Showing papers in "Medicinal Research Reviews in 2016"

The Keap1-Nrf2-ARE Pathway As a Potential Preventive and Therapeutic Target: An Update.

Abstract: The Keap1-Nrf2-ARE ((Kelch-like ECH-Associating protein 1) nuclear factor erythroid 2 related factor 2-antioxidant response element) pathway is one of the most important defense mechanisms against oxidative and/or electrophilic stresses, and it is closely associated with inflammatory diseases, including cancer, neurodegenerative diseases, cardiovascular diseases, and aging. In recent years, progress has been made in strategies aimed at modulating the Keap1-Nrf2-ARE pathway. The Nrf2 activator DMF (Dimethylfumarates) has been approved by the FDA as a new first-line oral drug to treat patients with relapsing forms of multiple sclerosis, while a phase 3 study of another promising candidate, CDDO-Me, was terminated for safety reasons. Directly inhibiting Keap1-Nrf2 protein-protein interactions as a novel Nrf2-modulating strategy has many advantages over using electrophilic Nrf2 activators. The development of Keap1-Nrf2 protein-protein interaction inhibitors has become a topic of intense research, and potent inhibitors of this target have been identified. In addition, inhibiting Nrf2 activity has attracted an increasing amount of attention because it may provide an alternative cancer therapy. This review summarizes the molecular mechanisms and biological functions of the Keap1-Nrf2-ARE system. The main focus of this review is on recent progress in studies of agents that target the Keap1-Nrf2-ARE pathway and the therapeutic applications of such agents.

Lipopeptides from Bacillus and Paenibacillus spp.: A Gold Mine of Antibiotic Candidates

Abstract: The emergence of multidrug-resistant bacteria has placed a strain on health care systems and highlighted the need for new classes of antibiotics. Bacterial lipopeptides are secondary metabolites, generally produced by nonribosomal peptide synthetases that often exhibit broad-spectrum antimicrobial activity. Only two new structural types of antibiotics have entered the market in the last 40 years, linezolid and the bacterial lipopeptide daptomycin. A wide variety of bacteria produce lipopeptides, however Bacillus and Paenibacillus spp. in particular have yielded several potent antimicrobial lipopeptides. Many of the lipopeptides produced by these bacteria have been known for decades and represent a potential gold mine of antibiotic candidates. This list includes the polymyxins, octapeptins, polypeptins, iturins, surfactins, fengycins, fusaricidins, and tridecaptins, as well as some novel examples, including the kurstakins. These lipopeptides have a wide variety of activities, ranging from antibacterial and antifungal, to anticancer and antiviral. This review presents a reasonably comprehensive list of each class of lipopeptide and their known homologues. Emphasis has been placed on their antimicrobial activities, as well other potential applications for this interesting class of substances.

Anthraquinones As Pharmacological Tools and Drugs

Abstract: Anthraquinones (9,10-dioxoanthracenes) constitute an important class of natural and synthetic compounds with a wide range of applications. Besides their utilization as colorants, anthraquinone derivatives have been used since centuries for medical applications, for example, as laxatives and antimicrobial and antiinflammatory agents. Current therapeutic indications include constipation, arthritis, multiple sclerosis, and cancer. Moreover, biologically active anthraquinones derived from Reactive Blue 2 have been utilized as valuable tool compounds for biochemical and pharmacological studies. They may serve as lead structures for the development of future drugs. However, the presence of the quinone moiety in the structure of anthraquinones raises safety concerns, and anthraquinone laxatives have therefore been under critical reassessment. This review article provides an overview of the chemistry, biology, and toxicology of anthraquinones focusing on their application as drugs.

Aurora-A Kinase: A Potent Oncogene and Target for Cancer Therapy

Abstract: The Aurora kinase family is comprised of three serine/threonine kinases, Aurora-A, Aurora-B, and Aurora-C. Among these, Aurora-A and Aurora-B play central roles in mitosis, whereas Aurora-C executes unique roles in meiosis. Overexpression or gene amplification of Aurora kinases has been reported in a broad range of human malignancies, pointing to their role as potent oncogenes in tumorigenesis. Aurora kinases therefore represent promising targets for anticancer therapeutics. A number of Aurora kinase inhibitors (AKIs) have been generated; some of which are currently undergoing clinical evaluation. Recent studies have unveiled novel unexpected functions of Aurora kinases during cancer development and the mechanisms underlying the anticancer actions of AKIs. In this review, we discuss the most recent advances in Aurora-A kinase research and targeted cancer therapy, focusing on the oncogenic roles and signaling pathways of Aurora-A kinases in promoting tumorigenesis, the recent preclinical and clinical AKI data, and potential alternative routes for Aurora-A kinase inhibition.

Direct Activation of Bax Protein for Cancer Therapy

Abstract: Bax, a central cell death regulator, is an indispensable gateway to mitochondrial dysfunction and a major proapoptotic member of the B-cell lymphoma 2 (Bcl-2) family proteins that control apoptosis in normal and cancer cells. Dysfunction of apoptosis renders the cancer cell resistant to treatment as well as promotes tumorigenesis. Bax activation induces mitochondrial membrane permeabilization, thereby leading to the release of apoptotic factor cytochrome c and consequently cancer cell death. A number of drugs in clinical use are known to indirectly activate Bax. Intriguingly, recent efforts demonstrate that Bax can serve as a promising direct target for small-molecule drug discovery. Several direct Bax activators have been identified to hold promise for cancer therapy with the advantages of specificity and the potential of overcoming chemo- and radioresistance. Further investigation of this new class of drug candidates will be needed to advance them into the clinic as a novel means to treat cancer.

Targeting Programmed Cell Death Using Small-Molecule Compounds to Improve Potential Cancer Therapy.

Abstract: Evasion of cell death is one of the hallmarks of cancer cells, beginning with long-established apoptosis and extending to other new forms of cell death. An elaboration of cell death pathways thus will contribute to a better understanding of cancer pathogenesis and therapeutics. With the recent substantial biochemical and genetic explorations of cell death subroutines, their classification has switched from primarily morphological to more molecular definitions. According to their measurable biochemical features and intricate mechanisms, cell death subroutines can be divided into apoptosis, autophagic cell death, mitotic catastrophe, necroptosis, parthanatos, ferroptosis, pyroptosis, pyronecrosis, anoikis, cornification, entosis, and NETosis. Supportive evidence has gradually revealed the prime molecular mechanisms of each subroutine and thus providing series of possible targets in cancer therapy, while the intricate relationships between different cell death subroutines still remain to be clarified. Over the past decades, cancer drug discovery has significantly benefited from the use of small-molecule compounds to target classical modalities of cell death such as apoptosis, while newly identified cell death subroutines has also emerging their potential for cancer drug discovery in recent years. In this review, we comprehensively focus on summarizing 12 cell death subroutines and discussing their corresponding small-molecule compounds in potential cancer therapy. Together, these inspiring findings may provide more evidence to fill in the gaps between cell death subroutines and small-molecule compounds to better develop novel cancer therapeutic strategies.

The Influenza Virus Polymerase Complex: An Update on Its Structure, Functions, and Significance for Antiviral Drug Design

Abstract: Influenza viruses cause seasonal epidemics and pandemic outbreaks associated with significant morbidity and mortality, and a huge cost. Since resistance to the existing anti-influenza drugs is rising, innovative inhibitors with a different mode of action are urgently needed. The influenza polymerase complex is widely recognized as a key drug target, given its critical role in virus replication and high degree of conservation among influenza A (of human or zoonotic origin) and B viruses. We here review the major progress that has been made in recent years in unravelling the structure and functions of this protein complex, enabling structure-aided drug design toward the core regions of the PA endonuclease, PB1 polymerase, or cap-binding PB2 subunit. Alternatively, inhibitors may target a protein-protein interaction site, a cellular factor involved in viral RNA synthesis, the viral RNA itself, or the nucleoprotein component of the viral ribonucleoprotein. The latest advances made for these diverse pharmacological targets have yielded agents in advanced (i.e., favipiravir and VX-787) or early clinical testing, besides several experimental inhibitors in various stages of development, which are all covered here.

Mitoxantrone, More than Just Another Topoisomerase II Poison.

Abstract: Mitoxantrone is a synthetic anthracenedione originally developed to improve the therapeutic profile of the anthracyclines and is commonly applied in the treatment of breast and prostate cancers, lymphomas, and leukemias. A comprehensive overview of the drug's molecular, biochemical, and cellular pharmacology is presented here, beginning with the cardiotoxic nature of its predecessor doxorubicin and how these properties shaped the pharmacology of mitoxantrone itself. Although mitoxantrone is firmly established as a DNA topoisomerase II poison within mammalian cells, it is now clear that the drug interacts with a much broader range of biological macromolecules both covalently and noncovalently. Here, we consider each of these interactions in the context of their wider biological relevance to cancer therapy and highlight how they may be exploited to further enhance the therapeutic value of mitoxantrone. In doing so, it is now clear that mitoxantrone is more than just another topoisomerase II poison.

Strategies for the Optimization of Natural Leads to Anticancer Drugs or Drug Candidates

Abstract: Natural products have made significant contribution to cancer chemotherapy over the past decades and remain an indispensable source of molecular and mechanistic diversity for anticancer drug discovery. More often than not, natural products may serve as leads for further drug development rather than as effective anticancer drugs by themselves. Generally, optimization of natural leads into anticancer drugs or drug candidates should not only address drug efficacy, but also improve absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles and chemical accessibility associated with the natural leads. Optimization strategies involve direct chemical manipulation of functional groups, structure-activity relationship directed optimization and pharmacophore-oriented molecular design based on the natural templates. Both fundamental medicinal chemistry principles (e.g., bioisosterism) and state-of-the-art computer-aided drug design techniques (e.g., structure-based design) can be applied to facilitate optimization efforts. In this review, the strategies to optimize natural leads to anticancer drugs or drug candidates are illustrated with examples and described according to their purposes. Furthermore, successful case studies on lead optimization of bioactive compounds performed in the Natural Products Research Laboratories at UNC are highlighted.

Small Molecules for Active Targeting in Cancer.

Abstract: For the purpose of this review, active targeting in cancer research encompasses strategies wherein a ligand for a cell surface receptor expressed on tumor cells is used to deliver a cytotoxic or imaging cargo. This area of research is more than two decades old, but in those 20 and more years, how many receptors have been studied extensively? What kinds of the ligands are used for active targeting? Are they mostly naturally occurring molecules such as folic acid, or synthetic substances developed in campaigns for medicinal chemistry efforts? This review outlines the most important receptor or ligand combinations that have been used in active targeting to answer these questions, and therefore to address the most important one of all: is research in active targeting affording diminishing returns, or is this an area for which the potential far exceeds progress made so far?

The Role of Cathepsin D in the Pathogenesis of Human Neurodegenerative Disorders.

Abstract: In familial neurodegenerative disorders, protein aggregates form continuously because of genetic mutations that drive the synthesis of truncated or unfolded proteins. The oxidative stress imposed by neurotransmitters and environmental neurotoxins constitutes an additional threat to the folding of the proteins and the integrity of organelle membranes in neurons. Failure in degrading such altered materials compromises the function of neurons and eventually leads to neurodegeneration. The lysosomal proteolytic enzyme Cathepsin D is the only aspartic-type protease ubiquitously expressed in all the cells of the human body, and it is expressed at high level in the brain. In general, cathepsin D mediated proteolysis is essential to neuronal cell homeostasis through the degradation of unfolded or oxidized protein aggregates delivered to lysosomes via autophagy or endocytosis. More specifically, many altered neuronal proteins that hallmark neurodegenerative diseases (e.g., the amyloid precursor, α-synuclein, and huntingtin) are physiologic substrates of cathepsin D and would abnormally accumulate if not efficiently degraded by this enzyme. Furthermore, experimental evidence indicates that cathepsin D activity is linked to the metabolism of cholesterol and of glycosaminoglycans, which accounts for its involvement in neuronal plasticity. This review focuses on the unique role of cathepsin D mediated proteolysis in the pathogenesis of human neurodegenerative diseases.

Radioprotective Agents: Strategies and Translational Advances.

Abstract: Radioprotectors are agents required to protect biological system exposed to radiation, either naturally or through radiation leakage, and they protect normal cells from radiation injury in cancer patients undergoing radiotherapy. It is imperative to study radioprotectors and their mechanism of action comprehensively, looking at their potential therapeutic applications. This review intimately chronicles the rich intellectual, pharmacological story of natural and synthetic radioprotectors. A continuous effort is going on by researchers to develop clinically promising radioprotective agents. In this article, for the first time we have discussed the impact of radioprotectors on different signaling pathways in cells, which will create a basis for scientific community working in this area to develop novel molecules with better therapeutic efficacy. The bright future of exceptionally noncytotoxic derivatives of bisbenzimidazoles is also described as radiomodulators. Amifostine, an effective radioprotectant, has been approved by the FDA for limited clinical use. However, due to its adverse side effects, it is not routinely used clinically. Recently, CBLB502 and several analog of a peptide are under clinical trial and showed high success against radiotherapy in cancer. This article reviews the different types of radioprotective agents with emphasis on the strategies for the development of novel radioprotectors for drug development. In addition, direction for future strategies relevant to the development of radioprotectors is also addressed.

Development and Applications of Lectins as Biological Tools in Biomedical Research.

Abstract: As a new and burgeoning area following genomics and proteomics, glycomics has become a hot issue due to its pivotal roles in many physiological and pathological processes. Glycans are much more complicated than genes or proteins since glycans are highly branched and dynamic. Antibodies and lectins are the two major molecular tools applied for glycan profiling. Though the study of antibodies and lectins started at almost the same time in 1880s, lectins gained much less attention than the antibodies until recent decades when the importance and difficulties of glycomics were realized. The present review summarizes the discovery history of lectins and their biological functions with a special emphasis on their various applications as biological tools. Both older techniques that had been developed in the last century and new technologies developed in recent years, especially lectin microarrays and lectin-based biosensors, are included in this account.

Targeting MIF in Cancer: Therapeutic Strategies, Current Developments, and Future Opportunities

Abstract: Strong evidence has been presented linking chronic inflammation to the onset and pathogenesis of cancer. The multifunctional pro-inflammatory protein macrophage migration inhibitory factor (MIF) occupies a central role in the inflammatory pathway and has been implicated in the tumorigenesis, angiogenesis, and metastasis of many cancer phenotypes. This review highlights the current state of the art, which presents MIF, and the second member of the MIF structural superfamily, D-DT (MIF2), as significant mediators in the inflammatory-cancer axis. Although the mechanism by which MIF asserts its biological activity has yet to be fully understood, it has become clear in recent years that for certain phenotypes of cancer, MIF represents a valid therapeutic target. Current research efforts have focused on small molecule approaches that target MIF's unique tautomerase active site and neutralization of MIF with anti-MIF antibodies. These approaches have yielded promising results in a number of preclinical murine cancer models and have helped to increase our understanding of MIF biological activity. More recently, MIF's involvement in a number of key protein-protein interactions, such as with CD74 and HSP90, has been highlighted and provides a novel platform for the development of anti-MIF chemotherapeutic strategies in the future.

Therapeutic Potential of Steroidal Alkaloids in Cancer and Other Diseases.

Abstract: Steroidal alkaloids are a class of secondary metabolites isolated from plants, amphibians, and marine invertebrates. Evidence accumulated in the recent two decades demonstrates that steroidal alkaloids have a wide range of bioactivities including anticancer, antimicrobial, anti-inflammatory, antinociceptive, etc., suggesting their great potential for application. It is therefore necessary to comprehensively summarize the bioactivities, especially anticancer activities and mechanisms of steroidal alkaloids. Here we systematically highlight the anticancer profiles both in vitro and in vivo of steroidal alkaloids such as dendrogenin, solanidine, solasodine, tomatidine, cyclopamine, and their derivatives. Furthermore, other bioactivities of steroidal alkaloids are also discussed. The integrated molecular mechanisms in this review can increase our understanding on the utilization of steroidal alkaloids and contribute to the development of new drug candidates. Although the therapeutic potentials of steroidal alkaloids look promising in the preclinical and clinical studies, further pharmacokinetic and clinical studies are mandated to define their efficacy and safety in cancer and other diseases.

Natural Product Inspired N-Terminal Hsp90 Inhibitors: From Bench to Bedside?

Abstract: The 90 kDa heat shock proteins (Hsp90) are responsible for the conformational maturation of nascent polypeptides and the rematuration of denatured proteins. Proteins dependent upon Hsp90 are associated with all six hallmarks of cancer. Upon Hsp90 inhibition, protein substrates are degraded via the ubiquitin-proteasome pathway. Consequentially, inhibition of Hsp90 offers a therapeutic opportunity for the treatment of cancer. Natural product inhibitors of Hsp90 have been identified in vitro, which have served as leads for the development of more efficacious inhibitors and analogs that have entered clinical trials. This review highlights the development of natural product analogs, as well as the development of clinically important inhibitors that arose from natural products.

Spotlight on Volasertib: Preclinical and Clinical Evaluation of a Promising Plk1 Inhibitor.

Abstract: Considering the important side effects of conventional microtubule targeting agents, more and more research focuses on regulatory proteins for the development of mitosis-specific agents. Polo-like kinase 1 (Plk1), a master regulator of several cell cycle events, has arisen as an intriguing target in this research field. The observed overexpression of Plk1 in a broad range of human malignancies has given rise to the development of several potent and specific small molecule inhibitors targeting the kinase. In this review, we focus on volasertib (BI6727), the lead agent in category of Plk1 inhibitors at the moment. Numerous preclinical experiments have demonstrated that BI6727 is highly active across a variety of carcinoma cell lines, and the inhibitor has been reported to induce tumor regression in several xenograft models. Moreover, volasertib has shown clinical efficacy in multiple tumor types. As a result, Food and Drug Administration (FDA) has recently awarded volasertib the Breakthrough Therapy status after significant benefit was observed in acute myeloid leukemia (AML) patients treated with the Plk1 inhibitor. Here, we discuss both preclinical and clinical data available for volasertib administered as monotherapy or in combination with other anticancer therapies in a broad range of tumor types.

Medicinal Chemistry Strategies to Disrupt the p53-MDM2/MDMX Interaction.

Abstract: The growth inhibitory activity of p53 tumor suppressor is tightly regulated by interaction with two negative regulatory proteins, murine double minute 2 (MDM2) and X (MDMX), which are overexpressed in about half of all human tumors. The elucidation of crystallographic structures of MDM2/MDMX complexes with p53 has been pivotal for the identification of several classes of inhibitors of the p53-MDM2/MDMX interaction. The present review provides in silico strategies and screening approaches used in drug discovery as well as an overview of the most relevant classes of small-molecule inhibitors of the p53-MDM2/MDMX interaction, their progress in pipeline, and highlights particularities of each class of inhibitors. Most of the progress made with high-throughput screening has led to the development of inhibitors belonging to the cis-imidazoline, piperidinone, and spiro-oxindole series. However, novel potent and selective classes of inhibitors of the p53-MDM2 interaction with promising antitumor activity are emerging. Even with the discovery of the 3D structure of complex p53-MDMX, only two small molecules were reported as selective p53-MDMX antagonists, WK298 and SJ-172550. Dual inhibition of the p53-MDM2/MDMX interaction has shown to be an alternative approach since it results in full activation of the p53-dependent pathway. The knowledge of structural requirements crucial to the development of small-molecule inhibitors of the p53-MDMs interactions has enabled the identification of novel antitumor agents with improved in vivo efficacy.

Fibroblast Growth Factor 21 As an Emerging Therapeutic Target for Type 2 Diabetes Mellitus

Abstract: Fibroblast growth factor (FGF) 21 is a distinctive member of the FGF family that functions as an endocrine factor. It is expressed predominantly in the liver, but is also found in adipose tissue and the pancreas. Pharmacological studies have shown that FGF21 normalizes glucose and lipid homeostasis, thereby preventing the development of metabolic disorders, such as obesity and diabetes. Despite growing evidence for the therapeutic potential of FGF21, paradoxical increases of FGF21 in different disease conditions point to the existence of FGF21 resistance. In this review, we give a critical appraisal of recent advances in the understanding of the regulation of FGF21 production under various physiological conditions, its antidiabetic actions, and the clinical implications. We also discuss recent preclinical and clinical trials using engineered FGF21 analogs in the management of diabetes, as well as the potential side effects of FGF21 therapy.

Stem Cell-Based Therapies for Ischemic Stroke: Preclinical Results and the Potential of Imaging-Assisted Evaluation of Donor Cell Fate and Mechanisms of Brain Regeneration.

Abstract: Stroke is the second most common cause of death and is a major cause of permanent disability. Given the current demographic trend of an ageing population and associated increased risk, the prevalence of and socioeconomic burden caused by stroke will continue to rise. Current therapies are unable to sufficiently ameliorate the disease outcome and are not applicable to all patients. Therefore, strategies such as cell-based therapies with mesenchymal stem cell (MSC) or induced pluripotent stem cell (iPSC) pave the way for new treatment options for stroke. These cells showed great preclinical promise despite the fact that the precise mechanism of action and the optimal administration route are unknown. To gain dynamic insights into the underlying repair processes after stem cell engraftment, noninvasive imaging modalities were developed to provide detailed spatial and functional information on the donor cell fate and host microenvironment. This review will focus on MSCs and iPSCs as types of widely used stem cell sources in current (bio)medical research and compare their efficacy and potential to ameliorate the disease outcome in animal stroke models. In addition, novel noninvasive imaging strategies allowing temporospatial in vivo tracking of transplanted cells and coinciding evaluation of neuronal repair following stroke will be discussed.

miRNA-Regulated Key Components of Cytokine Signaling Pathways and Inflammation in Rheumatoid Arthritis.

Abstract: Rheumatoid arthritis (RA) is an inflammatory disease that primarily affects joints. This autoimmune disease pathogenesis is related to cytokine signaling. In this review, we have described the existence of various microRNAs (miRNAs) involved in regulation of major protein cascades of cytokine signaling associated with RA. Moreover, we have tried to portray the role of various miRNAs in different cytokines such as TNF-α, IL-1, IL-6, IL-10, IL-17, IL-18, IL-21, and granulocyte macrophage colony-stimulating factor (GMCSF). Along with this, we have also discussed the miRNA regulation in T cells and synovial tissue. From the analyzed data, we suggest that miR-146a and miR-155 might be the potential therapeutic target for treating RA. The insight illustrated in this review will offer a better understanding of the role of miRNA in cytokine signaling pathways and inflammation during RA and could project them as diagnostic or therapeutic agents in near future.

Microtubule-Binding Proteins as Promising Biomarkers of Paclitaxel Sensitivity in Cancer Chemotherapy

Abstract: Microtubules, tirelessly animated and highly dynamic structures, are vital for most cellular processes and their intricacies are still being revealed even after a century since their discovery. The importance of microtubules as chemotherapeutic targets cannot be overstated, and their clinical role is unlikely to abate in the near future. Indeed, improved understanding of microtubule biology could herald a new epoch of anticancer drug design by permitting fine-tuning of microtubule-targeting agents, the clinical utility of which is presently often limited by primary or acquired resistance. Paclitaxel, one such agent belonging to the taxane family, has proven a resoundingly successful treatment for many cancer patients; however, for too many others with paclitaxel-refractory tumors, the drug has offered nothing but side effects. Accumulating evidence suggests that microtubule-binding proteins (MBPs) can regulate paclitaxel sensitivity in a wide range of cancer types. Improved understanding of how these proteins can be assayed to predict treatment responses or manipulated pharmacologically to improve clinical outcomes could transform modern chemotherapy and is urgently awaited.

COX-1 Inhibitors: Beyond Structure Toward Therapy.

Abstract: Biosynthesis of prostaglandins from arachidonic acid (AA) is catalyzed by cyclooxygenase (COX), which exists as COX-1 and COX-2. AA is in turn released from the cell membrane upon neopathological stimuli. COX inhibitors interfere in this catalytic and disease onset process. The recent prominent discovery involvements of COX-1 are mainly in cancer and inflammation. Five classes of COX-1 inhibitors are known up to now and this classification is based on chemical features of both synthetic compounds and substances from natural sources. Physicochemical interactions identification between such molecules and COX-1 active site was achieved through X-ray, mutagenesis experiments, specific assays and docking investigations, as well as through a pharmacometric predictive model building. All these insights allowed the design of new highly selective COX-1 inhibitors to be tested into those disease models in which COX-1 is involved. Particularly, COX-1 is expressed at high levels in the early to advanced stages of human epithelial ovarian cancer, and it also seems to play a pivotal role in cancer progression. The refinement of COX-1 selective inhibitor structure has progressed to the stage that some of the inhibitors described in this review could be considered as promising active principle ingredients of drugs and hence part of specific therapeutic protocols. This review aims to outline achievements, in the last 5 years, dealing with the identification of highly selective synthetic and from plant extracts COX-1 inhibitors and their theranostic use in neuroinflammation and ovarian cancer. Their gastrotoxic effect is also discussed.

Prospects for Creation of Cardioprotective and Antiarrhythmic Drugs Based on Opioid Receptor Agonists

Abstract: It has now been demonstrated that the μ, δ1 , δ2 , and κ1 opioid receptor (OR) agonists represent the most promising group of opioids for the creation of drugs enhancing cardiac tolerance to the detrimental effects of ischemia/reperfusion (I/R). Opioids are able to prevent necrosis and apoptosis of cardiomyocytes during I/R and improve cardiac contractility in the reperfusion period. The OR agonists exert an infarct-reducing effect with prophylactic administration and prevent reperfusion-induced cardiomyocyte death when ischemic injury of heart has already occurred; that is, opioids can mimic preconditioning and postconditioning phenomena. Furthermore, opioids are also effective in preventing ischemia-induced arrhythmias.

Mechanisms for the Specific Properties of γ-Hydroxybutyrate in Brain

Abstract: γ-Hydroxybutyrate (GHB) is both a natural brain compound with neuromodulatory properties at central GABAergic synapses (micromolar concentration range) and also a drug (Xyrem(R) ) clinically used for the treatment of various neurological symptoms (millimolar dose range). However, this drug has abuse potential and can be addictive for some patients. Here, we review the basic mechanistic role of endogenous GHB in brain as well as the properties and mechanisms of action for therapeutic clinical doses of exogenous GHB. Several hypotheses are discussed with a preference for a molecular mechanism that conciliates most of the findings available. This conciliatory model may help for the design of GHB-like drugs active at lower doses and devoid of major side effects.

Integrin Ligands with α/β-Hybrid Peptide Structure: Design, Bioactivity, and Conformational Aspects.

Abstract: Integrins are cell surface receptors for proteins of the extracellular matrix and plasma-borne adhesive proteins. Their involvement in diverse pathologies prompted medicinal chemists to develop small-molecule antagonists, and very often such molecules are peptidomimetics designed on the basis of the short native ligand-integrin recognition motifs. This review deals with peptidomimetic integrin ligands composed of α- and β-amino acids. The roles exerted by the β-amino acid components are discussed in terms of biological activity, bioavailability, and selectivity. Special attention is paid to the synthetic accessibility and efficiency of conformationally constrained heterocyclic scaffolds incorporating α/β-amino acid span.

Cylindromatosis-A Protective Molecule against Liver Diseases.

Abstract: Cylindromatosis (CYLD) is a deubiquitination enzyme involved in the regulation of different cellular processes including inflammation, fibrosis, and cancer. The function of CYLD is via deubiquitination of specific substrates in different signaling pathways including NF-κB, Notch, and JNK. CYLD contributes to hepatic homeostasis and restoration upon liver injury. Mutation or disruption of the activity of CYLD in animals aggravates acute as well as chronic liver injury and promotes development and progression of hepatocellular cancer. This is mediated by a shift of the balance toward pro-inflammatory, pro-fibrogenic, and pro-oncogenic pathways. In this review, we will explain the liver-associated signaling pathways that CYLD regulates in hepatocytes and nonparenchymal liver cells under physiological and pathological conditions. We will also describe the most recent findings concerning CYLD-mediated downstream signaling in the liver in situations such as injury, infection, inflammation, and cancer. Furthermore, we will discuss the potential of novel diagnostic tools and treatment strategies utilizing CYLD and its target genes.

Marinopyrroles: Unique Drug Discoveries Based on Marine Natural Products.

Abstract: Natural products provide a successful supply of new chemical entities (NCEs) for drug discovery to treat human diseases. Approximately half of the NCEs are based on natural products and their derivatives. Notably, marine natural products, a largely untapped resource, have contributed to drug discovery and development with eight drugs or cosmeceuticals approved by the U.S. Food and Drug Administration and European Medicines Agency, and ten candidates undergoing clinical trials. Collaborative efforts from drug developers, biologists, organic, medicinal, and natural product chemists have elevated drug discoveries to new levels. These efforts are expected to continue to improve the efficiency of natural product-based drugs. Marinopyrroles are examined here as a case study for potential anticancer and antibiotic agents.

Short Anabolic Peptides for Bone Growth.

Abstract: Loss of bone occurs in the age-related skeletal disorder, osteoporosis, leading to bone fragility and increased incidence of fractures, which are associated with enormous costs and substantial morbidity and mortality. Recent data indicate that osteoporotic fractures are more common than other diseases, which usually attract public attention (e.g., heart attack and breast cancer). The prevention and treatment of this skeletal disorder are therefore of paramount importance. Majority of osteoporosis medications restore skeletal balance by reducing osteoclastic activity, thereby reducing bone resorption. These agents, however, do not regenerate damaged bone tissue, leaving limited options for patients once bone loss has occurred. Recently, attention has turned to bone-anabolic agents. Such agents have the ability to increase bone mass and strength, potentially reversing structural damage. To date, only one bone-anabolic drug is available in the market. The discovery of more novel, cost-effective bone anabolic agents is therefore a priority to treat those suffering from this disabling condition. Short peptides offer an important alternative for the development of novel bone-anabolic agents given their high target binding specificity, which translates into potent activity with limited side effects. This review summarizes attempts in the identification of bone-anabolic peptides, and their development for promoting bone growth.

Role of Ets Proteins in Development, Differentiation, and Function of T-Cell Subsets

Abstract: Through positive selection, double-positive cells in the thymus differentiate into CD4(+) or CD8(+) T single-positive cells that subsequently develop into different types of effective T cells, such as T-helper and cytotoxic T lymphocyte cells, that play distinctive roles in the immune system. Development, differentiation, and function of thymocytes and CD4(+) and CD8(+) T cells are controlled by a multitude of secreted and intracellular factors, ranging from cytokine signaling modules to transcription factors and epigenetic modifiers. Members of the E26 transformation specific (Ets) family of transcription factors, in particular, are potent regulators of these CD4(+) or CD8(+) T-cell processes. In this review, we summarize and discuss the functions and underlying mechanisms of the Ets family members that have been characterized as involved in these processes. Ongoing research of these factors is expected to identify practical applications for the Ets family members as novel therapeutic targets for inflammation-related diseases.