3,5,3'-Triiodothyronine nuclear receptors and their role in the thyroid hormone action

Thyroid hormones are involved in a complex arrangement of physiological and developmental responses in several tissues of higher vertebrates. Thyroxine, the main product of the thyroid gland, circulates in the blood stream being bouird either to specific plasma proteins (i.e. thyroxine binding globulin and transthyretin) or non-specifically to albumin. In the target tissue it is transported into the intracellular space by both the diffusion and energy dependent process (KRENNING et al. 198i). In the cytoplasmic space there is a "pool" of thyroid hormones containing the biologically active metabolite of thyroxine-3,5,3'-L-triiodothyronine (Tr) which originates from the monodeiodination of thyroxine. The T, enters the cell nucleus probably in the free form where it is specifically bound to nuclear receptors.Peer reviewe

Assessment of the stability of new chemotherapeutic selenium-kojic acid derivative using HPLC and MS analysis

ABSTRACT The stability of the new chemotherapeutic selenium kojic acid derivative, 5-benzyloxy-2-selenocyanatomethyl-4-pyranone (P763), was evaluated in simulated gastric and intestinal fluids as well as in human plasma at 37 o C ± 1. A stability-indicating HPLC procedure with C8 RP column and a mobile phase of acetonitrile/water (1:1) at a flow rate 1 ml/min was used. The eluted P763 compound and its degradation products were detected at 254 nm. The accelerated stability profiles were established. Kinetic studies under controlled experimental conditions have proved that P763 underwent fast hydrolysis in simulated intestinal fluid (phosphate buffer solution, pH 7.4), however the compound showed an appropriate stability at gastric acid solution (0.1M HCl solution) and in human plasma. The kinetics have indicated that the compound's degradation followed pseudo first-order reaction with relatively higher k deg and lower t 1/2 and t 90 values in simulated intestinal fluid compared to those in simulated gastric acid solution and plasma. The degradation of P763 compound at basic solution was confirmed by MS and MS/MS analysis, where the characteristic signals of the molecular (m/z 322) and fragment (m/z 91, 198) mass ions of compound disappeared. The obtained results suggest that the stability of P763 compound should be considered for future biopharmaceutical and biological studies

Genotoxic Effects of Tributyltin and Triphenyltin Isothiocyanates, Cognate RXR Ligands: Comparison in Human Breast Carcinoma MCF 7 and MDA-MB-231 Cells

The cytotoxicity of two recently synthesized triorganotin isothiocyanate derivatives, nuclear retinoid X receptor ligands, was tested and compared in estrogen-receptor-positive MCF 7 and -negative MDA-MB-231 human breast carcinoma cell lines. A 48 h MTT assay indicated that tributyltin isothiocyanate (TBT-ITC) is more cytotoxic than triphenyltin isothiocyanate (TPT-ITC) in MCF 7 cells, and the same trend was observed in the MDA-MB-231 cell line. A comet assay revealed the presence of both crosslinks and increasing DNA damage levels after the 17 h treatment with both derivatives. Differences in cytotoxicity of TBT-ITC and TPT-ITC detected by FDA staining correspond to the MTT data, communicating more pronounced effects in MCF 7 than in the MDA-MB-231 cell line. Both derivatives were found to cause apoptosis, as shown by the mitochondrial membrane potential (MMP) depolarization and caspase-3/7 activation. The onset of caspase activation correlated with MMP dissipation and the total cytotoxicity more than with the amount of active caspases. In conclusion, our data suggest that the DNA damage induced by TBT-ITC and TPT-ITC treatment could underlie their cytotoxicity in the cell lines studied

Triorganotin Derivatives Induce Cell Death Effects on L1210 Leukemia Cells at Submicromolar Concentrations Independently of P-glycoprotein Expression

The acceleration of drug efflux activity realized by plasma membrane transporters in neoplastic cells, particularly by P-glycoprotein (P-gp, ABCB1 member of the ABC transporter family), represents a frequently observed molecular cause of multidrug resistance (MDR). This multiple resistance represents a real obstacle in the effective chemotherapy of neoplastic diseases. Therefore, identifying cytotoxic substances that are also effective in P-gp overexpressing cells may be useful for the rational design of substances for the treatment of malignancies with developed MDR. Here, we showed that triorganotin derivatives—tributyltin-chloride (TBT-Cl), tributyltin-bromide (TBT-Br), tributyltin-iodide (TBT-I) and tributyltin-isothiocyanate (TBT-NCS) or triphenyltin-chloride (TPT-Cl) and triphenyltin-isothiocyanate (TPT-NCS)—could induce the death of L1210 mice leukemia cells at a submicromolar concentration independently of P-gp overexpression. The median lethal concentration obtained for triorganotin derivatives did not exceed 0.5 µM in the induction of cell death of either P-gp negative or P-gp positive L1210 cells. Apoptosis related to regulatory pathway of Bcl-2 family proteins seems to be the predominant mode of cell death in either P-gp negative or P-gp positive L1210 cells. TBT-Cl and TBT-Br were more efficient with L1210 cells overexpressing P-gp than with their counterpart P-gp negative cells. In contrast, TBT-I and TPT-NCS induced a more pronounced cell death effect on P-gp negative cells than on P-gp positive cells. Triorganotin derivatives did not affect P-gp efflux in native cells measured by calcein retention within the cells. Taken together, we assumed that triorganotin derivatives represent substances suitable for suppressing the viability of P-gp positive malignant cells

Targeting the pregnane X receptor using microbial metabolite mimicry

The human PXR (pregnane X receptor), a master regulator of drug metabolism, has essential roles in intestinal homeostasis and abrogating inflammation. Existing PXR ligands have substantial offtarget toxicity. Based on prior work that established microbial (indole) metabolites as PXR ligands, we proposed microbial metabolite mimicry as a novel strategy for drug discovery that allows exploiting previously unexplored parts of chemical space. Here, we report functionalized indole derivatives as first-in-class non-cytotoxic PXR agonists as a proof of concept for microbial metabolite mimicry. The lead compound, FKK6 (Felix Kopp Kortagere 6), binds directly to PXR protein in solution, induces PXRspecific target gene expression in cells, human organoids, and mice. FKK6 significantly represses pro-inflammatory cytokine production cells and abrogates inflammation in mice expressing the human PXR gene. The development of FKK6 demonstrates for the first time that microbial metabolite mimicry is a viable strategy for drug discovery and opens the door to underexploited regions of chemical space

Neutrophils are immune cells preferentially targeted by retinoic acid in elderly subjects

<p>Abstract</p> <p>Background</p> <p>The immune system gradually deteriorates with age and nutritional status is a major factor in immunosenescence. Of the many nutritional factors implicated in age-related immune dysfunction, vitamin A may be a good candidate, since vitamin A concentrations classically decrease during aging whereas it may possess important immunomodulatory properties via its active metabolites, the retinoic acids. This prompted us to investigate the immune response induced by retinoids in adults and elderly healthy subjects. Before and after oral supplementation with 13cis retinoic acid (0.5 mg/kg/day during 28 days), whole blood cells were phenotyped, and functions of peripheral blood mononuclear cells (PBMC) and polymorphonuclear cells (PMN) were investigated by flow cytometry and ELISA tests.</p> <p>Results</p> <p>In both young adults (<it>n </it>= 20, 25 ± 4 years) and older subjects (<it>n </it>= 20, 65 ± 4 years), retinoic acid supplementation had no effect on the distribution of leukocyte subpopulations or on the functions of PBMC (Il-2 and sIl-2R production, membrane expression of CD25). Concerning PMN, retinoic acid induced an increase in both spontaneous migration and cell surface expression of CD11b in the two different age populations, whereas bactericidal activity and phagocytosis remained unchanged.</p> <p>Conclusions</p> <p>We demonstrated that retinoic acid induces the same intensity of immune response between adult and older subjects, and more specifically affects PMN functions, i.e. adhesion and migration, than PBMC functions.</p