ABSTRACT
Pharmacokinetics of SN-38 in patients with end-stage kidney disease (ESKD) is partially varied because of fluctuations in transporters expression and/or function by high protein bound-uremic toxins concentration. The fluctuations may induce variations in anticancer drugs sensitivity to cancer cells. We aimed to clarify the variations in sensitivity of SN-38 to cancer patients with ESKD and investigate this mechanism, by human colon cancer cells exposed to uremic serum residue. LS180 cells were exposed to normal or uremic serum residue (LS/NSR or LS/USR cells) for a month. IC50 values of SN-38 in LS/NSR or LS/USR cells were calculated from viability of each cells treated SN-38. mRNA expression and intracellular SN-38 accumulation was evaluated by RT-PCR and HPLC-fluorescence methods, respectively. The IC50 value in LS/USR cells was higher than that in LS/NSR cells. Organic anion transporter polypeptide (OATP) 2B1 mRNA expression was lower in LS/USR cells than in LS/NSR cells, and SN-38 accumulation in LS/USR cells was lower than that in LS/NSR cells. Only co-treatment baicalin, which is OATP2B1 inhibitor, almost negated the difference in SN-38 accumulation between LS/NSR and LS/USR. Anticancer effects of substrates of OATP2B1, such as SN-38, were reduced in ESKD patients at the same plasma substrate concentration.
Subject(s)
Irinotecan/pharmacology , Organic Anion Transporters/antagonists & inhibitors , Topoisomerase I Inhibitors/pharmacology , Uremia/blood , Cell Line, Tumor , HEK293 Cells , Humans , Irinotecan/pharmacokinetics , Kidney Failure, Chronic/metabolism , Topoisomerase I Inhibitors/pharmacokineticsABSTRACT
Octacalcium phosphate (OCP) is regarded as an in vivo precursor of hydroxyapatite (HA). It is important to understand the mechanism of transformation of OCP to HA in order to reveal the mechanism of mineralization and help in the development of artificial bone-repairing materials. Herein, we have examined the behavior of OCP in a simulated body fluid (SBF) and pure water. The OCP particles immersed in the SBF at 37 °C did not transform to HA even after 720 h of immersion, though the particles showed crystal growth. In distilled water at 60 °C, the OCP particles transformed to HA but the unreactive period was observed. Although the immersed solution became supersaturated with HA within 12h of immersion, the OCP was not transformed in the first 36 h of immersion. These results indicate that the nucleation of HA is the rate-determining step in the transformation of OCP to HA.
Subject(s)
Calcium Phosphates/chemistry , Durapatite/chemistry , Body Fluids/chemistry , Humans , Temperature , Time Factors , Water/chemistryABSTRACT
DJ-1, Parkinson's disease PARK7, acts as an oxidative stress sensor in neural cells. Recently, we identified the DJ-1 modulator UCP0054278 by in silico virtual screening. However, the effect of the peripheral administration of UCP0054278 on an in vivo Parkinson's disease (PD) model is unclear. Therefore, in the present study, we examined the effects of the peripheral administration of UCP0054278 on both 6-OHDA-microinjected rats and rotenone-treated mice as acute and chronic animal models of PD, respectively. The peripheral administration of UCP0054278 prevented 6-OHDA- and rotenone-induced dopaminergic neural cell death and restored the defect in locomotion in these models of PD. In addition, 6-OHDA- or rotenone-induced neural cell death and the production of reactive oxygen species were significantly inhibited by UCP0054278 in normal SH-SY5Y cells, but not in DJ-1-knockdown cells. These results suggest that UCP0054278 interacts with endogenous DJ-1 and then produces antioxidant and neuroprotective responses in both in vivo and in vitro models of PD. The present study raises the possibility that DJ-1 stimulatory modulators, such as UCP0054278, may be a new type of dopaminergic neuroprotective drug for the treatment of PD.
Subject(s)
Benzamides/therapeutic use , Benzodioxoles/therapeutic use , Disease Models, Animal , Intracellular Signaling Peptides and Proteins/metabolism , Neuroprotective Agents/therapeutic use , Oncogene Proteins/metabolism , Parkinson Disease/drug therapy , Animals , Behavior, Animal/drug effects , Benzamides/pharmacology , Benzodioxoles/pharmacology , CD11b Antigen/metabolism , Cell Line, Tumor , Dopaminergic Neurons/drug effects , Dopaminergic Neurons/metabolism , Dopaminergic Neurons/pathology , Gene Knockdown Techniques , Glial Fibrillary Acidic Protein/metabolism , Humans , Intracellular Signaling Peptides and Proteins/genetics , Male , Mice , Mice, Inbred C57BL , Neuroglia/drug effects , Neuroglia/metabolism , Neuroprotective Agents/pharmacology , Neurotoxins , Oncogene Proteins/genetics , Oxidation-Reduction , Oxidative Stress/drug effects , Oxidopamine , Parkinson Disease/etiology , Parkinson Disease/metabolism , Protein Deglycase DJ-1 , Rats , Rats, Wistar , Rotenone , Substantia Nigra/drug effects , Substantia Nigra/metabolism , Substantia Nigra/pathology , Tyrosine 3-Monooxygenase/metabolismABSTRACT
The Arabidopsis homeotic gene AGAMOUS (AG) is necessary for the specification of reproductive organs (stamens and carpels) during the early steps of flower development. AG encodes a transcription factor of the MADS-box family that is expressed in stamen and carpel primordia. At later stages of development, AG is expressed in distinct regions of the reproductive organs. This suggests that AG might function during the maturation of stamens and carpels, as well as in their early development. However, the developmental processes that AG might control during organogenesis and the genes that are regulated by this factor are largely unknown. Here we show that microsporogenesis, the process leading to pollen formation, is induced by AG through activation of the SPOROCYTELESS gene (SPL, also known as NOZZLE,NZZ), a regulator of sporogenesis. Furthermore, we demonstrate that SPL can induce microsporogenesis in the absence of AG function, suggesting that AG controls a specific process during organogenesis by activating another regulator that performs a subset of its functions.
Subject(s)
AGAMOUS Protein, Arabidopsis/metabolism , Arabidopsis Proteins/genetics , Arabidopsis/growth & development , Arabidopsis/genetics , Gene Expression Regulation, Plant , Nuclear Proteins/genetics , Repressor Proteins/genetics , Spores/growth & development , Spores/genetics , AGAMOUS Protein, Arabidopsis/genetics , Arabidopsis/metabolism , Base Sequence , Binding Sites , Consensus Sequence/genetics , DNA/genetics , DNA/metabolism , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Flowers/genetics , Flowers/growth & development , Flowers/metabolism , Gene Expression Regulation, Developmental , Genes, Plant/genetics , Mutation/genetics , Oligonucleotide Array Sequence Analysis , Phenotype , RNA, Messenger/genetics , RNA, Messenger/metabolism , RNA, Plant/genetics , RNA, Plant/metabolism , Response Elements/genetics , Spores/metabolism , Up-RegulationABSTRACT
The Arabidopsis shepherd (shd) mutant shows expanded shoot apical meristems (SAM) and floral meristems (FM), disorganized root apical meristems, and defects in pollen tube elongation. We have discovered that SHD encodes an ortholog of GRP94, an ER-resident HSP90-like protein. Since the shd phenotypes in SAM and FM are similar to those of the clavata (clv) mutants, we have explored the possibility that CLV complex members could be SHD targets. The SAM and FM morphology of shd clv double mutants are indistinguishable from those of clv single mutants, and the wuschel (wus) mutation is completely epistatic to the shd mutation, indicating that SHD and CLV act in the same genetic pathway to suppress WUS function. Moreover, the effects of CLV3 overexpression that result in the elimination of SAM activity were abolished in the shd mutant, indicating that CLV function is dependent on SHD function. Therefore, we conclude that the SHD protein is required for the correct folding and/or complex formation of CLV proteins.