Current Drug Targets - Volume 18, Issue 9, 2017

Background: Endometriosis remains a challenging condition for clinicians to treat. To improve our results, we have to develop new treatment strategies based on pathophysiological mechanisms targeting the etiologic and pathogenic processes involved. Objectives: Revise new inflammatory pathogenic mechanisms involved in endometriosis, namely inflammasome. Method: Literature review for the updating of data to give new clues for different options of treatments. Results: Inflammasome has been described as a multiprotein complex and is considered a key regulator of the innate and adaptive host response that surveys the cytosol and other compartments into the cell. It is involved in the immediate detection and responds to the presence of danger- and pathogen-associated molecular patterns named DAMPs and PAMPs respectively, and has been described in several cells, mainly on immune cells of the myeloid lineage and epithelial cells in tissues with mucosal surfaces. Four inflammasome are formed in a stimulus-dependent manner of distinct composition. They are the Noll Like Receptors (NLR) proteins Nlrp1b, Nlrp3, Nlrc4, and Nlrp6, as well as the absent in melanoma 2 (AIM2). They activate the production of IL-1β and IL-18 that induce a host response such as pyroptosis, a proinflammatory cell death and the secretion of leaderless cytokines and growth factors. Inflammasome is linked to atherosclerosis, periodic fever syndromes, vitiligo, Crohn’s disease, gout, asbestosis, silicosis, Alzheimer’s disease and periodontitis. Endometriosis has been related with IL-1β and Another NLR, Nlrp7, was correlated with myometrial invasion in human endometrial cancer tissue. Conclusions: These new clues regarding the pathogenic mechanisms involving the inflammasome may be crucial in the future development for endometriosis therapy.

Background: An intricate interplay between innate and adaptive immune cells is crucial for an effective immune response during disease, infection and vaccination. This interplay is mainly performed by dendritic cells (DCs), which are professional antigen presenting cells with unparalleled capacity to translate innate to adaptive immunity. They effectively recognize and uptake antigens, migrate to lymphoid tissues, and activate naïve T-cells. Indeed, DCs have numerous germline encoded pattern recognition receptors (PRR) that recognize conserved pathogen associated molecular patterns (PAMPs) or danger associated molecular patterns (DAMPs). While some PRRs like Toll-like receptors (TLRs) recognize PAMPs and DAMPs at the cell surface and in endosomal/lysosomal compartments, others, such as NOD-like receptors (NLRs), act as cytosolic sensors. NLRs activation through recognition of PAMPs and DAMPs leads to the assembly of signaling multimeric protein complexes named inflammasomes. Inflammasomes are important regulators of caspase 1, the enzyme responsible for the proteolytically cleavage of precursors’ pro-IL-1β and pro-IL-18 into their active form. Objective: To unveil how inflammasomes are related to maturation, migration, antigen presenting function and DCs ability to fine tune adaptive immune responses. Conclusion: Several studies show that in danger/infectious scenarios NLR and TLR synergize to expand DCs maturation, migration, antigen presenting function and adaptive immune system activation. However, in the absence of a danger scenario, and without TLR engagement, inflammasome activation stimulates an immunosuppressive profile on DCs. Overall, it is clear from literature that activation of the inflammasome in DCs should not be viewed in isolation of inflammasome involvement in multiple inflammatory and immune diseases, this information is but rather considering its interconnections with the various PPRdriven pathways. Due to the increasing evidencesof utmost importance since precise inflammasome pharmacological targeting could lead to considerable clinical utility through fine-tuned targeted therapies.

Background: The intracellular multiprotein complex termed the inflammasome functions as a platform of pro-inflammatory cytokine production such as IL-1β and IL-18. Under certain conditions, however, the inflammasome produces non-canonical effects such as induction of cell death, pyroptosis and cell metabolism alterations. Objective: In mammalian cells, several types of inflammasomes were identified, but the most widely studied one is the inflammasome containing NOD-like receptor with pyrin domain 3 (NLRP3), which has recently been reported as a central pathogenic mechanism of chronic degenerative diseases. Many activators or risk factors exert their actions through the activation of the NLRP3 inflammasome to produce a variety of functional changes in different cells including inflammatory, metabolic or survival responses. Several molecular signaling pathways are shown to mediate the activation of the NLRP3 inflammasome, and they are related to the modifications in K+ efflux, increased lysosome leakage and activation of cathepsin B or enhanced reactive oxygen species (ROS) production. In the kidney, inflammation is believed to mediate or promote the progression of glomerular sclerotic pathologies resulting in end-stage renal disease (ESRD). NLRP3 inflammasome activation may turn on glomerular inflammation and other cell damages, contributing to the onset of glomerular injury and ESRD. This inflammasome activation not only occurs in immune cells, but also in residential cells such as endothelial cells and podocytes in the glomeruli. Summary: This review briefly summarizes current evidence of NLRP3 inflammasome activation and related molecular mechanisms in renal glomeruli. The possible canonical and non-canonical effects of this inflammasome activation and its potential implication in the development of different glomerular diseases are highlighted.

Background: The molecular crosstalk between inflammation and autophagy is an emerging field of research that is essential for the understanding of multicellular organism homeostasis and how these processes influence a variety of pathological conditions. Objective: In this review, we briefly describe the relationship between autophagy and inflammasome activation. The central role that mitochondria play in both cellular processes is also discussed. Conclusion: Inflammasome and autophagy often modulate each other by common inhibitory mechanisms that are controlled by different input pathways. Thus, inflammasome components coordinate autophagy and autophagy regulates inflammasome activation, making the balance between both processes a fundamental player in cellular homeostasis.

Background: Recently high-resolution, noninvasive, multimodality in-vivo molecular imaging with PET, SPECT, CT and MRI, employing fusion algorithms has revolutionized personalized medicine. However, novel discovery of specific radiopharmaceuticals (RPs) for the accurate diagnosis and effective treatment of progressive neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, drug addiction, and other cognitive impairments still remains a significant challenge. Objective: The primary objective of this review is to highlight the clinical significance of multimodality fusion neuroimaging for the determination of: pharmacokinetics and pre-clinical development of radiopharmaceuticals (RPs); in-vivo monitoring of stem cell transplantation therapy; nicotinic acetylcholine receptors (nAChRs) investigations; and regional cerebral blood flow and glucose metabolism in cognitively-impaired subjects employing multimodality noninvasive PET, CT, MRI/MRS, and SPECT imaging. Method: Recent methodology to perform multimodality imaging employing computer-based fusion algorithms is provided with a primary emphasis on nanoSPECT/CT, PET-CT, and PET-MRI in experimental animals. Multimodality imaging is performed to detect CNS infections using 99mTc-HMPAO SPECT and 18F-FDG PET/CT. Furthermore, limitations of individual neuroimaging system, body movements due to cardiorespiratory activity, and co-registration of multimodality neuroimaging data are described. Results: Multimodality neuroimaging is clinically-significant because it emphasizes the importance of complementary imaging for theranostic applications and minimizes the inherent limitations of individual neuroimaging approach. However, it may increase the radiation dose to a susceptible pediatric population. Conclusion: Future developments in specific RPs with minimum radiation exposure will facilitate early differential diagnosis, prevent, slowdown and/or cure neurodegenerative diseases, cardiovascular diseases, and cancer. Eventually, conventional and functional neuroimaging, combined with clinical, laboratory and - omics analyses will facilitate theranostics to accomplish the ultimate goal of personalized medicine.

Osteoporosis, a bone disease resulting in the loss of bone density and microstructure quality, is often associated with fragility fractures, and the latter imposes a great burden on the patient and society. Although there are several different treatments available for osteoporosis such as hormone replacement therapy, bisphosphonates, Denosumab, and parathyroid hormone, some concerns have been raised regarding the inherent side effects of their long term use. It would be of great relevance to search for alternative natural compounds, which could complementarily overcome the limitations of the currently available therapy. Herein, we review current literature on natural compounds that might have therapeutic values for osteoporosis. Search terms included bone resorption, bone density, osteoporosis, postmenopausal, osteoporosis or bone density conservation agents, and any of the terms related to traditional, herbal, natural therapy, natural health, diet, or phytoestrogens. All the compounds and herbs included in the review are naturally bioactive or are used in folk herbal medicine and have been reported to be capable of attenuating osteopenia or osteoporosis in vivo or in vitro, through various mechanisms – estrogen-like activity, antioxidant and anti-inflammatory properties, or by modulating the key signaling pathways in the pathogenesis of osteoporosis. Through our assessment of the therapeutic potential and outlook of alternative medicine, we aim to provide an appealing perspective for the consideration of the application of a complementary anti-osteoporotic treatment option and prevention strategy for osteoporosis or osteolytic bone disorders.

Background: The validation of drug targets in malaria and other human diseases remains a highly difficult and laborious process. In the vast majority of cases, highly specific small molecule tools to inhibit a proteins function in vivo are simply not available. Additionally, the use of genetic tools in the analysis of malarial pathways is challenging. These issues result in difficulties in specifically modulating a hypothetical drug target’s function in vivo. Objective: The current “toolbox” of various methods and techniques to identify a protein’s function in vivo remains very limited and there is a pressing need for expansion. New approaches are urgently required to support target validation in the drug discovery process. Method: Oligomerisation is the natural assembly of multiple copies of a single protein into one object and this self-assembly is present in more than half of all protein structures. Thus, oligomerisation plays a central role in the generation of functional biomolecules. A key feature of oligomerisation is that the oligomeric interfaces between the individual parts of the final assembly are highly specific. However, these interfaces have not yet been systematically explored or exploited to dissect biochemical pathways in vivo. Results and Conclusion: This mini review will describe the current state of the antimalarial toolset as well as the potentially druggable malarial pathways. A specific focus is drawn to the initial efforts to exploit oligomerisation surfaces in drug target validation. As alternative to the conventional methods, Protein Interference Assay (PIA) can be used for specific distortion of the target protein function and pathway assessment in vivo.

Phytometabolites are functional elements derived from plants and most of them exhibit therapeutic characteristics such as anti-cancer, anti-inflammatory and anti-oxidant effects. Phytometabolites exert their anti-cancer effect by targeting multiple signaling pathways. One of the remarkable phenomena targeted by phytometabolites is the Warburg effect. The Warburg effect describes the observation that cancer cells exhibit an increased rate of glycolysis and aberrant redox activity compared to normal cells. This phenomenon promotes further cancer development and progression. Recent observations revealed that some phytometabolites could target metabolic-related enzymes (e.g. Hexokinase, Pyruvate kinase M2, HIF-1) in cancer cells, with little or no harm to normal cells. Since hyper-proliferation of cancer cells is fueled by higher cellular metabolism, phytometabolites targeting these metabolic pathways can create synergistic crosstalk with induced apoptotic pathways and sensitize cancer cells to chemotherapeutic agents. In this review, we discuss phytometabolites that target the Warburg effect and the underlying molecular mechanism that leads to tumor growth suppression.

Background & Objective: Thioredoxin-interacting protein (TXNIP) also known as thioredoxin binding protein-2 is a ubiquitously expressed protein that interacts and negatively regulates expression and function of Thioredoxin (TXN). Over the last few years, TXNIP has attracted considerable attention due to its wide-ranging functions impacting several aspects of energy metabolism. TXNIP acts as an important regulator of glucose and lipid metabolism through pleiotropic actions including regulation of β-cell function, hepatic glucose production, peripheral glucose uptake, adipogenesis, and substrate utilization. Overexpression of TXNIP in animal models has been shown to induce apoptosis of pancreatic β-cells, reduce insulin sensitivity in peripheral tissues like skeletal muscle and adipose, and decrease energy expenditure. On the contrary, TXNIP deficient animals are protected from diet induced insulin resistance and type 2 diabetes. Summary: Consequently, targeting TXNIP is thought to offer novel therapeutic opportunity and TXNIP inhibitors have the potential to become a powerful therapeutic tool for the treatment of diabetes mellitus. Here we summarize the current state of our understanding of TXNIP biology, highlight its role in metabolic regulation and raise critical questions that could help future research to exploit TXNIP as a therapeutic target.

Background: Cyclin-dependent kinases (CDKs) comprise an important protein family for development of drugs, mostly aimed for use in treatment of cancer but there is also potential for development of drugs for neurodegenerative diseases and diabetes. Since the early 1990s, structural studies have been carried out on CDKs, in order to determine the structural basis for inhibition of this protein target. Objective: Our goal here is to review recent structural studies focused on CDKs. We concentrate on latest developments in the understanding of the structural basis for inhibition of CDKs, relating structures and ligand-binding information. Method: Protein crystallography has been successfully applied to elucidate over 400 CDK structures. Most of these structures are complexed with inhibitors. We use this richness of structural information to describe the major structural features determining the inhibition of this enzyme. Results: Structures of CDK1, 2, 4-9, 12 13, and 16 have been elucidated. Analysis of these structures in complex with a wide range of different competitive inhibitors, strongly indicate some common features that can be used to guide the development of CDK inhibitors, such as a pattern of hydrogen bonding and the presence of halogen atoms in the ligand structure. Conclusion: Nowadays we have structural information for hundreds of CDKs. Combining the structural and functional information we may say that a pattern of intermolecular hydrogen bonds is of pivotal importance for inhibitor specificity. In addition, machine learning techniques have shown improvements in predicting binding affinity for CDKs.