manner, in vivo and in vitro phenotypes observed with loss of Gfi1. Moreover, in a manner conserved in Drosophila anterior/posterior patterning, we demonstrate that these factors can compete for occupancy of DNA sequences encoding composite Gfi1-HoxA9-Pbx1-Meis1 binding sites. Finally, the expression of Gfi1 and HoxA9 are inverse and stratify human myeloid leukemias, suggesting a role for HoxA9- Gfi1 antagonism in human AML. In agreement with this, a myeloproliferative disorder progresses into a rapid, lethal and transplantable myeloid leukemia in a Gfi1−/− setting. We conclude that the lifespan and oncogenic transformation of hematopoietic progenitor cells is regulated through a conserved competition between Gfi1 and HoxA9-Pbx1-Meis1.

EVIDENCE FOR THE SECRETION OF INHIBIN-LIKE IMMUNOREACTIVITY FROM CULTURED HUMAN ADRENAL CELLS

1991 ◽  
Vol 128 (3) ◽  
pp. R13-R16 ◽  
Author(s):  
M. Haji ◽  
Y. Nishi ◽  
S. Tanaka ◽  
M. Ohashi ◽  
K. Sekiya ◽  
...  
Keyword(s):  
Adrenal Gland ◽  
Adrenal Glands ◽  
Displacement Curve ◽  
Dependent Manner ◽  
Adrenal Cells ◽  
Gland Extract ◽  
Wet Weight ◽  
Dose Dependent

ABSTRACT We have studied the production and release of inhibin-like immunoreactivity in the human adrenal gland. Extract of human adrenal glands showed a displacement curve paralled with the inhibin standard. Inhibin-like immunoreactivity contents in the adrenal gland was 1893±474 (mean±S.D.) IU/g wet weight tissue. ACTH stimulated the secretion of inhibin-like immunoreactivity as well as cortisol and aldosterone in a dose-dependent manner in the cultured adrenal cells. These results indicate that the human adrenal gland produces and secretes inhibin-like peptide in response to ACTH.

scholarly journals Effects of Enoxaparin Emulsion on Dimethylbenzanthracene-induced Breast Cancer in Female Rats

2018 ◽  
Vol 5 (4) ◽  
pp. 23
Author(s):  
Bolandpayeh M ◽  
Hassanpour-Ezzati M ◽  
Mousavi Z
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Tumor Volume ◽  
Positive Control ◽  
Female Rats ◽  
Positive Control Group ◽  
Control Group ◽  
Dependent Manner ◽  
Angiogenic Proteins ◽  
Dose Dependent

Introduction: Enoxaparin is an anticoagulant medication. Anticoagulation inhibits tumor cell-mediated release of angiogenic proteins and diminishes angiogenic response. Angiogenesis is an important event in various cancers such as breast cancer. Angiogenesis provide oxygen and nutrients to tumor cells and causes tumor progression. The aim of the present study was to evaluate the anti-angiogenesis effect of an enoxaparin cream on breast cancer induced by dimethylbenzanthracene in rats. Methods: In this experimental in vivo study, 50 Wistar female rats were divided into negative control (vehicle), positive control (cream base), and 3 groups with enoxaparin treatment (40, 60, and 80 mg/ml). After one month of treatment along with breast cancer induction by dimethylbenzanthracene, breast tissue samples were isolated and stained with hematoxylin-eosin, and tumor growth suppression rate was calculated. Tumor size (length and width) was measured using a clipper, and the tumor volume was calculated using the following formula: V = (L × W × W)/2, where V is tumor volume, W is tumor width, L is tumor length. The data were analyzed using one-way ANOVA and Tukey’s post hoc test. Results: Tumor suppression was significantly increased in enoxaparin treatment groups compared to the positive control group (40 mg/ml of enoxaparin treated versus positive control group; P = 0.017, 60 mg/ml of enoxaparin treated versus positive control; P = 0.015, 40 mg/ml of enoxaparin treated versus positive control; P = 0.009, 60 mg/ml of enoxaparin treated versus 40 mg/ml of enoxaparin treated; P = 0.019, and 80 mg/ml of enoxaparin treated versus 40 mg/ml of enoxaparin treated; P = 0.011 in a dose-dependent manner. Conclusion: Enoxaparin inhibits breast cancer in a dose-dependent manner. The application of enoxaparin cream in patients with breast cancer may considerably reduce tumor growth. 

scholarly journals EPH/EPHRIN SIGNALING CONTROLS PROGENITOR IDENTITIES IN THE VENTRAL SPINAL CORD

2016 ◽  
Author(s):  
Julien Laussu ◽  
Christophe Audouard ◽  
Anthony Kischel ◽  
Poincyane Assis-Nascimento ◽  
Nathalie Escalas ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Sonic Hedgehog ◽  
Cell Communication ◽  
Dependent Manner ◽  
Eph Receptors ◽  
Loss Of Function ◽  
Summary Statement ◽  
Dose Dependent ◽  
Ventral Spinal Cord

SUMMARY STATEMENTThis article by Laussu et al. describes a role for Eph:ephrin signaling in controlling the identity of neural progenitors in the ventral spinal cord.Early specification of progenitors of the ventral spinal cord involves the morphogen Sonic Hedgehog which induces distinct progenitor identities in a dose-dependent manner. Following these initial patterning events, progenitor identities have to be maintained in order to generate appropriate numbers of progeny. Here we provide evidence that communication via Eph:ephrin signaling is required to maintain progenitor identities in the ventral spinal cord. We show that ephrinB2 and ephrinB3 are expressed in restricted progenitor domains in the ventral spinal cord while several Eph receptors are more broadly expressed. Further, we provide evidence that expression of Efnb3 and EphA4 is controlled by Shh. Genetic loss-of-function analyses indicate that expression of ephrinB2 and ephrinB3 is required to control progenitor identities and in vitro experiments reveal that activation of Eph forward signaling in spinal progenitors up-regulates the expression of the identity transcription factor Nkx2.2. Altogether our results indicate that cell-to-cell communication is necessary to control progenitor identity in the ventral spinal cord.

scholarly journals The induction of guerin's carcinoma cytochrome P450 hydroxylase activity by retinoids

2012 ◽  
Vol 58 (5) ◽  
pp. 539-548
Author(s):  
I.A. Shmarakov ◽  
N.V. Katan
Keyword(s):  
Cytochrome P450 ◽  
Vitamin A ◽  
Tumor Growth ◽  
The Body ◽  
Dependent Manner ◽  
Liposomal Form ◽  
Cytochrome P450 Hydroxylase ◽  
All Trans Retinoic Acid ◽  
Guerin’S Carcinoma ◽  
Dose Dependent

The interconnection of tumor growth process and the provision of the body with vitamin A was studied. The replenishment of vitamin A stores of vitamin-deficient tumor bearing animals modulated Guerin's carcinoma growth rate in a dose dependent manner (r=0,83). The morphological parameters of tumor growth at different provision with vitamin A positively correlated with hydroxylase (r=0,81) and demethylase (r=0,49) activities of the Guerin's carcinoma cytochrome P450 system. The induction of hydroxylase and demethylase activities of cytochrome P450 in Guerin's carcinoma microsomal fraction, observed either under conditions of overdose supplementation, or selective liposomal form of all-trans-retinoic acid, suggests the stimulatory effect of retinoids on tumor growth.

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