The anti-cancer agent guttiferone-A permeabilizes mitochondrial membrane: Ensuing energetic and oxidative stress implications

Guttiferone-A (GA) is a natural occurring polyisoprenylated benzophenone with cytotoxic action in vitro and anti-tumor action in rodent models. We addressed a potential involvement of mitochondria in GA toxicity (1-25 mu M) toward cancer cells by employing both hepatic carcinoma (HepG2) cells and succinate-energized mitochondria, isolated from rat liver. In HepG2 cells GA decreased viability, dissipated mitochondrial membrane potential, depleted ATP and increased reactive oxygen species (ROS) levels. In isolated rat-liver mitochondria GA promoted membrane fluidity increase, cyclosporine A/EGTA-insensitive membrane permeabilization, uncoupling (membrane potential dissipation/state 4 respiration rate increase), Ca(2+) efflux, ATP depletion, NAD(P)H depletion/oxidation and ROS levels increase. All effects in cells, except mitochondrial membrane potential dissipation, as well as NADPH depletion/oxidation and permeabilization in isolated mitochondria, were partly prevented by the a NAD(P)H regenerating substrate isocitrate. The results suggest the following sequence of events: 1) GA interaction with mitochondrial membrane promoting its permeabilization; 2) mitochondrial membrane potential dissipation; 3) NAD(P)H oxidation/depletion due to inability of membrane potential-sensitive NADP(+) transhydrogenase of sustaining its reduced state; 4) ROS accumulation inside mitochondria and cells; 5) additional mitochondrial membrane permeabilization due to ROS; and 6) ATP depletion. These GA actions are potentially implicated in the well-documented anti-cancer property of GA/structure related compounds. (C) 2011 Elsevier Inc. All rights reserved.

The anti-cancer agent nemorosone is a new potent protonophoric mitochondrial uncoupler

Nemorosone, a natural-occurring polycyclic polyprenylated acylphloroglucinol, has received increasing attention due to its strong in vitro anti-cancer action. Here, we have demonstrated the toxic effect of nemorosone (1-25 mu M) on HepG2 cells by means of the MTT assay, as well as early mitochondrial membrane potential dissipation and ATP depletion in this cancer cell line. In mitochondria isolated from rat liver, nemorosone (50-500 nM) displayed a protonophoric uncoupling activity, showing potency comparable to the classic protonophore, carbonyl cyanide m-chlorophenyl hydrazone (CCCP). Nemorosone enhanced the succinate-supported state 4 respiration rate, dissipated mitochondrial membrane potential, released Ca(2+) from Ca(2+)-loaded mitochondria, decreased Ca(2+) uptake and depleted ATP. The protonophoric property of nemorosone was attested by the induction of mitochondrial swelling in hyposmotic K(+)-acetate medium in the presence of valinomycin. In addition, uncoupling concentrations of nemorosone in the presence of Ca(2+) plus ruthenium red induced the mitochondrial permeability transition process. Therefore, nemorosone is a new potent protonophoric mitochondrial uncoupler and this property is potentially involved in its toxicity on cancer cells. (C) 2010 Elsevier B.V. and Mitochondria Research Society. All rights reserved.

HPLC separation, NMR and QTOF/MS/MS structure elucidation of a prominent nitric oxide donor agent based on an isomeric composition of a nitrosyl ruthenium complex

A new and promising nitrosyl ruthenium complex, [Ru(NO)(bdqi-COOH)(terpy)](PF(6))(3), bdqi-COOH is 3,4-diiminebenzoic acid and terpy is 2,2`-terpyridine, has been synthesized as a NO donor agent. The procedure used for [Ru(NO)(bdqi-COOH)(terpy)](PF(6))(3) synthesis has, apparently, yielded the formation of two isomers in which the ligand bdqi-COOH appears to be coordinated in its reduced form (bdcat-COOH), which could have differences in their pharmacological properties. Therefore, it was intended to separate the two possible isomers by high-performance liquid chromatography (HPLC) and to characterize them by high resolution mass spectrometry (QTOF MS) and by magnetic nuclear resonance spectroscopy (NMR). The results obtained by MS showed that the ESI-MS mass spectra of both HPLC column fractions, e.g. peak 1 and peak 2, are essentially equal, showing that both isomers display nearly identical gas-phase behavior with clusters of isotopologue ions centered at m/z 573, m/z 543 and m/z 513. Regarding the NMR analysis, the results showed that the positional isomerism is located in the bdqi-COOH ligand. From the observed results it can be concluded that the synthesis procedure that has been used results in the formation of two [Ru(terpy)(bdqi-COOH)NO](PF(6))(3) isomers. (c) 2009 Elsevier B.V. All rights reserved.

Synthesis, antichagasic in vitro evaluation, cytotoxicity assays, molecular modeling and SAR/QSAR studies of a 2-phenyl-3-(1-phenyl-1H-pyrazol-4-yl)-acrylic acid benzylidene-carbohydrazide series

Chagas disease (American trypanosomiasis) is one of the most important parasitic diseases with serious social and economic impacts mainly on Latin America. This work reports the synthesis, in vitro trypanocidal evaluation, cytotoxicity assays, and molecular modeling and SAR/QSAR studies of a new series of N-phenylpyrazole benzylidene-carbohydrazides. The results pointed 6k (X = H, Y = p-NO(2), pIC(50) = 4.55 M) and 6l (X = F, Y = p-CN, pIC(50) = 4.27 M) as the most potent derivatives compared to crystal violet (pIC(50) = 3.77 M). The halogen-benzylidene-carbohydrazide presented the lowest potency whereas 6l showed the most promising pro. le with low toxicity (0% of cell death). The best equation from the 4D-QSAR analysis (Model 1) was able to explain 85% of the activity variability. The QSAR graphical representation revealed that bulky X-substituents decreased the potency whereas hydrophobic and hydrogen bond acceptor Y-substituents increased it. (C) 2008 Elsevier Ltd. All rights reserved.

DR-NEGOTIATE - A system for automated agent negotiation with defeasible logic-based strategies

This paper reports on a system for automated agent negotiation, based on a formal and executable approach to capture the behavior of parties involved in a negotiation. It uses the JADE agent framework, and its major distinctive feature is the use of declarative negotiation strategies. The negotiation strategies are expressed in a declarative rules language, defeasible logic, and are applied using the implemented system DR-DEVICE. The key ideas and the overall system architecture are described, and a particular negotiation case is presented in detail.

A Step-by-Step Approach to Transit Oriented Development Project Delivery

A major challenge in successfully implementing transit-oriented development (TOD) is having a robust process that ensures effective appraisal, initiation and delivery of multi-stakeholder TOD projects. A step-by step project development process can assist in the methodic design, evaluation, and initiation of TOD projects. Successful TOD requires attention to transit, mixed-use development and public space. Brisbane, Australia provides a case-study where recent planning policies and infrastructure documents have laid a foundation for TOD, but where barriers lie in precinct level planning and project implementation. In this context and perhaps in others, the research effort needs to shift toward identification of appropriate project processes and strategies. This paper presents the outcomes of research conducted to date. Drawing on the mainstream approach to project development and financial evaluation for property projects, key steps for potential use in successful delivery of TOD projects have been identified, including: establish the framework; location selection; precinct context review; preliminary precinct design; the initial financial viability study; the decision stage; establishment of project structure; land acquisition; development application; and project delivery. The appropriateness of this mainstream development and appraisal process will be tested through stakeholder research, and the proposed process will then be refined for adoption in TOD projects. It is suggested that the criteria for successful TOD should be broadened beyond financial concerns in order to deliver public sector support for project initiation.

Modeling control objectives for business process compliance

Business process design is primarily driven by process improvement objectives. However, the role of control objectives stemming from regulations and standards is becoming increasingly important for businesses in light of recent events that led to some of the largest scandals in corporate history. As organizations strive to meet compliance agendas, there is an evident need to provide systematic approaches that assist in the understanding of the interplay between (often conflicting) business and control objectives during business process design. In this paper, our objective is twofold. We will firstly present a research agenda in the space of business process compliance, identifying major technical and organizational challenges. We then tackle a part of the overall problem space, which deals with the effective modeling of control objectives and subsequently their propagation onto business process models. Control objective modeling is proposed through a specialized modal logic based on normative systems theory, and the visualization of control objectives on business process models is achieved procedurally. The proposed approach is demonstrated in the context of a purchase-to-pay scenario.

Modeling ex vivo hematopoiesis using chemical engineering metaphors

Ex vivo hematopoiesis is increasingly used for clinical applications. Models of ex vivo hematopoiesis are required to better understand the complex dynamics and to optimize hematopoietic culture processes. A general mathematical modeling framework is developed which uses traditional chemical engineering metaphors to describe the complex hematopoietic dynamics. Tanks and tubular reactors are used to describe the (pseudo-) stochastic and deterministic elements of hematopoiesis, respectively. Cells at any point in the differentiation process can belong to either an immobilized, inert phase (quiescent cells) or a mobile, active phase (cycling cells). The model describes five processes: (1) flow (differentiation), (2) autocatalytic formation (growth),(3) degradation (death), (4) phase transition from immobilized to mobile phase (quiescent to cycling transition), and (5) phase transition from mobile to immobilized phase (cycling to quiescent transition). The modeling framework is illustrated with an example concerning the effect of TGF-beta 1 on erythropoiesis. (C) 1998 Published by Elsevier Science Ltd. All rights reserved.

Sensitive and specific detection of Clavibacter xyli subsp. xyli, causal agent of ratoon stunting disease of sugarcane, with a polymerase chain reaction-based assay

A sensitive, specific polymerase chain reaction-based assay was developed for the detection of the causal agent of ratoon stunting disease of sugarcane, Clavibacter xyli subsp. xyli. This assay uses oligonucleotide primers derived from the internal transcribed spacer region between the 16S and 23S rRNA genes of the bacterial rRNA operon. The assay is specific for C. xyli subsp. xyli and does not produce an amplification product from the template of the closely related bacterium C. xyli subsp. cynodontis, nor from other bacterial species. The assay was successfully applied to the detection of C. xyli subsp. xyli in fibrovascular fluid extracted from sugarcane and was sensitive to approximately 22 cells per PCR assay. A multiplex PCR test was also developed which identified and differentiated C. xyli subsp. xyli and C. xyli subsp. cynodontis in a single PCR assay.

Reactivity of chars and carbons: New insights through molecular modeling

A new model proposed for the gasification of chars and carbons incorporates features of the turbostratic nanoscale structure that exists in such materials. The model also considers the effect of initial surface chemistry and different reactivities perpendicular to the edges and to the faces of the underlying crystallite planes comprising the turbostratic structure. It may be more realistic than earlier models based on pore or grain structure idealizations when the carbon contains large amounts of crystallite matter. Shrinkage of the carbon particles in the chemically controlled regime is also possible due to the random complete gasification of crystallitic planes. This mechanism can explain observations in the literature of particle size reduction. Based on the model predictions, both initial surface chemistry and the number of stacked planes in the crystallites strongly influence the reactivity and particle shrinkage. Its test results agree well with literature data on the air-oxidation of Spherocarb and show that it accurately predicts the variation of particle size with conversion. Model parameters are determined entirely from rate measurements.

A state-contingent production approach to principal-agent problems with an application to point-source pollution control

Two basic representations of principal-agent relationships, the 'state-space' and 'parameterized distribution' formulations, have emerged. Although the state-space formulation appears more natural, analytical studies using this formulation have had limited success. This paper develops a state-space formulation of the moral-hazard problem using a general representation of production under uncertainty. A closed-form solution for the agency-cost problem is derived. Comparative-static results are deduced. Next we solve the principal's problem of selecting the optimal output given the agency-cost function. The analysis is applied to the problem of point-source pollution control. (C) 1998 Published by Elsevier Science S.A. All rights reserved.

Modeling the optical constants of GaP, InP, and InAs

An extension of the Adachi model with the adjustable broadening function, instead of the Lorentzian one, is employed to model the optical constants of GaP, InP, and InAs. Adjustable broadening is modeled by replacing the damping constant with the frequency-dependent expression. The improved flexibility of the model enables achieving an excellent agreement with the experimental data. The relative rms errors obtained for the refractive index equal 1.2% for GaP, 1.0% for InP, and 1.6% for InAs. (C) 1999 American Institute of Physics. [S0021-8979(99)05807-7].

Modeling the fluid-flow-induced stress and collapse in a dendritic network

An analytical approach to the stress development in the coherent dendritic network during solidification is proposed. Under the assumption that stresses are developed in the network as a result of the friction resisting shrinkage-induced interdendritic fluid flow, the model predicts the stresses in the solid. The calculations reflect the expected effects of postponed dendrite coherency, slower solidification conditions, and variations of eutectic volume fraction and shrinkage. Comparing the calculated stresses to the measured shear strength of equiaxed mushy zones shows that it is possible for the stresses to exceed the strength, thereby resulting in reorientation or collapse of the dendritic network.

Modeling the optical constants of AlxGa1-xAs alloys

The extension of Adachi's model with a Gaussian-like broadening function, in place of Lorentzian, is used to model the optical dielectric function of the alloy AlxGa1-xAs. Gaussian-like broadening is accomplished by replacing the damping constant in the Lorentzian line shape with a frequency dependent expression. In this way, the comparative simplicity of the analytic formulas of the model is preserved, while the accuracy becomes comparable to that of more intricate models, and/or models with significantly more parameters. The employed model accurately describes the optical dielectric function in the spectral range from 1.5 to 6.0 eV within the entire alloy composition range. The relative rms error obtained for the refractive index is below 2.2% for all compositions. (C) 1999 American Institute of Physics. [S0021-8979(99)00512-5].

Modeling the optical properties of AlSb, GaSb, and InSb

Optical constants of AlSb, GaSb, and InSb are modeled in the 1-6 eV spectral range. We employ an extension of Adachi's model of the optical constants of semiconductors. The model takes into account transitions at E-0, E-0 + Delta(0), E-1, and E-1 + Delta(1) critical points, as well as higher-lying transitions which are modeled with three damped harmonic oscillators. We do not consider indirect transitions contribution, since it represents a second-order perturbation and its strength should be low. Also, we do not take into account excitonic effects at E-1, E-1 + Delta(1) critical points, since we model the room temperature data. In spite of fewer contributions to the dielectric function compared to previous calculations involving Adachi's model, our calculations show significantly improved agreement with the experimental data. This is due to the two main distinguishing features of calculations presented here: use of adjustable line broadening instead of the conventional Lorentzian one, and employment of a global optimization routine for model parameter determination.