Two hydroxy pyridinecarboxylic acid derivatives as a possible chelating agents in neurodegenerative disease; equilibrium complexation studies with Cu(II), Zn(II).

The metal ion chelators 4-hydroxy-5-methyl-3-pyridinecarboxylic acid (DQ5) and 1,5-dimethyl-4-hydroxy-3-pyridinecarboxylic acid (DQ715) and Cu(II) and Zn(II) were investigated with the aim to restore the homeostasis of the brain Cu(II) and Zn(II) in neurodegenerative diseases. The proton dissociation constants of the ligands, the stability constants, and the coordination modes of the metal complexes formed were determined by pH-potentiometric, and spectral (UV–Vis and EPR or 1H NMR) methods. The results show that in slightly acidic and neutral pH range mono and bis complexes are formed through bidentate coordination of the ligands. The biological MTT-test reveals that the DQ715 ligand is able to lower the cytotoxic effect of Cu(II) in human embryonic kidney HEK-293 cells. Our studies revealed, however, that none of the chelators were efficient enough to withdraw these metal ions from the amyloid aggregates

Bayesian retrieval of complete posterior PDFs of oceanic rain rate from microwave observations

A new Bayesian algorithm for retrieving surface rain rate from Tropical Rainfall Measuring Mission (TRMM) Microwave Imager (TMI) over the ocean is presented, along with validations against estimates from the TRMM Precipitation Radar (PR). The Bayesian approach offers a rigorous basis for optimally combining multichannel observations with prior knowledge. While other rain-rate algorithms have been published that are based at least partly on Bayesian reasoning, this is believed to be the first self-contained algorithm that fully exploits Bayes’s theorem to yield not just a single rain rate, but rather a continuous posterior probability distribution of rain rate. To advance the understanding of theoretical benefits of the Bayesian approach, sensitivity analyses have been conducted based on two synthetic datasets for which the “true” conditional and prior distribution are known. Results demonstrate that even when the prior and conditional likelihoods are specified perfectly, biased retrievals may occur at high rain rates. This bias is not the result of a defect of the Bayesian formalism, but rather represents the expected outcome when the physical constraint imposed by the radiometric observations is weak owing to saturation effects. It is also suggested that both the choice of the estimators and the prior information are crucial to the retrieval. In addition, the performance of the Bayesian algorithm herein is found to be comparable to that of other benchmark algorithms in real-world applications, while having the additional advantage of providing a complete continuous posterior probability distribution of surface rain rate

A novel copper(I) induces ER stress-mediated apoptosis in leukemia cell lines

Recently, a novel phosphine copper(I) complex [Cu(thp)4][PF6] (CP), was identified as an efficient, in vitro antitumoral agents. It has also been demonstrated that it induces in colon cancer cells a programmed nonapototic cell death called paraptosis or type III cell death. In this study we evaluated CP antiproliferative activity on a panel of leukemia cell lines and it significantly inhibited cancer cells growth at micro and submicromolar concentration, especially against SEM and RS4;11 cell lines. Flow cytometric analysis demonstrated that CP did not affected cell cycle in RS4;11 and SEM cell line but we observed a concentration-dependent increase of the cell population with a hypodiploid DNA content peak (subG1), suggesting that CP may induce apoptosis. To better characterize the mode of cell death induced by CP, a biparametric cytofluorimetric analysis was performed using propidium iodide (PI), which stains DNA and is permeable only to dead cells, and fluorescent immunolabeling of the protein annexin-V, which binds to PS in a highly selective manner. We found a concentration-dependent increase in annexin-V positive cells in well agreement with the appearance of hypodipolid peak. Western blot analysis demonstrated that the activation of the apical caspase-9 and the two effector caspase-3 and 7 occur after treatment with CP, while caspase-8 was not affected by the treatment. Interestingly we did not observed mitochondrial depolarization or cytochrome c release into the cytoplasm, suggesting that mitochondria was not involved in the process of cell death. Previous observations indicated that CP may induces functional suppression of the ubiquitin–proteasome pathway thus triggering endoplasmic reticulum stress in solid tumor cells. We also evaluated if CP exerts ER stress in leukemia cell lines. Western blot analysis showed a remarkable increase of GRP78 in RS4;11 and SEM, a well known marker of ER stress. Moreover the protein synthesis inhibitor cicloheximide significantly protected the cells from CP-induced cell death suggesting that protein synthesis machinery is involved in the mechanism of action. To evaluate if CP directly inhibits the proteasome, semipurified proteasome from cell extracts were incubated with increasing concentrations of CP and the chymotrypsin-like activity was measured. The results showed a decreased activity in a concentration-dependent way, with an IC50 of approximately 12 μM. It is well known that copper represent an excellent catalyst of redox cycle and therefore it can stimulate ROS production. Interestingly the CP-induced cell death was significantly reduced in presence of ROS scavenger such as tocopherol, nacetyl cysteine (NAC) and butylated hydroxyanisole (BHA) suggesting that also ROS may contribute to the process of cell death. Further experiments are in progress to elucidate the mechanism of action of this copper complex and the results will be discussed

Hydroxypyridinecarboxylic acid derivatives influencing metal ion levels in the brain: Equilibrium complexation studies with Cu(II) and Zn(II)

none8siThe metal ion chelators 4-hydroxy-5-methyl-3-pyridinecarboxylic acid (DQ5) and 1,5-dimethyl-4- hydroxy-3-pyridinecarboxylic acid (DQ715) and Cu(II) and Zn(II) were investigated with the aim to restore the homeostasis of the brain Cu(II) and Zn(II) in neurodegenerative diseases. The proton dissociation constants of the ligands, the stability constants, and the coordination modes of the metal complexes formed were determined by pH-potentiometric, and spectral (UV–Vis and EPR or 1H NMR) methods. The results show that in slightly acidic and neutral pH range mono and bis complexes are formed through bidentate coordination of the ligands. The biological MTT-test reveals that the DQ715 ligand is able to lower the cytotoxic effect of Cu(II) in human embryonic kidney HEK-293 cells. Our studies revealed, however, that none of the chelators were efficient enough to withdraw these metal ions from the amyloid aggregates.mixedÉva Sija; Nóra Veronika Nagy; Valentina Gandin; Christine Marzano; Tamás Jakusch; Annalisa Dean; Valerio B. Di Marco; Tamás KissÉva, Sija; Nóra Veronika, Nagy; Gandin, Valentina; Marzano, Cristina; Tamás, Jakusch; Dean, Annalisa; DI MARCO, Valerio; Tamás, Kis