Teratologische Prüfung einiger Thalidomid-Metabolite

Summary The teratogenicity of 3 hydrolysis products of thalidomide, 2-(o-carboxybenzamido)-glutaric acid, phthalic acid and glutamic acid, was determined by administering 25% Tween 20 i.p. to pregnant SWS-mice. Under these experimental conditions, the tested products were devoid of any teratogenic properties, whereas thel-isomer of phthaloyl-glutamic acid showed the well-known embryotoxic and teratogenic activity.     

Kompensation der teratogenen Wirkung eines Thalidomid-Metaboliten durchl-Glutaminsäure

Summary Skeletal defects were observed in the off-spring of SWS-mice following i.p. administration of phthaloyl-l-glutamic acid, a metabolite of thalidomide. The fetuses of animals which receivedl-glutamic acid in addition to the teratogenic drug, did not show any malformations, whereas concurrent i.p. administration of thed-isomer of glutamic acid failed to reverse teratogenicity induced by phthaloyl-l-glutamic acid.     

Intermolekulare Wechselwirkungen der Folsäure mit N-phthaloyl-dl-glutaminsäure. ein beitrag zur Frage der teratogenen wirkung des thalidomid

Summary With the addition of N-phthaloyl-dl-glutamic acid, a metabolite of thalidomide, the solubility of folic acid rises owing to greater complexity. These results could explain the teratogenic effect of thalidomide.     

Teratogene Wirkung der N-Phthalyl-dl-glutaminsäure nach intraperitonealer Applikation bei der Maus

Summary Phthaloyl-dl-glutamic acid, a metabolite of thalidomide, was found to exert a teratogenic effect after i.p. administration to pregnant mice. The injected solution contained Tween 20 as solubilizer.     

Plurality in the determinism of organophosphorus teratogenic effects (author's transl)]

In Quail embryos, nicotinamide prevents beak and legs abnormalities produced by bidrin but remains inefficient against vertebral defects induced by bidrin and parathion. In contrast, the vertebral deficiencies are greatly alleviated or abolished by pralidoxim, an antidote known and used in organophosphorus intoxications. From these observations, a plurality in the determinism of teratogenic effects induced by organophosphorus compounds is evident.     

Ultrastructural changes in the dorsal root ganglia evoked by thalidomide in rabbits.

Administration of the teratogenic drug thalidomide to pregnant does produces ultrastructural changes in foetal ganglion cells, Schwann cells and axons in the posterior root ganglia corresponding to forelimb segments deformed by the orug. Ultrastructural changes in ganglia appear on the 13th day of gestation, i.e., preceding the appearance of limb malformation.     

Pluralité dans le déterminisme des effets tératogènes des composés organophosphorés

Summary In Quail embryos, nicotinamide prevents beak and legs abnormalities produced by bidrin but remains inefficient against vertebral defects induced by bidrin and parathion. In contrast, the vertebral deficiencies are greatly alleviated or abolished by pralidoxim, an antidote known and used in organophosphorus intoxications. From these observations, a plurality in the determinism of teratogenic effects induced by organophosphorus compounds is evident.     

Sorting receptor SORLA: cellular mechanisms and implications for disease

Sorting-related receptor with A-type repeats (SORLA) is an intracellular sorting receptor that directs cargo proteins, such as kinases, phosphatases, and signaling receptors, to their correct location within the cell. The activity of SORLA assures proper function of cells and tissues, and receptor dysfunction is the underlying cause of common human malignancies, including Alzheimer’s disease, atherosclerosis, and obesity. Here, we discuss the molecular mechanisms that govern sorting of SORLA and its cargo in multiple cell types, and why genetic defects in this receptor results in devastating diseases.     

Current insights into the role of PKA phosphorylation in CFTR channel activity and the pharmacological rescue of cystic fibrosis disease-causing mutants

Cystic fibrosis transmembrane conductance regulator (CFTR) channel gating is predominantly regulated by protein kinase A (PKA)-dependent phosphorylation. In addition to regulating CFTR channel activity, PKA phosphorylation is also involved in enhancing CFTR trafficking and mediating conformational changes at the interdomain interfaces of the protein. The major cystic fibrosis (CF)-causing mutation is the deletion of phenylalanine at position 508 (F508del); it causes many defects that affect CFTR trafficking, stability, and gating at the cell surface. Due to the multiple roles of PKA phosphorylation, there is growing interest in targeting PKA-dependent signaling for rescuing the trafficking and functional defects of F508del-CFTR. This review will discuss the effects of PKA phosphorylation on wild-type CFTR, the consequences of CF mutations on PKA phosphorylation, and the development of therapies that target PKA-mediated signaling.     

Insulin receptors: Structure and function

Summary and conclusions The recent characterization of the human insulin receptor structure and its intrinsic tyrosine kinase activity represent major advances in our understanding of the mechanism of insulin action. It is reasonable to think that the insulin-induced autophosphorylation and activation of its receptor kinase represent an important event in the action of insulin on cell metabolism and growth. The fundamental research reviewed may be followed by the discovery of molecular receptor defects in clinical syndromes of insulin resistance.     

Insulin receptors: structure and function

The recent characterization of the human insulin receptor structure and its intrinsic tyrosine kinase activity represent major advances in our understanding of the mechanism of insulin action. It is reasonable to think that the insulin-induced autophosphorylation and activation of its receptor kinase represent an important event in the action of insulin on cell metabolism and growth. The fundamental research reviewed may be followed by the discovery of molecular receptor defects in clinical syndromes of insulin resistance.     

Ultrastructural changes in the dorsal root ganglia evoked by thalidomide in rabbits

Summary Administration of the teratogenic drug thalidomide to pregnant does produces ultrastructural changes in foetal ganglion cells, Schwann cells and axons in the posterior root ganglia corresponding to forelimb segments deformed by the drug. Ultrasttructural changes in ganglia appear on the 13th day of gestation, i.e., preceding the appearance of limb malformation.This work was supported by a grant from Foundation 41.We are grateful to MissC. Ellis and Mr.P. Westphal for technical assistance.     

Teratologische Prüfung der Hydrolysenprodukte des Thalidomids

Summary N-(o-Carboxybenzoyl)-dl-glutamic acid imide anddl-glutamic acid imide · HCl did not lead to fetal malformations after i.p. administration to pregnant mice; the injected solutions contained 25% Tween 20. Thus, of the 12 hydrolysis products of thalidomide only those 3 which contain the phthalimide moiety show teratogenic activity, i.e. 2-phthalimido-dl-glutaramic acid, 4-phthalimido-dl-glutaramic acid and 2-phthalimido-dl-glutaric acid.     

Cellular senescence: a view throughout organismal life

Cellular senescence is the final fate of most cells in response to specific stimuli, but is not the end. Indeed, it is the beginning of a singular life, with multiple side roads leading to diverse effects on the organism. Many studies have been done in the last few years to elucidate the intriguing role of senescent cells in the organism, demonstrating them as the cause of several age-related diseases. However, these cells are also positively implicated in other important pathways, such as embryogenesis and wound healing. It appears that the multiple effects are time-dependent: long-term senescence is mostly implicated in chronic inflammation and disease, whereas in the short term, senescent cells seem to be beneficial, being rapidly targeted by the innate immune system. The influence of senescent cells on their neighbors by paracrine factors, differential activity depending on developmental stage, and duration of the effects make the cellular senescent program a unique spatial–temporal mechanism. During pathological conditions such as progeroid syndromes, this mechanism is deregulated, leading to accelerated onset of some aging-related diseases and a shorter lifespan, among other physiological defects. Here, we review the three primary cell senescence programs described so far (replicative, stress-induced, and developmentally programmed senescence), their onset during development, and their potential roles in diseases with premature aging. Finally, we discuss the role of immune cells in keeping senescence burden below the threshold of disease.     

Vaspin inhibits kallikrein 7 by serpin mechanism

The molecular target of the adipokine vaspin (visceral adipose tissue-derived serpin; serpinA12) and its mode of action are unknown. Here, we provide the vaspin crystal structure and identify human kallikrein 7 (hK7) as a first protease target of vaspin inhibited by classical serpin mechanism with high specificity in vitro. We detect vaspin–hK7 complexes in human plasma and find co-expression of both proteins in murine pancreatic β-cells. We further demonstrate that hK7 cleaves human insulin in the A- and B-chain. Vaspin treatment of isolated pancreatic islets leads to increased insulin concentration in the media upon glucose stimulation without influencing insulin secretion. By application of vaspin and generated inactive mutants, we find the significantly improved glucose tolerance in C57BL/6NTac and db/db mice treated with recombinant vaspin fully dependent on the vaspin serpin activity and not related to vaspin-mediated changes in insulin sensitivity as determined by euglycemic-hyperinsulinemic clamp studies. Improved glucose metabolism could be mediated by increased insulin plasma concentrations 150 min after a glucose challenge in db/db mice, supporting the hypothesis that vaspin may inhibit insulin degradation by hK7 in the circulation. In conclusion, we demonstrate the inhibitory serpin nature and the first protease target of the adipose tissue-derived serpin vaspin, and our findings suggest hK7 inhibition by vaspin as an underlying physiological mechanism for its compensatory actions on obesity-induced insulin resistance.     

Key factors in mTOR regulation

Mammalian target of rapamycin (mTOR) is a protein serine/threonine kinase that controls a wide range of growth-related cellular processes. In the past several years, many factors have been identified that are involved in controlling mTOR activity. Those factors in turn are regulated by diverse signaling cascades responsive to changes in intracellular and environmental conditions. The molecular connections between mTOR and its regulators form a complex signaling network that governs cellular metabolism, growth and proliferation. In this review, we discuss some key factors in mTOR regulation and mechanisms by which these factors control mTOR activity.     

Considerations on mTOR regulation at serine 2448: implications for muscle metabolism studies

The mammalian target of rapamycin (mTOR) complex exerts a pivotal role in protein anabolism and cell growth. Despite its importance, few studies adequately address the complexity of phosphorylation of the mTOR protein itself to enable conclusions to be drawn on the extent of kinase activation following this event. In particular, a large number of studies in the skeletal muscle biology field have measured Serine 2448 (Ser2448) phosphorylation as a proxy of mTOR kinase activity. However, the evidence to be described is that Ser2448 is not a measure of mTOR kinase activity nor is a target of AKT activity and instead has inhibitory effects on the kinase that is targeted by the downstream effector p70S6K in a negative feedback loop mechanism, which is evident when revisiting muscle research studies. It is proposed that this residue modification acts as a fine-tuning mechanism that has been gained during vertebrate evolution. In conclusion, it is recommended that Ser2448 is an inadequate measure and that preferential analysis of mTORC1 activation should focus on the downstream and effector proteins, including p70S6K and 4E-BP1, along mTOR protein partners that bind to mTOR protein to form the active complexes 1 and 2.