Pharmacology of iron transport Byrne, Shaina L; Krishnamurthy, Divya; Wessling-Resnick, Marianne
Annual review of pharmacology and toxicology,
01/2013, Letnik:
53
Journal Article
Recenzirano
Odprti dostop
Elucidating the molecular basis for the regulation of iron uptake, storage, and distribution is necessary to understand iron homeostasis. Pharmacological tools are emerging to identify and ...distinguish among different iron transport pathways. Stimulatory or inhibitory small molecules with effects on iron uptake can help characterize the mechanistic elements of iron transport and the roles of the transporters involved in these processes. In particular, iron chelators can serve as potential pharmacological tools to alleviate diseases of iron overload. This review focuses on the pharmacology of iron transport, introducing iron transport membrane proteins and known inhibitors.
Gold(I) complexes containing N-heterocyclic carbene ligands were synthesized, characterized, and along with the antiarthritic drug, auranofin, tested as inhibitors of the cysteine-dependent protein ...tyrosine phosphatases, which are implicated in several disease states. These compounds exhibit potencies in the low micromolar range against the enzymes in vitro. At therapeutically relevant concentrations, all compounds inhibit PTP activity in Jurkat T leukemia cells with some selectivity. In addition, the gold−carbene compounds inhibit phosphatase activity in primary mouse thymocytes.
Many chronic diseases are associated with hypothalamic-pituitary-adrenal axis dysfunction. Therefore, proteomic profiling of the pituitary gland has potential to uncover new information on the ...underlying pathways affected in these conditions. This could lead to identification of new biomarkers or drug targets for development of novel therapeutics. Here we present a protocol for preparation of pituitary protein extracts and analysis of the major hormones and accessory proteins using liquid chromatography tandem mass spectrometry (LC-MS/MS). The same methods can be applied in the study of other tissues of the diffuse neuroendocrine system.
Summary Despite decades of research, the pathophysiology and aetiology of schizophrenia remains incompletely understood. The disorder is frequently accompanied by metabolic symptoms including ...dyslipidaemia, hyperinsulinaemia, type 2 diabetes and obesity. These symptoms are a common side effect of currently available antipsychotic medications. However, reports of metabolic dysfunction in schizophrenia predate the antipsychotic era and have also been observed in first onset patients prior to antipsychotic treatment. Here, we review the evidence for abnormalities in metabolism in schizophrenia patients, both in the central nervous system and periphery. Molecular analysis of post mortem brain tissue has pointed towards alterations in glucose metabolism and insulin signalling pathways, and blood-based molecular profiling analyses have demonstrated hyperinsulinaemia and abnormalities in secretion of insulin and co-released factors at first presentation of symptoms. Nonetheless, such features are not observed for all subjects with the disorder and not all individuals with such abnormalities suffer the symptoms of schizophrenia. One interpretation of these data is the presence of an underlying metabolic vulnerability in a subset of individuals which interacts with environmental or genetic factors to produce the overt symptoms of the disorder. Further investigation of metabolic aspects of schizophrenia may prove critical for diagnosis, improvement of existing treatment based on patient stratification/personalised medicine strategies and development of novel antipsychotic agents.
Psychiatric disorders have been associated with perturbations of the hypothalamic-pituitary-adrenal axis. Therefore, proteomic studies of the pituitary gland have the potential to provide new ...insights into the underlying pathways affected in these conditions as well as identify new biomarkers or targets for use in developing improved medications. This chapter describes a protocol for preparation of pituitary protein extracts followed by characterization of the pituitary proteome by label-free liquid chromatography-tandem mass spectrometry in expression mode (LC-MS
). The main focus was on establishing a method for identifying the major pituitary hormones and accessory proteins as many of these have already been implicated in psychiatric diseases.
This chapter describes a protocol for measuring prolyl oligopeptidase (POP) activity using a biotinylated peptide substrate coupled to magnetic microspheres. The complex is incubated in the presence ...of a pituitary extract and activity can be detected by loss of the biotin label. The assay can be multiplexed for measuring multiple proprotein-cleaving enzymes simultaneously and can be used in analyses of neuropsychiatric diseases in which proteolytic cleavage of biologically active peptides is known to play a role.
Summary Recently, we showed that the circulating levels of insulin-related peptides and the secretory granule protein chromogranin A were increased in small cohorts of first onset schizophrenia ...patients. Assuming that this effect was associated with impaired insulin signalling, we investigated the possibility that secretion of other hormones is also affected in schizophrenia. Multiplex immunoassay analysis of 21 hormones and hormone-related molecules was carried out using sera from 236 first and recent onset schizophrenia patients and 230 matched controls. Serum concentrations of insulin and chromogranin A were increased in schizophrenia subjects, consistent with our previous study. In addition, we found elevated concentrations of pancreatic polypeptide, prolactin, progesterone and cortisol, and decreased levels of growth hormone. We also found that growth hormone levels were decreased in post-mortem pituitaries obtained from chronic schizophrenia patients. It will be important to determine whether any of these molecules are involved in the pathosphysiology of schizophrenia or if they reflect the associated insulin resistance. We conclude that function of multiple components of the hypothalamic-pituitary-adrenal-gonadal axis may be affected in schizophrenia. This could have important implications for future biomarker discovery efforts and personalized medicine strategies based on patient stratification for the treatment of this debilitating disorder.
Therapeutic inhibition of protein tyrosine phosphatase activity is a compelling yet challenging approach to the treatment of human disease. Toward this end, a library of 40 gold complexes with the ...general formula R3P−Au−Cl was screened to identify novel inhibitors of PTP activity. The most promising inhibitor obtained for the lymphoid tyrosine phosphatase LYP, (2-pyridine)(Ph2)P−Au−Cl, is one of the most potent and selective LYP inhibitors identified to date with an IC50 of 1.5 ± 0.3 μM, 10-fold selectivity for LYP over PTP-PEST, HePTP, and CD45 in vitro, and activity in cellular studies as well.
Studies of pituitary-related disorders would be facilitated by enhanced knowledge of the pituitary proteome. To construct a data set of human pituitary proteins, separate protein extracts were ...prepared from 15 post-mortem pituitaries and analyzed by data independent label-free nanoflow liquid chromatography mass spectrometry (nLC-MSE). The detected mass/time features were aligned and quantified using the Rosetta Elucidator® system and annotated using results from ProteinLynx Global Server. The resulting data set comprised 1007 unique proteins, with stringent identification by a minimum of two distinct peptides. These proteins consisted predominantly of enzymes, transporters, transcription/translation factors, cell structure and secreted proteins.
The protein tyrosine phosphatases are a family of enzymes that play critical roles in regulating physiological processes including cellular signaling, growth, differentiation, and the immune ...response. As new roles emerge for these enzymes in human disease, interest in understanding their mechanism of regulation and function has increased correspondingly. The recent development of mechanism-based probes for phosphatase activity has paved the way for detailed studies of tyrosine phosphatase activity and regulation in both physiological and pathological cellular signaling.
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