Current Drug Targets - Volume 19, Issue 16, 2018

Background: Glioblastoma Multiforme (GBM) is the most common and lethal brain malignancy. Recent evidence suggests that the presence of stem-like cells (GSCs) inside the tumor with high self-renewal, resistance to chemotherapy and invasiveness/migration potential is associated with poor GBM prognosis. GSC aggressiveness seems to be linked to an important process involved in tumorigenesis and cancer metastasis called Epithelial-to-Mesenchymal Transition (EMT), which is responsible for several biochemical changes and the acquisition of a more mesenchymal phenotype by GSCs, that enhance their migration, invasiveness and resistance to apoptosis. Objective: Since previous reports demonstrated that purines, interacting with their own receptors, exerted anti-tumor effects in GBM and derived cells, we tried to investigate the ability of these compounds to reduce tumor cell migration/invasion acting on EMT-associated genes/activators and/or signal pathways. Methods: Search in the literature of relevant articles related to the objective. Results: Papers examining the activity of purines on EMT signaling pathways/markers in GSCs are still few whereas literature is more abundant as for other kinds of tumors. Conclusion: Considering the significance of EMT in GBM aggressiveness and the promising involvement of purines in this process, we think that further research in this regard may open the way towards a new therapeutic approach for the control of GBM invasiveness/recurrence.

Background: Asthma and COPD are complex, heterogeneous conditions comprising a wide range of phenotypes, some of which are refractory to currently available treatments. Elucidation of these phenotypes and identification of biomarkers with which to recognize them and guide appropriate treatment remain a priority. Objective: This review describes the utility of blood eosinophils as a surrogate biomarker of eosinophilic airway inflammation, a common feature of specific asthma and COPD phenotypes. The role of blood eosinophils in airway disease is described, as is their relevance in reflecting airway eosinophilia. Each disease is discussed separately as the manner in which blood eosinophils might be used as biomarkers differs. Focusing on patients with severe disease (persistent eosinophilic asthma and exacerbating COPD), we evaluate evidence examining eosinophils as biomarkers. Results: In asthma, the rationale for using blood eosinophils to guide treatment is clearly defined, backed by prospective, well-controlled studies. Higher eosinophil counts identify patients with more severe disease and poorer outcomes, patients for whom biologic therapies targeting allergic and/or eosinophilic pathways are recommended. In COPD, the evidence is less robust. High blood eosinophil counts are a modest predictor of future exacerbations, and may predict a favourable response to ICS on top of LABA/LAMA, especially in patients with a history of frequent exacerbations. Conclusion: Before extensive application in clinical practice, further evaluation of these findings in prospective clinical studies, and standardization of the appropriate thresholds of clinically relevant eosinophilia are needed, together with establishing whether single or multiple measurements are required in different clinical settings.

Background: Recently, a great interest has been paid to the development of hybrid proteininorganic nanoparticles (NPs) for tissue engineering applications to combine the merits of both inorganic and protein nanocarriers. Objective: This short review primarily discusses the most important advances in the application of the hybrids of proteins (gelatin, zein, silk fibroin,….etc) with inorganic NPs (calcium phosphate NPs, cadmium QDs, carbon nanotubes,…etc) in tissue engineering. Results: Various strategies that have been utilized for the preparation of protein-functionalized inorganic NPs are discussed. Nanocomposite films, electrospun nanofibrous scaffolds, nanostructured colloidal composite gels and nanocomposite lyophilized sponges are among the most common platforms of protein-inorganic nanohybrid formulations used in regenerative medicine. Conclusion: protein-inorganic nanohybrids could serve as promising platforms for different biomedical applications including bone and cartilage tissue regeneration, imaging of engineered tissues, development of antithrombogenic implant biomaterials and anti-bacterial wound dressing as well.

This chapter explores therapeutic targets and the anti-inflammatory nature of some naturally- occurring compounds and the current or potential use of these compounds in the treatment of chronic inflammatory pain states. We will review the mechanisms of chronic inflammatory pain, the molecular targets of selected natural compounds in inhibiting inflammatory pain, and the traditional and current approaches to treating pain using these compounds. Previous research on experimental as well as clinical pain will be summarized from in vitro to animal and human models. Potential areas for further research will also be discussed.

Continued emergence and spread of multidrug-resistant bacteria behooved the development of alternative treatment strategies, including antimicrobial drugs. A hopeful approach is to target cellto- cell communications, commonly known as quorum-sensing (QS) and microbial biofilm formation. Quorum Sensing is a method used on bacteria to determine their physiological behavior and coordinate gene expression based on the cell to cell signaling. Many physiological functions of bacteria are controlled by quorum sensings such as virulence, motility, sporulation, luminescence, and biofilm formation. Microbial biofilms are organized aggregations of cells attached to a substratum and surrounded by a self-produced extrapolymeric substance (EPS) matrix. Currently, biofilm formation and quorum sensing are considered as a prospective novel target for antimicrobial therapy to control multidrug- resistant infections. Plant-based natural products have been comprehensively studied in this context. In this review, a comprehensive overview of various research papers published in the last decade on plant-derived molecules that are capable of inhibiting quorum sensing or microbial biofilm formation is reviewed, mentioning the biosynthetic classes of active compounds and their biological activity in the performed assays.

Background: Nuclear factor ΚB (NF-ΚB) comprises a family of proteins that act as transcription factors promoting the expression of many genes. Activation of NF-ΚB biochemical cascades is associated with the regulation of innate and adaptive immune responses and inflammation, among other physiological responses. However, genetic abnormalities and continuous stimulation of the NF- ΚB-IKKβ pathway are directly related to many types of inflammatory and autoimmune diseases, as well as to the genesis and survival of tumor cells. Objectives: Inhibition of the NF-ΚB-IKKβ cascade can be considered an attractive therapeutic method for the genesis of new prototypes to combat these chronic multifactorial diseases. Results: This review describes some prototypes and drugs that act to inhibit the NF-ΚB-IKKβ pathway, highlighting the realities, challenges and perspectives for therapeutic use. Conclusion: Although only proteasome inhibitors, such as bortezomib and carfilzomib, are a reality as therapeutically useful drugs among the known modulators of possible targets in the NF-ΚB-IKKβ pathway, some other prototypes described as IKKβ inhibitors have entered clinical stages as drug candidates for the control of inflammatory diseases. It is important to note that some classical drugs available on the pharmaceutical market, such as acetylsalicylic acid, were also described more recently as NF-ΚB pathway modulators as IKKβ inhibitors.

This review summarizes recent progress in understanding the role of p53-upregulated mediator of apoptosis (PUMA) in molecular pathways with respect to its potential therapeutic applications. Particular emphasis is given to the PUMA´s role in ionizing radiation-induced signalling as radiotoxicity of normal tissue is mediated mostly via apoptosis. PUMA and its p53-dependent and p53- independent induction are described and potential use as a new target for the development of radioprotective agents is suggested. Further implications, including targeting PUMA to prevent and treat cardiovascular and neurodegenerative diseases, are also discussed together with an overview of other therapeutic applications. Finally, basic chemical structures for the development of novel PUMA modulators such as pifithrine derivatives, kinase inhibitors or modulators of Bcl-2 protein family are described.

The herbal plant extract of Enicostemma littorale is widely used to medicate and treat type II Diabetes. This extract in medicine has shown its value in reducing blood glucose & lipid levels, and improving the kidney functioning, lipid profile, controlling blood pressure and heart rate. The well characterized chemical components such as iridoid and secoiridoid glycosides are present in aqueous and ethanolic extracts of the plant. Swertiamarin, a secoiridoid glycoside, is identified as the lead compound that confers anti-hyperglycemic & anti-hyperlipidemic effects. The swertiamarin binds with one or more molecular targets to alter their expression and/or activity. The in silico, in vivo and in vitro studies have been carried out to uncover the underlying molecular mechanism of action of swertiamarin and its derivatives for showing the better anti-diabetic & anti-hyperlipidemic activities. In brief, the present review focuses on unraveling the information about molecular targets of swertiamarin. Our review will open new avenues to develop therapeutic approaches and drugs to treat diabetes and other inflammatory diseases.

Aldosterone, the main mineralocorticoid hormone, plays a crucial role in the regulation of electrolyte homeostasis and blood pressure. Although this role is undoubtedly important, it is not a hormonal action that attracts the most attention. Aldosterone seems to be very important as a local messenger in the pathology of cardiovascular diseases (CVD). In the last few years, the attention was focused on the correlation between raised aldosterone level and increased risk of cardiovascular events. It has been demonstrated that aldosterone contributes to fibrosis, inflammation, endothelial dysfunction, fibrinolytic disorders, and oxidative stress leading to CVD development and progression. It used to be thought that the effects of aldosterone are mediated via classic nuclear receptors – mineralocorticoid receptors (MRs). Now we know that the mechanism of aldosterone action in the cardiovascular system (CVS) is much more complex since experimental and clinical studies indicate that MR blockade may be not sufficient to abolish aldosterone-induced harmful effects in CVS. Thus, the involvement of some other than MR, receptors, and factors is suggested. Moreover, in addition to the generally known genomic action of aldosterone, which involves MR activation, the nongenomic pathways are postulated in the mode of hormone action. More and more attention is focused on the membrane-coupled receptors, which mediate the rapid effects of aldosterone and have been already confirmed in different cells and tissues of CVS. Therefore, this brief review summarizes recent findings about new sides of aldosterone action in CVS that could be potential targets for therapeutic intervention.

Diabetic nephropathy is one of the major causes of kidney failure, accounting for ~44% of all cases. In spite of the significant mortality rate of diabetic nephropathy, specific and effective treatment is still eluding. Identification of genetic determinants and understanding their role in the progression of disease are essential for developing diagnostic tools and effective therapy. Drosophila melanogaster is a genetically tractable model organism and is being used for understanding the genetic basis of several human diseases. Drosophila has a well developed renal system and shares conserved developmental and functional processes with humans. Apart from similarities in renal system, type 1 and type 2 diabetes can be induced in Drosophila following mechanisms similar to those in human. This review discusses the current therapies available for diabetic nephropathy and examines the potential of Drosophila renal system as a model for identifying drug targets for diabetic nephropathy and screening of the potential drugs for their efficacy.

Background: This review aims to address procedures and indications for the application of the adipose-derived stem cells (ADSCs) for regenerative dentistry. ADSCs have rarely been used in this particular field; conversely, experience from other clinical fields and basic research seems to recommend the suitability of this application. Aims and Methods: We reviewed 32 out of 193 articles on Medline sorted by the relevance option. The main purpose of this paper is to perform a short review of the application of stem cells in regenerative dentistry, describing a multilineage differentiation as a safe and useful alternative way of harvesting and selection of ADSCs. Results and Conclusion: The most common derivation of stem cells for regenerative dentistry is from the adipose tissue. There are conditions in which the levy adipose cannot be easily achieved, or where large amount of grafting is not needed. For this purpose, the possibility of selecting stromal stem cells directly from the lax subcutaneous connective tissue, preferably of the head region, would allow a technical simplification.