scholarly journals TSPO mutations in rats and a human polymorphism impair the rate of steroid synthesis

2017 ◽  
Vol 474 (23) ◽  
pp. 3985-3999 ◽  
Author(s):  
David R. Owen ◽  
Jinjiang Fan ◽  
Enrico Campioli ◽  
Sathvika Venugopal ◽  
Andrew Midzak ◽  
...  
Keyword(s):  
Translocator Protein ◽  
Rat Tissues ◽  
Steroid Synthesis ◽  
Rate Limiting Step ◽  
Steroid Dependent ◽  
Proliferation And Apoptosis ◽  
Numerous Cell ◽  
Human Polymorphism ◽  
Hormone Biosynthesis ◽  
Rate Limiting

The 18 kDa translocator protein (TSPO) is a ubiquitous conserved outer mitochondrial membrane protein implicated in numerous cell and tissue functions, including steroid hormone biosynthesis, respiration, cell proliferation, and apoptosis. TSPO binds with high affinity to cholesterol and numerous compounds, is expressed at high levels in steroid-synthesizing tissues, and mediates cholesterol import into mitochondria, which is the rate-limiting step in steroid formation. In humans, the rs6971 polymorphism on the TSPO gene leads to an amino acid substitution in the fifth transmembrane loop of the protein, which is where the cholesterol-binding domain of TSPO is located, and this polymorphism has been associated with anxiety-related disorders. However, recent knockout mouse models have provided inconsistent conclusions of whether TSPO is directly involved in steroid synthesis. In this report, we show that TSPO deletion mutations in rat and its corresponding rs6971 polymorphism in humans alter adrenocorticotropic hormone-induced plasma corticosteroid concentrations. Rat tissues examined show increased cholesteryl ester accumulation, and neurosteroid formation was undetectable in homozygous rats. These results also support a role for TSPO ligands in diseases with steroid-dependent stress and anxiety elements.

scholarly journals The Role of Cyclooxygenase-2 in Cell Proliferation and Cell Death in Human Malignancies

2010 ◽  
Vol 2010 ◽  
pp. 1-21 ◽  
Author(s):  
Cyril Sobolewski ◽  
Claudia Cerella ◽  
Mario Dicato ◽  
Lina Ghibelli ◽  
Marc Diederich
Keyword(s):  
Cell Proliferation ◽  
Rate Limiting Step ◽  
Proliferation And Apoptosis ◽  
Cox 2 ◽  
Prostate Cancers ◽  
Cox 2 Inhibitors ◽  
Rate Limiting ◽  
Brain And Spinal Cord ◽  
Cox 1

It is well admitted that the link between chronic inflammation and cancer involves cytokines and mediators of inflammatory pathways, which act during the different steps of tumorigenesis. The cyclooxygenases (COXs) are a family of enzymes, which catalyze the rate-limiting step of prostaglandin biosynthesis. This family contains three members: ubiquitously expressed COX-1, which is involved in homeostasis; the inducible COX-2 isoform, which is upregulated during both inflammation and cancer; and COX-3, expressed in brain and spinal cord, whose functions remain to be elucidated. COX-2 was described to modulate cell proliferation and apoptosis mainly in solid tumors, that is, colorectal, breast, and prostate cancers, and, more recently, in hematological malignancies. These findings prompt us to analyze here the effects of a combination of COX-2 inhibitors together with different clinically used therapeutic strategies in order to further improve the efficiency of future anticancer treatments. COX-2 modulation is a promising field investigated by many research groups.

scholarly journals Translocator protein and steroidogenesis

2018 ◽  
Vol 475 (5) ◽  
pp. 901-904 ◽  
Author(s):  
Barbara Costa ◽  
Eleonora Da Pozzo ◽  
Claudia Martini
Keyword(s):  
Genetic Manipulation ◽  
Translocator Protein ◽  
Accurate Information ◽  
Hormonal Stimulation ◽  
Steroid Synthesis ◽  
Genetic Manipulations ◽  
Biochemical Journal ◽  
Human Polymorphism

Two interesting papers by Barren et al. and Owen et al. have been very recently published in Biochemical Journal, reporting the role of translocator protein (TSPO) in steroidogenesis. The involvement of TSPO in the steroid biosynthesis has been suggested by 30 years of researches, using biochemical, pharmacological and genetic experimental approaches. In the last 3 years, however, the TSPO involvement in steroidogenesis has been intensively and profoundly discussed. Using in vivo genetic manipulations aimed at deleting TSPO, some researchers have excluded its role in steroid production. Other research groups, using similar genetic manipulation techniques, have presented different results, corroborating the role of TSPO in steroidogenesis, in particular, when hormonal stimulation occurs. In this scenario, the publications by Barron et al. about ‘Steroidogenic abnormalities in translocator protein knockout mice and significance in the aging male’ and by Owen et al. about ‘TSPO mutations in rats and a human polymorphism impair the rate of steroid synthesis’ are part of this debate and provide further and more accurate information supporting the importance of TSPO as a steroidogenesis regulator.

Steroidogenic abnormalities in translocator protein knockout mice and significance in the aging male

2018 ◽  
Vol 475 (1) ◽  
pp. 75-85 ◽  
Author(s):  
Anna M. Barron ◽  
Bin Ji ◽  
Seiji Kito ◽  
Tetsuya Suhara ◽  
Makoto Higuchi
Keyword(s):  
Young Male ◽  
Translocator Protein ◽  
Compensatory Mechanisms ◽  
Hormone Synthesis ◽  
Rate Limiting Step ◽  
Limiting Step ◽  
Adrenal Steroidogenesis ◽  
Age Dependent ◽  
Mitochondrial Cholesterol ◽  
Rate Limiting

The translocator protein (TSPO) has been proposed to act as a key component in a complex important for mitochondrial cholesterol importation, which is the rate-limiting step in steroid hormone synthesis. However, TSPO function in steroidogenesis has recently been challenged by the development of TSPO knockout (TSPO-KO) mice, as they exhibit normal baseline gonadal testosterone and adrenal corticosteroid production. Here, we demonstrate that despite normal androgen levels in young male TSPO-KO mice, TSPO deficiency alters steroidogenic flux and results in reduced total steroidogenic output. Specific reductions in the levels of progesterone and corticosterone as well as age-dependent androgen deficiency were observed in both young and aged male TSPO-KO mice. Collectively, these findings indicate that while TSPO is not critical for achieving baseline testicular and adrenal steroidogenesis, either indirect effects of TSPO on steroidogenic processes, or compensatory mechanisms and functional redundancy, lead to subtle steroidogenic abnormalities which become exacerbated with aging.

Ornithine Decarboxylase Activity in Cultured Endothelial Cells Stimulated by Serum, Thrombin and Serotonin

1978 ◽  
Vol 39 (02) ◽  
pp. 496-503 ◽  
Author(s):  
P A D’Amore ◽  
H B Hechtman ◽  
D Shepro
Keyword(s):  
Endothelial Cells ◽  
Ornithine Decarboxylase ◽  
Decarboxylase Activity ◽  
Aortic Endothelial Cells ◽  
Ornithine Decarboxylase Activity ◽  
Rate Limiting Step ◽  
Bovine Aortic Endothelial Cells ◽  
Limiting Step ◽  
Rate Limiting ◽  
Serum Serotonin

SummaryOrnithine decarboxylase (ODC) activity, the rate-limiting step in the synthesis of polyamines, can be demonstrated in cultured, bovine, aortic endothelial cells (EC). Serum, serotonin and thrombin produce a rise in ODC activity. The serotonin-induced ODC activity is significantly blocked by imipramine (10-5 M) or Lilly 11 0140 (10-6M). Preincubation of EC with these blockers together almost completely depresses the 5-HT-stimulated ODC activity. These observations suggest a manner by which platelets may maintain EC structural and metabolic soundness.

Dynamics of hepatic and peripheral insulin effects suggest common rate-limiting step in vivo

Diabetes ◽  
1993 ◽  
Vol 42 (2) ◽  
pp. 296-306 ◽  
Author(s):  
D. C. Bradley ◽  
R. A. Poulin ◽  
R. N. Bergman
Keyword(s):  
Rate Limiting Step ◽  
Limiting Step ◽  
Rate Limiting

Cobalt/Lewis Acid Catalysis for Hydrocarbofunctionalization of Alkynes via Cooperative C–H Activation

2020 ◽  
Author(s):  
Chang-Sheng Wang ◽  
Sabrina Monaco ◽  
Anh Ngoc Thai ◽  
Md. Shafiqur Rahman ◽  
Chen Wang ◽  
...  
Keyword(s):  
Catalytic System ◽  
Lewis Acid ◽  
Hydrogen Transfer ◽  
Acid Catalysis ◽  
Rate Limiting Step ◽  
Site Selectivity ◽  
Set Up ◽  
Site Selective ◽  
First Time ◽  
Rate Limiting

A catalytic system comprised of a cobalt-diphosphine complex and a Lewis acid (LA) such as AlMe3 has been found to promote hydrocarbofunctionalization reactions of alkynes with Lewis basic and electron-deficient substrates such as formamides, pyridones, pyridines, and azole derivatives through site-selective C-H activation. Compared with known Ni/LA catalytic system for analogous transformations, the present catalytic system not only feature convenient set up using inexpensive and bench-stable precatalyst and ligand such as Co(acac)3 and 1,3-bis(diphenylphosphino)propane (dppp), but also display distinct site-selectivity toward C-H activation of pyridone and pyridine derivatives. In particular, a completely C4-selective alkenylation of pyridine has been achieved for the first time. Mechanistic stidies including DFT calculations on the Co/Al-catalyzed addition of formamide to alkyne have suggested that the reaction involves cleavage of the carbamoyl C-H bond as the rate-limiting step, which proceeds through a ligand-to-ligand hydrogen transfer (LLHT) mechanism leading to an alkyl(carbamoyl)cobalt intermediate.

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