Multi-target Evaluation Research Articles

Helmet Radio Frequency Phased Array Applicators Enhance Thermal Magnetic Resonance of Brain Tumors.

Thermal Magnetic Resonance (ThermalMR) integrates Magnetic Resonance Imaging (MRI) diagnostics and targeted radio-frequency (RF) heating in a single theranostic device. The requirements for MRI (magnetic field) and targeted RF heating (electric field) govern the design of ThermalMR applicators. We hypothesize that helmet RF applicators (HPA) improve the efficacy of ThermalMR of brain tumors versus an annular phased RF array (APA). An HPA was designed using eight broadband self-grounded bow-tie (SGBT) antennae plus two SGBTs placed on top of the head. An APA of 10 equally spaced SGBTs was used as a reference. Electromagnetic field (EMF) simulations were performed for a test object (phantom) and a human head model. For a clinical scenario, the head model was modified with a tumor volume obtained from a patient with glioblastoma multiforme. To assess performance, we introduced multi-target evaluation (MTE) to ensure whole-brain slice accessibility. We implemented time multiplexed vector field shaping to optimize RF excitation. Our EMF and temperature simulations demonstrate that the HPA improves performance criteria critical to MRI and enhances targeted RF and temperature focusing versus the APA. Our findings are a foundation for the experimental implementation and application of a HPA en route to ThermalMR of brain tumors.

Multitarget evaluation of molecules from marine animals against Alzheimer's disease, related to gamma‐ and beta‐secretases and cathepsin B protein targets

AbstractBackgroundOne of the causes for Alzheimer’s disease (AD) is the secretase activity on the APP protein, producing ß‐amyloid peptides (Aß) that aggregate and accumulate in regions of the brain, causing cell death (WAKABAYASHI; STROOPER, 2008). Secretase (β and γ) inhibitors have been studied as an alternative to treatment, but they have exhibited toxicity or ineffectiveness; however, these enzymes are still considered potentially effective therapeutic targets. Besides these inhibitors, cathepsin B is considered another possible inhibitory target for its involvement in protein clearance and neuroinflammation (CHITRANSHI et al, 2021). Thus, this work aimed to analyze, by virtual screening, the inhibition of such enzymes, among molecules described from marine animals, in order to obtain a new prototype for amyloid plaques decrease.MethodMolecules from marine animals were searched in scientific articles and prepared for docking, conducted by Swiss Dock server, to predict molecular interaction with β and γ‐secretases and cathepsin B (selected on PDB). Results were analyzed by UCSF Chimera and, by predicting the molecular interaction, the molecules were selected if they were positioned in the enzyme active site, with distance lower than 3 Å and binding energy lower than ‐5 kcal/mol.ResultAmong 50 molecules, Sebastianine A obtained a positioning exactly in the active site of the β‐secretase, presenting favorable binding energy of ‐6.74 kcal/mol and the binding distance of 2.395 Å with the amino acid Thr72. Regarding the γ‐secretase, it was observed the lowest binding energy of ‐6.86 kcal/mol, and 2.42 Å to the amino acid Lys380. Lastly, in the case of cathepsin B, it was possible to identify a distance of 3.091 Å and binding energy ‐6.45 kcal/mol to the amino acid Gln25.ConclusionSebastianine A has the potential to inhibit 3 important enzymes for the AD development, in a multitarget approach, relevant for this complex disease. This result represents a promising drug candidate for this disease without cure so far.

Treating leishmaniasis in Amazonia, part 2: Multi-target evaluation of widely used plants to understand medicinal practices

Ethnopharmacological relevanceLeishmaniasis are widely distributed among tropical and subtropical countries, and remains a crucial health issue in Amazonia. Indigenous groups across Amazonia have developed abundant knowledge about medicinal plants related to this pathology. Aim of the studyWe intent to explore the weight of different pharmacological activities driving taxa selection for medicinal use in Amazonian communities. Our hypothesis is that specific activity against Leishmania parasites is only one factor along other (anti-inflammatory, wound healing, immunomodulating, antimicrobial) activities. Materials and methodsThe twelve most widespread plant species used against leishmaniasis in Amazonia, according to their cultural and biogeographical importance determined through a wide bibliographical survey (475 use reports), were selected for this study. Plant extracts were prepared to mimic their traditional preparations. Antiparasitic activity was evaluated against promastigotes of reference and clinical New-World strains of Leishmania (L. guyanensis, L. braziliensis and L. amazonensis) and L. amazonensis intracellular amastigotes. We concurrently assessed the extracts immunomodulatory properties on PHA-stimulated human PBMCs and RAW264.7 cells, and on L. guyanensis antigens-stimulated PBMCs obtained from Leishmania-infected patients, as well as antifungal activity and wound healing properties (human keratinocyte migration assay) of the selected extracts. The cytotoxicity of the extracts against various cell lines (HFF1, THP-1, HepG2, PBMCs, RAW264.7 and HaCaT cells) was also considered. The biological activity pattern of the extracts was represented through PCA analysis, and a correlation matrix was calculated. ResultsSpondias mombin L. bark and Anacardium occidentale L. stem and leaves extracts displayed high anti-promatigotes activity, with IC50 ≤ 32 μg/mL against L. guyanensis promastigotes for S. mombin and IC50 of 67 and 47 μg/mL against L. braziliensis and L. guyanensis promastigotes, respectively, for A. occidentale. In addition to the antiparasitic effect, antifungal activity measured against C. albicans and T. rubrum (MIC in the 16–64 μg/mL range) was observed. However, in the case of Leishmania amastigotes, the most active species were Bixa orellana L. (seeds), Chelonantus alatus (Aubl.) Pulle (leaves), Jacaranda copaia (Aubl.) D. Don. (leaves) and Plantago major L. (leaves) with IC50 < 20 μg/mL and infection rates of 14–25% compared to the control. Concerning immunomodulatory activity, P. major and B. orellana were highlighted as the most potent species for the wider range of cytokines in all tested conditions despite overall contrasting results depending on the model. Most of the species led to moderate to low cytotoxic extracts except for C. alatus, which exhibited strong cytotoxic activity in almost all models. None of the tested extracts displayed wound healing properties. ConclusionsWe highlighted pharmacologically active extracts either on the parasite or on associated pathophysiological aspects, thus supporting the hypothesis that antiparasitic activities are not the only biological factor useful for antileishmanial evaluation. This result should however be supplemented by in vivo studies, and attracts once again the attention on the importance of the choice of biological models for an ethnophamacologically consistent study. Moreover, plant cultural importance, ecological status and availability were discussed in relation with biological results, thus contributing to link ethnobotany, medical anthropology and biology.

Treating Leishmaniasis in Amazonia, Part 2: Multi-Target Evaluation of Widely Used Plants to Understand Medicinal Practices

Treating Leishmaniasis in Amazonia, Part 2: Multi-Target Evaluation of Widely Used Plants to Understand Medicinal Practices

Synthetic approaches, anticancer potential, HSP90 inhibition, multitarget evaluation, molecular modeling and apoptosis mechanistic study of thioquinazolinone skeleton: Promising antibreast cancer agent

New series of compounds bearing 2-thioquinazolinone scaffold were designed, synthesized as HSP90 inhibitors. Anti-proliferative activity of the synthesized compounds was evaluated against HCT-116, Hela and MCF-7 cell lines and compound 5k was found to be the most active member of the entire study with IC50 of 4.47, 7.55 and 4.04 μM, respectively, compared to DOX (IC50 of 5.23, 5.57 and 4.17 μM, respectively). Most of the tested compounds revealed lower cytotoxicity against normal fibroblast cells WI-38. Compounds 5b, 5k and 8a showed potent HSP90 inhibitory activities with IC50 values in nanomolar range; 71.32, 25.07 and 56.78 nm, respectively, against Tanespimycin (IC50 of 86.45 nm). Their HSP90 inhibitory activities were confirmed by their down regulation of HSP90 client protein Her2 and up regulation of chaperone HSP70 levels. Compound 5k had shown potent multi-target inhibitory activities against EGFR, VEGFR-2 and Topoisomerase-2 with IC50 values in nanomolar range; 38.5, 126.95 and 25.85 nm, respectively. Compound 5k was further evaluated for cell cycle distribution and apoptosis induction on MCF-7 cells using flow cytometry. Compound 5k arrested the cell cycle on MCF-7 at a G2/M phase by 35.06% and induced apoptosis by 19.82%. Mechanistic evaluation of apoptosis induction was studied by following ways triggering mitochondrial apoptotic pathway through inducing ROS accumulation, increasing Bax/Bcl-2 ratio and activation of caspases 6, 7 and 9. Comparative molecular modeling study was performed between active and inactive HSP90 inhibitors. Docking studies into the active site of HSP90 N-terminal domain showed good agreement with the obtained biological results. ADMET analysis and parameters of Lipinski’s rule of five were calculated where compound 5k had reasonable drug-likeness with acceptable physicochemical properties so it could be used as promising orally absorbed antibreast targeted therapy.

Multitarget Evaluation of the Photocatalytic Activity of P25-SiO2 Prepared by Atomic Layer Deposition

Multitarget Evaluation of the Photocatalytic Activity of P25-SiO2 Prepared by Atomic Layer Deposition

Multitarget Evaluation of the Photocatalytic Activity of P25-SiO2 Prepared by Atomic Layer Deposition

This work presents the evaluation of the photocatalytic activity of P25 TiO2 particles, coated with SiO2, using atomic layer deposition (ALD) for the photocatalytic removal of methylene blue, oxidation of methanol and inactivation of Escherichia coli bacteria in water and its comparative evaluation with bare P25 TiO2. Two different reactor configurations were used, a slurry reactor with the catalyst in suspension, and a structured reactor with the catalyst immobilized in macroporous foams, that enables the long-term operation of the process in continuous mode, without the necessity of separation of the particles. The results show that the incorporation of SiO2 decreases the efficiency of the photocatalytic oxidation of methanol, whereas a significant improvement in the removal of methylene blue is achieved, and no significant changes are observed in the photocatalytic inactivation of bacteria. Adsorption tests showed that the improvements, observed in the removal of methylene blue by the incorporation of SiO2, was mainly due to an increase in its adsorption. The improvement in the adsorption step as part of the global photocatalytic process led to a significant increase in its removal efficiency. Similar conclusions were reached for bacterial inactivation where the loss of photocatalytic efficiency, suggested by the methanol oxidation tests, was counteracted with a better adherence of bacteria to the catalyst that improved its elimination. With respect to the use of macroporous foams as support, a reduction in the photocatalytic efficiency is observed, as expected from the decrease in the available surface area. Nevertheless, this lower efficiency can be counteracted by the operational improvement derived from the easy catalyst reuse.

Research on the Key Technology of Multi-Target Evaluation for Products

The thesis systematically researches the theory and methodology of multi-target industrial design evaluation with computer-aided technology. A prototype of multi-target industrial design evaluation system based on the expert system technology has been structured. The system includes three sub modules：evaluation target tree, evaluation target tree model and evaluation toolkit. The construction, content and realization of the four models are discussed in details. Last, this system has been validated according to an instance.

Fishing and Knockout (FAK) Strategy for Quality Control of Traditional Chinese Medicines (TCMs)

Herbs and preparations have been the basis of traditional Chinese medicines (TCMs) for thousands of years, and continue to be considered valuable composition in health care system. One of the biggest challenges of herbal research is the complexity of its chemical constituents and their analysis. Thus, a wide range of analytical methods need to be used to fully characterize these 'magical components' and used for quality control (QC) purpose. The effects of TCMs are, of course, induced by their chemical constituents. For effective quality control and efficacy evaluation, we should know: What exist in TCMs? Which are biologically active? And how the components induce integrative functions? During the last decade, our research team used multidisciplinary theory and technology to develop novel methods for multi-component and multi-target evaluation of TCMs. First, a diagnostic ion filtering strategy was proposed for rapid screening and identification of non-target compounds in complex TCM samples by UPLC-Q-TOF/MS. Next, a novel chemical markers' fishing and knockout (FAK) strategy was proposed for screening bioactive compounds and studying component-component interactions. A two-dimensional turbulent flow chromatography on-line coupled with LC-MS strategy was introduced to screen out the bioactive compounds from TCMs binding target proteins. Then, to prove whether the obtained/assumed constituents are active compounds for the extract, a chemical markers' knockout strategy was recommended to prepare an extract in which the assumed compound(s) is removed, called a ''knockout'' extract. After bioactivity comparison of samples with various components-knockouts or target compounds collections, the fingerprinting-efficacy relationship of TCMs, component-component interactions could be predicted by statistic analysis. With collaborative expertise in chemistry, chemometrics, biology, and bioinformatics, we believe that there are good prospects for obtaining new insights into drug discovery and clinical utility by the continued study of TCMs. Acknowledgements: This work was supported in part by the National Key Technologies R&D Program of China (No. 2008BAI51B01), Program for Changjiang Scholars and Innovative Research Teams in Universities (No. IRT0868).

General Design Process Model Based on Axiomatic Design

Due to the current axiomatic and general-design theories have some disadvantages such as strict constraint and unreasonable design evaluation,an extended general design process model is proposed,which integrates both the independent axiom and information axiom of the axiomatic design,and the QUINT model of general design theory.And a multi-target evaluation method is proposed for the extended general design process model,which includes the coupling degree,information content,technical indicator,economic indicator and social indicator.Based on the proposed model and evaluation method,a mechanical postage meter header is optimally designed.It achieves the anticipated targets for the practical manufacture applications,which proves the effectiveness of the general-design process model.

Evaluation of Multi-Target and Single-Target Liposomal Drugs for the Treatment of Gastric Cancer

We studied the effects of multi- and single-target liposomal drugs on human gastric cancer cell AGS both in vitro and in vivo. The cytotoxic effect of dihydrotanshinone I was significantly enhanced by treatment with octreotide-polyethylene glycol(PEG)-liposome, Arg-Gly-Asp(RGD)-PEG-liposome, and RGD/octreotide-PEG-liposome encapsulated with 0.5 mug/ml of dihydrotanshinone I to AGS cell for 24 h, compared to control. Furthermore, the AGS cell survival rate for multi-target versus single target liposomal drugs was significantly suppressed. Microscopic examination revealed that significant cell death occurred in the multi- and single-target liposomal encapsulated drug groups. Significant suppression of tumor growth in AGS cell xenograft nude mice given octreotide-PEG-liposome, RGD/octreotide-PEG-liposome encapsulated drug, versus those given a free drug was noted after 13 d of experimentation with the multi-targeted liposome: up to 60.75% and 41.2% reduction of tumor volume as compared to dimethylsulfoxide (DMSO) control and the free drug groups respectively. The treated animals showed no gross signs of toxicity. The results have potential clinical application.