Antiproliferative activity of two copper (II) complexes on colorectal cancer cell models: Impact on ROS production, apoptosis induction and NF-κB inhibition.

The main goal of this work was to screen the antiproliferative activity and mechanism of actions of two copper complexes: [Cu(dmp)2(CH3CN)]2+ (1) and [Cu(phen)2(CH3CN)]2+ (2) on 2D and 3D colorectal cancer cells models. Cell viability studies on three colorectal cancer cell lines (HT-29, LS174T, Caco-2) displayed that 1 showed more robust antiproliferative activity than 2 and cisplatin. Intracellular copper content (63.24% and 48.06% for 1 and 2, respectively) can explain the differences in the cytotoxicity assay. ROS production is the primary mechanism of action involved in the antiproliferative activity of 1 showing 4-, 70- and 2.5- fold increased values of ROS level for HT-29, LS174T, Caco-2 cancer cell lines, respectively. This effect takes place along with the depolarization of the mitochondrial membrane at 2 µM. Besides, both complexes increased apoptosis on three cancer cell lines at low micromolar concentrations (0.5-2.5 µM). Moreover, 1 and 2 inhibited NF-κB pathway both in HT-29-NF-kB-hrGFP monolayer (0.5 to 1 µM) and spheroids HT-29 GFP (5 to 10 µM). This inhibitory effect leads to an inactivation of the MMP-9 expression on HT-29 cell line. Altogether, these results showed that 1 exhibits antiproliferative activity on human colorectal cancer cells in the monolayer and the 3D model.

Formant-Based Recognition of Words and Other Naturalistic Sounds in Rhesus Monkeys.

In social animals, identifying sounds is critical for communication. In humans, the acoustic parameters involved in speech recognition, such as the formant frequencies derived from the resonance of the supralaryngeal vocal tract, have been well documented. However, how formants contribute to recognizing learned sounds in non-human primates remains unclear. To determine this, we trained two rhesus monkeys to discriminate target and non-target sounds presented in sequences of 1-3 sounds. After training, we performed three experiments: (1) We tested the monkeys' accuracy and reaction times during the discrimination of various acoustic categories; (2) their ability to discriminate morphing sounds; and (3) their ability to identify sounds consisting of formant 1 (F1), formant 2 (F2), or F1 and F2 (F1F2) pass filters. Our results indicate that macaques can learn diverse sounds and discriminate from morphs and formants F1 and F2, suggesting that information from few acoustic parameters suffice for recognizing complex sounds. We anticipate that future neurophysiological experiments in this paradigm may help elucidate how formants contribute to the recognition of sounds.

Synergy of DNA intercalation and catalytic activity of a copper complex towards improved polymerase inhibition and cancer cell cytotoxicity.

Improving the binding of metal complexes to DNA to boost cancer cell cytotoxicity requires fine tuning of their structural and chemical properties. Copper has been used as a metal center in compounds containing intercalating ligands due to its ability to catalytically generate reactive oxygen species (ROS), such as hydroxyl radicals (OH˙). We envision the synergy of DNA binding and ROS generation in proximity to target DNA as a powerful chemotherapy treatment. Here, we explore the use of [Cu(2CP-Bz-SMe)]2+ (2CP-Bz-SMe = 1,3-bis(1,10-phenanthrolin-2-yloxy)-N-(4-(methylthio)benzylidene)propan-2-amine) for this purpose by characterizing its cytotoxicity, DNA binding, and ability to affect DNA replication through the polymerase chain reaction - PCR and nuclease assays. We determined the binding (Kb) and Stern-Volmer constants (KSV) for complex-DNA association of 5.8 ± 0.14 × 104 and 1.64 (±0.08), respectively, through absorption titration and competitive fluorescence experiments. These values were superior to those of other Cu-complex intercalators. We hypothesize that the distorted trigonal bipyramidal geometry of [Cu(2CP-Bz-SMe)]2+ allows the phenanthroline fragments to be better accommodated into the DNA double helix. Moreover, the aromaticity of these fragments increases the local hydrophobicity thus increasing the affinity for the hydrophobic domains of DNA. Nuclease assays in the presence of common reducing agents ascorbic acid, nicotinamide adenine dinucleotide, and glutathione showed the effective degradation of DNA due to the in situ generation of OH˙. The [Cu(2CP-Bz-SMe)]2+ complex showed cytotoxicity against the following human cancer cells lines A549, MCF-7, MDA-MB-231 and MG-63 with half maximal inhibitory concentration (IC50) values of 4.62 ± 0.48, 5.20 ± 0.76, 5.70 ± 0.42 and 2.88 ± 0.66 µM, respectively. These low values of IC50, which are promising if compared to that of cisplatin, are ascribed to the synergistic effect of ROS generation with the intercalation ability into the DNA minor grooves and blocking DNA replication. This study introduces new principles for synergizing the chemical and structural properties of intercalation compounds for improved drug-DNA interactions targeting cancer.

Auditory decisions in the supplementary motor area.

In human speech and communication across various species, recognizing and categorizing sounds is fundamental for the selection of appropriate behaviors. However, how does the brain decide which action to perform based on sounds? We explored whether the supplementary motor area (SMA), responsible for linking sensory information to motor programs, also accounts for auditory-driven decision making. To this end, we trained two rhesus monkeys to discriminate between numerous naturalistic sounds and words learned as target (T) or non-target (nT) categories. We found that the SMA at single and population neuronal levels perform decision-related computations that transition from auditory to movement representations in this task. Moreover, we demonstrated that the neural population is organized orthogonally during the auditory and the movement periods, implying that the SMA performs different computations. In conclusion, our results suggest that the SMA integrates acoustic information in order to form categorical signals that drive behavior.

Reactivity of CuIN4 Flattened Complexes: Interplay between Coordination Geometry and Ligand Flexibility.

The relation between redox activity and coordination geometry in CuIN4 complexes indicates that more flattened structures tend to be more reactive. Such a preorganization of the ligand confers to the complex geometries closer to a transition state, which has been termed the "entatic" state in metalloproteins, more recently extending this concept for copper complexes. However, many aspects of the redox chemistry of CuI complexes cannot be explained only by flattening. For instance, the role of ligand flexibility in this context is an open debate nowadays. To analyze this point, we studied oxidation properties of a series of five monometallic CuI Schiff-base complexes, [CuI(Ln)]+, which span a range of geometries from a distorted square planar (n = 3) to a distorted tetrahedron (n = 6, 7). This stepped control of the structure around the CuI atom allows us to explore the effect of the flattening distortion on both the electronic and redox properties through the series. Experimental studies were complemented by a theoretical analysis based on density functional theory calculations. As expected, oxidation was favored in the flattened structures, spanning a broad potential window of 370 mV for the complete series. This orderly behavior was tested in the reductive dehalogenation reaction of tetrachloroethane (TCE). Kinetic studies show that CuI oxidation by TCE is faster as the flattening distortion is higher and the oxidation potentials of the metal are lower. However, the most reactive complex was not the more planar, contradicting the trend expected from oxidation potentials. The origin of this irregularity is related to ligand flexibility and its connection with the atom/electron transfer reaction path, highlighting the need to consider effects beyond flattening distortion to better understand the reactivity of this important class of complexes.

Structural and Photochemical Properties of Zn(II) Phenanthroline-Derived Complexes: From Mononuclear to Bimetallic and Circular-Trimetallic Helicates.

In the design of self-assembled compounds, small variations in the linkers connecting the coordinating moieties can produce large differences in the obtained structures. Here, we report three novel zinc(II) complexes with phenanthroline-derived ligands as building blocks (L1-L3): A mononuclear complex, a bimetallic helicate, and a trimetallic circular helicate. The even-number spacer in L2 promotes the formation of a bimetallic helicate stabilized by π-π interactions of adjacent phenanthrolines. The addition of an extra methylene in L3 increases the distance between where the phenanthrolines can stack, and CH-π noncovalent interactions give stability to the circular helicate. When irradiated at 308 nm in acetonitrile, long-lived excited states are formed with all three complexes, which are able to participate in oxidation of 2-propanol and in reduction of methylviologen, MV2+. While the overall behavior of the three complexes is similar, the bimetallic helicate is able to form a ground-state adduct with MV2+, while the trimer reaches the excited state to form an exciplex with MV2+.

Tejido adiposo y su función endocrina / Adipose tissue and its endocrine function

Recientemente se ha descubierto que el tejido adiposo (TA) tiene una crucial influencia sobre diversos procesos fisiológicos a través de la secreción de múltiples factores endocrinos, paracrinos y autocrinos, conocidos como adipoquinas. Desde su descubrimiento, a gran parte de las adipoquinas se les ha atribuido un importante papel en el metabolismo energético, regulando el almacenaje y producción de triglicéridos y colesterol. Uno de los descubrimientos más importantes sobre las funciones del tejido adiposo es como el aumento de su tamaño estimula la secreción de citocinas con carácter pro-inflamatorio, influyendo así en el control de su propia celularidad, la angiogénesis y la migración de células inmunes. Estudios recientes han mostrado como, ante cambios en la homeostasia, el tejido adiposo puede modificar los procesos de coagulación y fibrinólisis. La participación del tejido adiposo en la vascularización y la angiogénesis ha dado nuevos y reveladores resultados, centrados en nuevas adipoquinas como la quemerina y la monobutirina. El estudio de las adipoquinas y su gama de efectos sobre el organismo amplían cada vez más el panorama de las funciones del tejido adiposo y su importancia en el control del metabolismo y la homeostasia. Considerando toda la nueva información disponible, esta revisión bibliográfica busca enumerar, describir y analizar las principales funciones endocrinas del TA. La metodología utilizada para ello consistió en una revisión bibliográfica de tipo descriptivo realizada mediante la revisión sistemática de artículos científicos, consultando diversas bases de datos. Finalmente, se seleccionaron 30 artículos de los útimos cinco años, en español e inglés...(AU)

Magnetic nanoparticles as a support for a copper (II) complex with nuclease activity.

Magnetic nanoparticles have been extensively explored for the development of platforms for drug delivery and imaging probes. In this work, we have used a modular capping strategy to produce magnetic gold-coated Fe3O4 (Fe3O4@Au) nanoparticles, which have been decorated with a copper (II) complex containing a thioether derivative of clip-phen (Fe3O4@Au@Cu), where the complex [Cu(2CP-Bz-SMe)]2+ has affinity to bind DNA and proven nuclease activity (2CP-Bz-SMe=1,3-bis((1,10-phenanthrolin-2-yl)oxy)-N-(4-(methylthio)benzylidene)propan-2-imine). The functionalization of Fe3O4@Au with the copper complex occurs through the sulfur atom of the thioether moiety, as indicated by Raman scattering on surface. The magnetic measurements showed the nanomaterial Fe3O4@Au@Cu is still magnetic although the gold shell and the functionalization with the copper complex have diminished the magnetization due to the dilution of the magnetic core. The nuclease assays performed with Fe3O4@Au@Cu indicate that the nuclease activity of the nanomaterial toward the plasmid DNA involves an oxidative pathway in which H2O2 species is involved as intermediate in a Fenton-like reaction. Based on the electron paramagnetic resonance spectra (aN = 15.07 G, aH = 14.99 G), such nuclease activity is assigned, essentially, to the HO species indicating that the radical production property of [Cu(2CP-Bz-SMe)]2+ is successfully transferred to the core-shell gold-coated Fe3O4 magnetic nanoparticles. To the best of our knowledge, this is the first study reporting nuclease activity due to the reactive oxygen species generated by a copper complex immobilized on a gold-coated magnetic nanoparticle.

Steric and Electronic Factors Affecting the Conformation of Bimetallic CuI Complexes: Effect of the Aliphatic Spacer of Tetracoordinating Schiff-Base Ligands.

A family of six homoleptic [CuI (Ln )]2 (ClO4 )2 and six heteroleptic [CuI (Ln )(PPh3 )2 ]2 (ClO4 )2 bimetallic complexes, in which Ln are bis-Schiff base ligands with alkyl spacers of variable length (n=2-7 -CH2 -), were prepared to evaluate the role of the spacer on the formation of helicates or mesocates. In the homoleptic series, spectroscopic and theoretical studies indicate that preferences for a conformation are based on energetic parameters, mainly, the establishment of noncovalent interactions. The odd-even nature of the spacers preconditions the superposition of the aromatic rings to allow the juxtaposition necessary for noncovalent interactions, whereas the increase of the length reduces the strength of such interactions. Consequently, complexes with even-spacers of short length were identified as helicates in solution, [CuI (Ln )]22+ (n=2, 4). Complexes [CuI (Ln )]22+ (n=3-7) dissociate in solution to produce the monometallic complexes in equilibrium, [CuI (Ln )]+ . The stability of the bimetallic species is discussed in terms of their conformations. The set of heteroleptic complexes was prepared to evaluate the reach of the "odd-even rule" in the solid, which is based on the "zig-zag" arrangements of the spacers. Based on crystallographic information, "S-" and "C"-type conformations of Ln are related to even and odd spacers, respectively. This trend is considered in addition to other factors to explain preferences for either a mesocate or helicate conformation in the homoleptic series.

Structural diversity in Cu(i) complexes of the PNP ligand: from pincer to binuclear coordination modes and their effects upon the electrochemical and photophysical properties.

A set of new copper(i) complexes is synthesized and characterized using a labile PNP pincer ligand (PNP = N,N'-bis(diphenylphosphine)-2,6-diaminopyridine). A homoleptic Cu(i) complex [Cu(PNP-κP1:κN1)2]+, (1), was prepared, and taking advantage of the uncoordinated phosphorus atoms in (1), reaction with a second Cu(i) atom bearing secondary ligands (PPh3, phen or dmp) allows the formation of new complexes: a bimetallic helicate [Cu(PNP)2(phen)]2+, (2), a mononuclear pincer complex [CuI(PNP)(PPh3)]+, (3), and a heteroleptic complex [CuI(PNP)(dmp)]+, (4). All complexes were characterized by X-ray crystallography, NMR (VT-NMR for (1) and (4)), cyclic-voltammetry, and steady-state and time-resolved luminescence spectroscopy. The fluxional behavior in (1) was studied by 31P VT-NMR, where an Ea value of 47.42 kJ mol-1 was calculated for the intramolecular alternating coordination of -PPh2 moieties in PNP to the metal atom. This set of compounds reveals the versatility of the PNP ligand when added to the coordinating properties of Cu(i). The four complexes exhibit emission in solution and complexes (2)-(4) display intense luminescence in the solid state. The oscillographic traces showing the decay of the luminescence were fitted to biexponential functions with time constants: 8.0 µs > τem,1 > 0.37 µs and 50 µs >τem, 2 > 2.2 µs for complexes (2), (3) and (4), respectively. Radiative relaxation is associated with electronic transitions in both the ligand PNP and metal-to-ligand charge transfer (MLCT).

The Time Is Up: Compression of Visual Time Interval Estimations of Bimodal Aperiodic Patterns.

The ability to estimate time intervals subserves many of our behaviors and perceptual experiences. However, it is not clear how aperiodic (AP) stimuli affect our perception of time intervals across sensory modalities. To address this question, we evaluated the human capacity to discriminate between two acoustic (A), visual (V) or audiovisual (AV) time intervals of trains of scattered pulses. We first measured the periodicity of those stimuli and then sought for correlations with the accuracy and reaction times (RTs) of the subjects. We found that, for all time intervals tested in our experiment, the visual system consistently perceived AP stimuli as being shorter than the periodic (P) ones. In contrast, such a compression phenomenon was not apparent during auditory trials. Our conclusions are: first, the subjects exposed to P stimuli are more likely to measure their durations accurately. Second, perceptual time compression occurs for AP visual stimuli. Lastly, AV discriminations are determined by A dominance rather than by AV enhancement.

Regulation of thermoTRPs by lipids.

The family of Transient Receptor Potential (TRP) ion channels is constituted by 7 subfamilies among which are those that respond to temperature, the thermoTRPs. These channels are versatile molecules of a polymodal nature that have been shown to be modulated in various fashions by molecules of a lipidic nature. Some of these molecules interact directly with the channels on specific regions of their structures and some of these promote changes in membrane fluidity or modify their gating properties in response to their agonists. Here, we have discussed how some of these lipids regulate the activity of thermoTRPs and included some of the available evidence for the molecular mechanisms underlying their effects on these channels.

Hydroxyl Radical Generation and DNA Nuclease Activity: A Mechanistic Study Based on a Surface-Immobilized Copper Thioether Clip-Phen Derivative.

Coordination compounds of copper have been invoked as major actors in processes involving the reduction of molecular oxygen, mostly with the generation of radical species the assignment for which has, so far, not been fully addressed. In the present work, we have carried out studies in solution and on surfaces to gain insights into the nature of the radical oxygen species (ROS) generated by a copper(II) coordination compound containing a thioether clip-phen derivative, 1,3-bis(1,10-phenanthrolin-2-yloxy)-N-(4-(methylthio)benzylidene)propan-2-amine (2CP-Bz-SMe), enabling its adsorption/immobilization to gold surfaces. Whereas surface plasmon resonance (SPR) and electrochemistry of the adsorbed complex indicated the formation of a dimeric Cu(I) intermediate containing molecular oxygen as a bridging ligand, scanning electrochemical microscopy (SECM) and nuclease assays pointed to the generation of a ROS species. Electron paramagnetic resonance (EPR) data reinforced such conclusions, indicating that radical production was dependent on the amount of oxygen and H2 O2 , thus pointing to a mechanism involving a Fenton-like reaction that results in the production of OH(.) .

Resolution and characterization of helicate dimer and trimer complexes of 1,3-bis(9-methyl-1,10-phenanthrolin-2-yl)propane with copper(I).

Complexation of copper(I) with the binucleating ligand, 1,3-bis(9-methyl-1,10-phenanthrolin-2-yl)propane, mphenpr, result in formation of helical dimers, [Cu2(mphenpr)2](2+). The resolution of the enantiomeric forms of the dimers has been carried out with Δ-[As(cat)3](-) as resolving agent and X-ray structures for two compounds, P-[Cu2(mphenpr)2](Δ-[As(cat)3])2 and P-[Cu2(mphenpr)2](Δ-[As(cat)3])2·4(CH3CN), are reported. The rate of racemization in poorly-coordinating solvents has been examined by (1)H NMR, and is slow. At saturating concentrations of [[Cu2(mphenpr)2](2+)] in acetonitrile, crystals of the helical trimeric complex [Cu3(mphenpr)3](ClO4)3 are obtained. The X-ray structure of the trimer is reported. This species has also been resolved. As with the helical dimer, racemization in poorly-coordinating solvents is slow, and circular dichroism and (1)H NMR spectra are reported. The absolute configuration of the resolved complex, P-[Cu3(mphenpr)3](Δ-[As(cat)3])3, has been determined by X-ray crystallography.

Sense, memory, and decision-making in the somatosensory cortical network.

The brain constructs representations of objects and concepts based in sensory information combined with experience. This mental process, that we call perception, is the result of a chain of events consisting of phenomena such as detection, memory, discrimination, categorization and decision-making. Although the phenomenon of perception is not necessarily dependent on a given sensory modality (e.g. visual perception, auditory, tactile), single sensory models are indispensable for studying the neural mechanisms that generate it. The somatosensory system is a suitable model for studying the manner in which presentation of a single physical variable (e.g. vibration) triggers a perceptual process. Here, we discuss some recent studies in the somatosensory system that in our view, constitute a breakthrough to understanding decision making.

Do sensory cortices process more than one sensory modality during perceptual judgments?

Recent studies have reported that sensory cortices process more than one sensory modality, challenging the long-lasting concept that they process only one. However, both the identity of these multimodal responses and whether they contribute to perceptual judgments is unclear. We recorded from single neurons in somatosensory cortices and primary auditory cortex while trained monkeys discriminated, on interleaved trials, either between two tactile flutter stimuli or between two acoustic flutter stimuli, and during discrimination sets that combined these two sensory modalities. We found neurons in these sensory cortices that responded to stimuli that are not of their principal sensory modality during these tasks. However, the identity of the stimulus could only be decoded from responses to their principal sensory modality during the stimulation periods and not during the processing steps that link sensation and decision making. These results suggest that multimodal encoding and perceptual judgments in these tasks occur outside the sensory cortices studied here.

Decoding a perceptual decision process across cortex.

Perceptual decisions arise from the activity of neurons distributed across brain circuits. But, decoding the mechanisms behind this cognitive operation across brain circuits has long posed a difficult problem. We recorded the neuronal activity of diverse cortical areas, while monkeys performed a vibrotactile discrimination task. We find that the encoding of the stimuli during the stimulus periods, working memory, and comparison periods is widely distributed across cortical areas. Notably, during the comparison and postponed decision report periods the activity of frontal brain circuits encode both the result of the sensory evaluation that corresponds to the monkey's possible choices and past information on which the decision is based. These results suggest that frontal lobe circuits are more engaged in the readout of sensory information from working memory, when it is required to be compared with other sensory inputs, than simply engaged in motor responses during this task.

Neural encoding of auditory discrimination in ventral premotor cortex.

Monkeys have the capacity to accurately discriminate the difference between two acoustic flutter stimuli. In this task, monkeys must compare information about the second stimulus to the memory trace of the first stimulus, and must postpone the decision report until a sensory cue triggers the beginning of the decision motor report. The neuronal processes associated with the different components of this task have been investigated in the primary auditory cortex (A1); but, A1 seems exclusively associated with the sensory and not with the working memory and decision components of this task. Here, we show that ventral premotor cortex (VPC) neurons reflect in their activities the current and remembered acoustic stimulus, their comparison, and the result of the animal's decision report. These results provide evidence that the neural dynamics of VPC is involved in the processing steps that link sensation and decision-making during auditory discrimination.

Neural codes for perceptual discrimination of acoustic flutter in the primate auditory cortex.

We recorded from single neurons of the primary auditory cortex (A1), while trained monkeys reported a decision based on the comparison of 2 acoustic flutter stimuli. Crucially, to form the decision, monkeys had to compare the second stimulus rate to the memory trace of the first stimulus rate. We found that the responses of A1 neurons encode stimulus rates both through their periodicity and through their firing rates during the stimulation periods, but not during the working memory and decision components of this task. Neurometric thresholds based on firing rate were very similar to the monkey's discrimination thresholds, whereas neurometric thresholds based on periodicity were lower than the experimental thresholds. Thus, an observer could solve this task with a precision similar to that of the monkey based only on the firing rates evoked by the stimuli. These results suggest that the A1 is exclusively associated with the sensory and not with the cognitive components of this task.