Current Medicinal Chemistry (v.23, #34)

Meet Our Editorial Board Member by Vito Ferro (3861-3861).

Circulating Advanced Oxidation Protein Products as Oxidative Stress Biomarkers and Progression Mediators in Pathological Conditions Related to Inflammation and Immune Dysregulation by Mariateresa Cristani, Antonio Speciale, Antonella Saija, Sebastiano Gangemi, Paola Lucia Minciullo, Francesco Cimino (3862-3882).
Evidence came out showing that oxidative stress has a pivotal role in development and maintenance of inflammation and aberrant immune responses. Biomarkers of oxidative stress may define the proportion of oxidative damage underlying pathological conditions, and also foresee and monitor the possible efficacy of therapeutic strategies designed to control these pathologies. New compounds, which can be used as biomarkers, have been identified, and among them advanced oxidation protein products (AOPPs), formed mainly by chlorinated oxidants resulting from activity of myeloperoxidase. Our paper is aimed to review clinical evidences concerning the valuable potential of AOPPs as biomarkers of oxidative injury in development and progression of diseases and chronic conditions related to inflammatory status and immune dysregulation. These pathologies include metabolic syndrome, obesity, immune-mediated inflammatory diseases, neurodegenerative diseases, and cancer. Due to the heterogeneity of pathologies reported to be characterized by AOPP accumulation, it is evident that AOPPs are not merely a marker of neutrophil activation, but at the same time AOPPs cannot always be disease determinants. The data reported in this review corroborate the opinion that AOPPs can be successfully used to in vitro confirm the diagnosis of inflammatory and immune-mediated diseases, but at the same time evidence is that, very likely due to the way through which AOPPs are formed as well as the effect they can contribute to induce, AOPP values cannot be clearly reflective of their involvement in the pathogenesis and in the evolution of a specific disease.

Cholesterol Efflux and Reverse Cholesterol Transport: Experimental Approaches by Dmitry Y. Litvinov, Eugeny V. Savushkin, Evdokiya A. Garaeva, Alexander D. Dergunov (3883-3908).
Background: Cholesterol efflux as a key event in reverse cholesterol transport (RCT) is considered now as both diagnostic tool and a promising target for the treatment of atherosclerosis. Radioactive in vitro cholesterol efflux assay (CEA) is the gold standard for determination of efflux at cellular level. Fluorescent tracers and stable isotope-labeled cholesterol gradually come into use as convenient tools for non-radioactive CEAs.
Results: We review the use of various tracer-based and tracer-free methods for CEAs and for measuring RCT with focus on macrophage-specific cholesterol efflux. CEA utilizing stable isotope-labeled cholesterol is equally reliable with radioactive assay and especially well suited for the determination of both cholesterol efflux and net cholesterol flux. Fluorescent tracers cannot fully mimic cholesterol; however, they are successfully applied in CEA in specific well-defined conditions. Fluorescent CEAs can be high throughput and can provide unique information on efflux from fast cholesterol pools or with single cell resolution. Enzymatic and chromatographic CEAs are net cholesterol flux assays, and they can be applied as efflux assays when used with specific acceptors only. In vivo tests are suited for studies of cholesterol efflux and RCT at the level of the organism. They include injection of tracer-loaded macrophages, a method suitable at present for animal models only, and recently invented modification of whole body tracer kinetics with multicompartment modeling that is capable to determine cholesterol efflux from macrophages.
Conclusion: Despite the decisive role of in vitro assays in our understanding of cholesterol efflux mechanism, the in vivo assays are highly desired to study cholesterol efflux in atherosclerotic lesions and RCT in whole body.

Current Tools and Methods in Molecular Dynamics (MD) Simulations for Drug Design by Maricarmen Hernández-Rodríguez, Martha C. Rosales-Hernández, Jessica E. Mendieta-Wejebe, Marlet Martínez-Archundia, José Correa Basurto (3909-3924).
Molecular Dynamics (MD) simulations is a computational method that employs Newton's laws to evaluate the motions of water, ions, small molecules, and macromolecules or more complex systems, for example, whole viruses, to reproduce the behavior of the biological environment, including water molecules and lipid membranes. Specifically, structural motions, such as those that are dependent of the temperature and solute/ solvent are very important to study the recognition pattern of ligandprotein or protein-protein complexes, in that sense, MD simulations are very useful because these motions can be modeled using this methodology. Furthermore, MD simulations for drug design provide insights into the structural cavities required to design novel structures with higher affinity to the target. Also, the employment of MD simulations to drug design can help to refine the three-dimensional (3D) structure of targets in order to obtain a better sampling of the binding poses and more reliable affinity values with better structural advantages, because they incorporate some biological conditions that include structural motions compared to traditional docking procedures.
This work analyzes the concepts and applicability of MD simulations for drug design because molecular structural motions are considered, and these help to identify hot spots, decipher structural details in the reported protein sites, as well as to eliminate sites that could be structural artifacts which could be originated from the structural characterization conditions from MD. Moreover, better free energy values for protein ligand recognition can also be obtained, and these can be validated under experimental procedures due to the robustness of the MD simulation methods.

The Potential of Flavonolignans in Prostate Cancer Management by Bao Vue, Qiao-Hong Chen (3925-3950).
Background: The generic name “flavonolignan” was created in 1968 for a relatively small class of naturally occurring hybrid molecules biogenetically originated from ubiquitous flavonoids and lignans (phenylpropanoids). The first group of flavonolignans was extracted from Silybum marianum that has long been used for hepatoprotection. Recently, the medicinal merit of flavonolignans has been extended to the prostate cancer management.
Methods: Systematic interpretation and summarization of the relevant literature.
Results: Over forty naturally occurring flavonolignans have so far been obtained from various plants. Certain flavonolignans have been demonstrated by in vitro cell-based and in vivo animal-based experiments, and human clinical studies i) to possess effective chemopreventive function against various tumor promoters; ii) to show the anti-angiogenic efficacy; iii) to have potential in treating prostate cancer; iv) to sensitize prostate tumors to chemotherapeutic agents through down-regulation of P-glycoprotein and other mechanisms; and v) to be used by prostate cancer patients to protect or treat the hepatotoxicity caused by several chemotherapies. Certain flavonolignans can synergize with well-established chemotherapeutic agents for prostate cancer.
Conclusion: This review provides a systematic and in-depth overview of the promise and potential of flavonolignans in prostate cancer management, which covers their chemopreventive effect, chemotherapeutic treatment, mechanisms of actions, synthetic derivatives, structure-activity relationships, and the difference in inhibiting prostate cancer cell proliferation between certain flavonoligans and their respective flavonoid counterpart. This summarization aims to provide valuable insights into further and rational development of flavonolignans for prostate cancer management by interpreting the data reported in the literature.

The Role of NF-κB Inhibitors in Cell Response to Radiation by Sajjad Molavi Pordanjani, Seyed Jalal Hosseinimehr (3951-3963).
It is well documented that ionizing radiation (IR) activates the transcription factor (NF-κB) which is a trigger for resistance cancer cells to treatment. It is involved in activation of pro-survival signaling pathways and resulting in cancer development and progression. In unstimulated condition, NF-κB is sequestered in cytoplasm but after the cell exposure to IR, proteasomal degradation of I?B flowing phosphorylation via IKK, leads to aberrantly NF-κB activation and nuclear translocation. Therefore, interruption in I?B degradation, proteasome action, IKK phosphorylation and NF-κB nuclear translocation provide robust strategies for inhibiting adverse effect of IR induced NF-κB. In spite of uncompleted elucidation of NF-κB molecular mechanisms, different NF-κB inhibitors have been used in order to inhibiting the IR induced NF-κB. The aim of this review is to highlight the role of IR induced-NF-κB inhibitors such as MG132, bortezomib, curcumin, DHMEQ, naringin, sorafenib, genistein and parthenolide in suppression of IR induced NF-κB adverse effects. Moreover, their chemical, structural characteristics and molecular mechanisms will be discussed.