Showing papers in "Current Drug Targets in 2019"

Molecular Docking: Challenges, Advances and its Use in Drug Discovery Perspective

Abstract: Molecular docking is a process through which small molecules are docked into the macromolecular structures for scoring its complementary values at the binding sites. It is a vibrant research area with dynamic utility in structure-based drug-designing, lead optimization, biochemical pathway and for drug designing being the most attractive tools. Two pillars for a successful docking experiment are correct pose and affinity prediction. Each program has its own advantages and drawbacks with respect to their docking accuracy, ranking accuracy and time consumption so a general conclusion cannot be drawn. Moreover, users don't always consider sufficient diversity in their test sets which results in certain programs to outperform others. In this review, the prime focus has been laid on the challenges of docking and troubleshooters in existing programs, underlying algorithmic background of docking, preferences regarding the use of docking programs for best results illustrated with examples, comparison of performance for existing tools and algorithms, state of art in docking, recent trends of diseases and current drug industries, evidence from clinical trials and post-marketing surveillance are discussed. These aspects of the molecular drug designing paradigm are quite controversial and challenging and this review would be an asset to the bioinformatics and drug designing communities.

PI3K/ Akt/ mTOR Pathway as a Therapeutic Target for Colorectal Cancer: A Review of Preclinical and Clinical Evidence.

Abstract: Background Phosphoinositide 3-kinase (PI3Ks) is a member of intracellular lipid kinases and involved in the regulation of cellular proliferation, differentiation and survival. Overexpression of the PI3K/Akt/mTOR signalling has been reported in various forms of cancers, especially in colorectal cancers (CRC). Due to their significant roles in the initiation and progression events of colorectal cancer, they are recognized as a striking therapeutic target. Objective The present review is aimed to provide a detailed outline on the role of PI3K/Akt/mTOR pathway in the initiation and progression events of colorectal cancers as well as its function in drug resistance. Further, the role of PI3K/Akt/mTOR inhibitors alone and in combination with other chemotherapeutic drugs, in alleviating colorectal cancer is also discussed. The review contains preclinical and clinical evidence as well as patent literature of the pathway inhibitors which are natural and synthetic in origin. Methods The data were obtained from PubMed/Medline databases, Scopus and Google patent literature. Results PI3K/Akt/mTOR signalling is an important event in colorectal carcinogenesis. In addition, it plays significant roles in acquiring drug resistance as well as metastatic initiation events of CRCs. Several small molecules of natural and synthetic origin have been found to be potent inhibitors of CRCs by effectively downregulating the pathway. Data from various clinical studies also support these pathway inhibitors and several among them are patented. Conclusion Inhibitors of the PI3K/mTOR pathway have been successful for the treatment of primary and metastatic colorectal cancers, rendering the pathway as a promising clinical cancer therapeutic target.

Celecoxib in Cancer Therapy and Prevention - Review.

Abstract: Background and objectives It is generally accepted that inflammatory cells found in the tumor microenvironment are involved in the neoplastic process, promoting cell proliferation, survival, and migration. Therefore, administering anti-inflammatory medication in cancer therapy seems to be justified. A potential pathway associated with the aforementioned issue is cyclooxygenase-2 inhibition, particularly as the overexpression of this enzyme has been proven to occur in cancer tissues and is also associated with a poor prognosis in several types of human malignancies. Celecoxib, a COX-2 selective inhibitor, has been utilized for over 20 years, particularly as an anti-inflammatory, analgesic and antipyretic medication. However, to date, its antineoplastic properties have not been sufficiently investigated. In recent years, the number of research studies on the antineoplastic effects of celecoxib has increased considerably. The vast majority of publications refers to preclinical studies attempting to elucidate its mechanisms of action. Clinical trials concerning celecoxib have focused primarily on the treatment of cancers of the colon, breast, lung, prostate, stomach, head and neck, as well as premalignant lesions such as familial adenoma polyposis. In this review article authors attempt to summarise the latest research which has elucidated celecoxib use in the treatment and prevention of cancer. Conclusion Both preclinical and clinical studies have demonstrated promising results of the role of celecoxib in the treatment and prevention of cancer - the best outcome was observed in colon, breast, prostate and head and neck cancers. However, more clinical trials providing real evidence-based clinical advances of celecoxib use are needed.

Essential Oils: An Impending Substitute of Synthetic Antimicrobial Agents to Overcome Antimicrobial Resistance

Abstract: Antimicrobial resistance (AMR) is an emerging problem in the world that has a significant impact on our society. AMR made conventional drugs futile against microorganisms and diseases untreatable. Plant-derived medicines are considered to be safe alternatives as compared to synthetic drugs. Active ingredients and the mixtures of these natural medicines have been used for centuries, due to their easy availability, low cost, and negligible side effects. Essential oils (EOs) are the secondary metabolites that are produced by aromatic plants to protect them from microorganisms. However, these EOs and their constituents have shown good fighting potential against drug-resistant pathogens. These oils have been proved extremely effective antimicrobial agents in comparison to antibiotics. Also, the combination of synthetic drugs with EOs or their components improve their efficacy. So, EOs can be established as an alternative to synthetic antimicrobial agents to eradicate tough form of infectious microorganisms. EO's can interact with multiple target sites, like the destruction of cytoplasm membrane or inhibition of protein synthesis and efflux pump, etc. The purpose of this review is to provide information about the antimicrobial activity of EOs attained from different plants, their combination with synthetic antimicrobials. In addition, mechanism of antimicrobial activity of several EOs and their constituents was reported.

Bioinformatics Approaches for Anti-cancer Drug Discovery.

Abstract: Drug discovery is important in cancer therapy and precision medicines. Traditional approaches of drug discovery are mainly based on in vivo animal experiments and in vitro drug screening, but these methods are usually expensive and laborious. In the last decade, omics data explosion provides an opportunity for computational prediction of anti-cancer drugs, improving the efficiency of drug discovery. High-throughput transcriptome data were widely used in biomarkers' identification and drug prediction by integrating with drug-response data. Moreover, biological network theory and methodology were also successfully applied to the anti-cancer drug discovery, such as studies based on protein-protein interaction network, drug-target network and disease-gene network. In this review, we summarized and discussed the bioinformatics approaches for predicting anti-cancer drugs and drug combinations based on the multi-omic data, including transcriptomics, toxicogenomics, functional genomics and biological network. We believe that the general overview of available databases and current computational methods will be helpful for the development of novel cancer therapy strategies.

Recognition of Plasminogen Activator Inhibitor Type 1 as the Primary Regulator of Fibrinolysis.

Abstract: The fibrinolytic system consists of a balance between rates of plasminogen activation and fibrin degradation, both of which are finely regulated by spatio-temporal mechanisms. Three distinct inhibitors of the fibrinolytic system that differently regulate these two steps are plasminogen activator inhibitor type-1 (PAI-1), α2-antiplasmin, and thrombin activatable fibrinolysis inhibitor (TAFI). In this review, we focus on the mechanisms by which PAI-1 governs total fibrinolytic activity to provide its essential role in many hemostatic disorders, including fibrinolytic shutdown after trauma. PAI-1 is a member of the serine protease inhibitor (SERPIN) superfamily and inhibits the protease activities of plasminogen activators (PAs) by forming complexes with PAs, thereby regulating fibrinolysis. The major PA in the vasculature is tissue-type PA (tPA) which is secreted from vascular endothelial cells (VECs) as an active enzyme and is retained on the surface of VECs. PAI-1, existing in molar excess to tPA in plasma, regulates the amount of free active tPA in plasma and on the surface of VECs by forming a tPA-PAI-1 complex. Thus, high plasma levels of PAI-1 are directly related to attenuated fibrinolysis and increased risk for thrombosis. Since plasma PAI-1 levels are highly elevated under a variety of pathological conditions, including infection and inflammation, the fibrinolytic potential in plasma and on VECs is readily suppressed to induce fibrinolytic shutdown. A congenital deficiency of PAI-1 in humans, in turn, leads to life-threatening bleeding. These considerations support the contention that PAI-1 is the primary regulator of the initial step of fibrinolysis and governs total fibrinolytic activity.

High Mobility Group Box-1 (HMGB1): A Potential Target in Therapeutics.

Abstract: High mobility group box-1 (HMGB1) mainly belongs to the non-histone DNA-binding protein. It has been studied as a nuclear protein that is present in eukaryotic cells. From the HMG family, HMGB1 protein has been focused particularly for its pivotal role in several pathologies. HMGB-1 is considered as an essential facilitator in diseases such as sepsis, collagen disease, atherosclerosis, cancers, arthritis, acute lung injury, epilepsy, myocardial infarction, and local and systemic inflammation. Modulation of HMGB1 levels in the human body provides a way in the management of these diseases. Various strategies, such as HMGB1-receptor antagonists, inhibitors of its signalling pathway, antibodies, RNA inhibitors, vagus nerve stimulation etc. have been used to inhibit expression, release or activity of HMGB1. This review encompasses the role of HMGB1 in various pathologies and discusses its therapeutic potential in these pathologies.

Opportunities of Bacterial Cellulose to Treat Epithelial Tissues.

Abstract: In this mini-review, we highlight the potential of the biopolymer bacterial cellulose to treat damaged epithelial tissues. Epithelial tissues are cell sheets that delimitate both the external body surfaces and the internal cavities and organs. Epithelia serve as physical protection to underlying organs, regulate the diffusion of molecules and ions, secrete substances and filtrate body fluids, among other vital functions. Because of their continuous exposure to environmental stressors, damage to epithelial tissues is highly prevalent. Here, we first compare the properties of bacterial cellulose to the current gold standard, collagen, and then we examine the use of bacterial cellulose patches to heal specific epithelial tissues; the outer skin, the ocular surface, the oral mucosa and other epithelial surfaces. Special emphasis is made on the dermis since, to date, this is the most widespread medical use of bacterial cellulose. It is important to note that some epithelial tissues represent only the outermost layer of more complex structures such as the skin or the cornea. In these situations, depending on the penetration of the lesion, bacterial cellulose might also be involved in the regeneration of, for instance, inner connective tissue.

Insight into Pain Modulation: Nociceptors Sensitization and Therapeutic Targets

Abstract: Pain is a complex multidimensional concept that facilitates the initiation of the signaling cascade in response to any noxious stimuli. Action potential generation in the peripheral nociceptor terminal and its transmission through various types of nociceptors corresponding to mechanical, chemical or thermal stimuli lead to the activation of receptors and further neuronal processing produces the sensation of pain. Numerous types of receptors are activated in pain sensation which vary in their signaling pathway. These signaling pathways can be regarded as a site for modulation of pain by targeting the pain transduction molecules to produce analgesia. On the basis of their anatomic location, transient receptor potential ion channels (TRPV1, TRPV2 and TRPM8), Piezo 2, acid-sensing ion channels (ASICs), purinergic (P2X and P2Y), bradykinin (B1 and B2), α-amino-3-hydroxy-5- methylisoxazole-4-propionate (AMPA), N-methyl-D-aspartate (NMDA), metabotropic glutamate (mGlu), neurokinin 1 (NK1) and calcitonin gene-related peptide (CGRP) receptors are activated during pain sensitization. Various inhibitors of TRPV1, TRPV2, TRPM8, Piezo 2, ASICs, P2X, P2Y, B1, B2, AMPA, NMDA, mGlu, NK1 and CGRP receptors have shown high therapeutic value in experimental models of pain. Similarly, local inhibitory regulation by the activation of opioid, adrenergic, serotonergic and cannabinoid receptors has shown analgesic properties by modulating the central and peripheral perception of painful stimuli. This review mainly focused on various classes of nociceptors involved in pain transduction, transmission and modulation, site of action of the nociceptors in modulating pain transmission pathways and the drugs (both clinical and preclinical data, relevant to targets) alleviating the painful stimuli by exploiting nociceptor-specific channels and receptors.

Saccharomyces cerevisiae (Baker's Yeast) as an Interfering RNA Expression and Delivery System.

Abstract: The broad application of RNA interference for disease prevention is dependent upon the production of dsRNA in an economically feasible, scalable, and sustainable fashion, as well as the identification of safe and effective methods for RNA delivery. Current research has sparked interest in the use of Saccharomyces cerevisiae for these applications. This review examines the potential for commercial development of yeast interfering RNA expression and delivery systems. S. cerevisiae is a genetic model organism that lacks a functional RNA interference system, which may make it an ideal system for expression and accumulation of high levels of recombinant interfering RNA. Moreover, recent studies in a variety of eukaryotic species suggest that this microbe may be an excellent and safe system for interfering RNA delivery. Key areas for further research and development include optimization of interfering RNA expression in S. cerevisiae, industrial-sized scaling of recombinant yeast cultures in which interfering RNA molecules are expressed, the development of methods for largescale drying of yeast that preserve interfering RNA integrity, and identification of encapsulating agents that promote yeast stability in various environmental conditions. The genetic tractability of S. cerevisiae and a long history of using this microbe in both the food and pharmaceutical industry will facilitate further development of this promising new technology, which has many potential applications of medical importance.

Understanding Membrane Protein Drug Targets in Computational Perspective

Abstract: Membrane proteins play crucial physiological roles in vivo and are the major category of drug targets for pharmaceuticals. The research on membrane protein is a significant part in the drug discovery. The biological process is a cycled network, and the membrane protein is a vital hub in the network since most drugs achieve the therapeutic effect via interacting with the membrane protein. In this review, typical membrane protein targets are described, including GPCRs, transporters and ion channels. Also, we conclude network servers and databases that are referring to the drug, drug-target information and their relevant data. Furthermore, we chiefly introduce the development and practice of modern medicines, particularly demonstrating a series of state-of-the-art computational models for the prediction of drug-target interaction containing network-based approach and machine-learningbased approach as well as showing current achievements. Finally, we discuss the prospective orientation of drug repurposing and drug discovery as well as propose some improved framework in bioactivity data, created or improved predicted approaches, alternative understanding approaches of drugs bioactivity and their biological processes.

Cyclin-Dependent Kinase 2 in Cellular Senescence and Cancer. A Structural and Functional Review.

Abstract: Background Cyclin-dependent kinase 2 (CDK2) has been studied due to its role in the cell-cycle progression. The elucidation of the CDK2 structure paved the way to investigate the molecular basis for inhibition of this enzyme, with the coordinated efforts combining crystallography with functional studies. Objective Our goal here is to review recent functional and structural studies directed to understanding the role of CDK2 in cancer and senescence. Methods There are over four hundreds of crystallographic structures available for CDK2, many of them with binding affinity information. We use this abundance of data to analyze the essential features responsible for the inhibition of CDK2 and its function in cancer and senescence. Results The structural and affinity data available CDK2 makes it possible to have a clear view of the vital CDK2 residues involved in molecular recognition. A detailed description of the structural basis for ligand binding is of pivotal importance in the design of CDK2 inhibitors. Our analysis shows the relevance of the residues Leu 83 and Asp 86 for binding affinity. The recent findings revealing the participation of CDK2 inhibition in senescence open the possibility to explore the richness of structural and affinity data for a new era in the development of CDK2 inhibitors, targeting cellular senescence. Conclusion Here, we analyzed structural information for CDK2 in combination with inhibitors and mapped the molecular aspects behind the strongest CDK2 inhibitors for which structures and ligandbinding affinity data were available. From this analysis, we identified the significant intermolecular interactions responsible for binding affinity. This knowledge may guide the future development of CDK2 inhibitors targeting cancer and cellular senescence.

A Survey for Predicting Enzyme Family Classes Using Machine Learning Methods.

Abstract: Enzymes are proteins that act as biological catalysts to speed up cellular biochemical processes. According to their main Enzyme Commission (EC) numbers, enzymes are divided into six categories: EC-1: oxidoreductase; EC-2: transferase; EC-3: hydrolase; EC-4: lyase; EC-5: isomerase and EC-6: synthetase. Different enzymes have different biological functions and acting objects. Therefore, knowing which family an enzyme belongs to can help infer its catalytic mechanism and provide information about the relevant biological function. With the large amount of protein sequences influxing into databanks in the post-genomics age, the annotation of the family for an enzyme is very important. Since the experimental methods are cost ineffective, bioinformatics tool will be a great help for accurately classifying the family of the enzymes. In this review, we summarized the application of machine learning methods in the prediction of enzyme family from different aspects. We hope that this review will provide insights and inspirations for the researches on enzyme family classification.

Estrogen Receptor Alpha and its Ubiquitination in Breast Cancer Cells.

Abstract: More than 70% of all breast cancer cases are estrogen receptor alpha-positive (ERα). ERα is a member of the nuclear receptor family, and its activity is implicated in the gene transcription linked to the proliferation of breast cancer cells, as well as in extranuclear signaling pathways related to the development of resistance to endocrine therapy. Protein-protein interactions and posttranslational modifications of ERα underlie critical mechanisms that modulate its activity. In this review, the relationship between ERα and ubiquitin protein (Ub), was investigated in the context of breast cancer cells. Interestingly, Ub can bind covalently or non-covalently to ERα resulting in either a proteolytic or non-proteolytic fate for this receptor. Thereby, Ub-dependent molecular pathways that modulate ERα signaling may play a central role in breast cancer progression, and consequently, present critical targets for treatment of this disease.

Potential Enzymatic Targets in Alzheimer's: A Comprehensive Review.

Abstract: Alzheimer's, a degenerative cause of the brain cells, is called as a progressive neurodegenerative disease and appears to have a heterogeneous etiology with main emphasis on amyloid-cascade and hyperphosphorylated tau-cascade hypotheses, that are directly linked with macromolecules called enzymes such as β- & γ-secretases, colinesterases, transglutaminases, and glycogen synthase kinase (GSK-3), cyclin-dependent kinase (cdk-5), microtubule affinity-regulating kinase (MARK) The catalytic activity of the above enzymes is the result of cognitive deficits, memory impairment and synaptic dysfunction and loss, and ultimately neuronal death However, some other enzymes also lead to these dysfunctional events when reduced to their normal activities and levels in the brain, such as α- secretase, protein kinase C, phosphatases etc; metabolized to neurotransmitters, enzymes like monoamine oxidase (MAO), catechol-O-methyltransferase (COMT) etc or these abnormalities can occur when enzymes act by other mechanisms such as phosphodiesterase reduces brain nucleotides (cGMP and cAMP) levels, phospholipase A2: PLA2 is associated with reactive oxygen species (ROS) production etc On therapeutic fronts, several significant clinical trials are underway by targeting different enzymes for development of new therapeutics to treat Alzheimer's, such as inhibitors for β-secretase, GSK-3, MAO, phosphodiesterase, PLA2, cholinesterases etc, modulators of α- & γ-secretase activities and activators for protein kinase C, sirtuins etc The last decades have perceived an increasing focus on findings and search for new putative and novel enzymatic targets for Alzheimer's Here, we review the functions, pathological roles, and worth of almost all the Alzheimer's associated enzymes that address to therapeutic strategies and preventive approaches for treatment of Alzheimer's

The Urokinase Plasminogen Activation System in Rheumatoid Arthritis: Pathophysiological Roles and Prospective Therapeutic Targets.

Abstract: Rheumatoid arthritis (RA) is a chronic and progressive inflammatory disease characterized in its early stages by synovial hyperplasia and inflammatory cell infiltration and later by irreversible joint tissue destruction. The plasminogen activation system (PAS) is associated with a wide range of physiological and pathophysiological states involving fibrinolysis, inflammation and tissue remodeling. Various components of the PAS are implicated in the pathophysiology of RA. Urokinase plasminogen activator (uPA) in particular is a pro-inflammatory mediator that appears to play an important role in the bone and cartilage destruction associated with RA. Clinical studies have shown that uPA and its receptor uPAR are overexpressed in synovia of patients with rheumatoid arthritis. Further, genetic knockdown and antibody-mediated neutralization of uPA have been shown to be protective against induction or progression of arthritis in animal models. The pro-arthritic role of uPA is differentiated from its haemodynamic counterpart, tissue plasminogen activator (tPA), which appears to play a protective role in RA animal models. This review summarises available evidence supporting the PAS as a critical determinant of RA pathogenesis and highlights opportunities for the development of novel uPAS-targeting therapeutics.

Helenalin - A Sesquiterpene Lactone with Multidirectional Activity

Abstract: Sesquiterpene lactones, secondary metabolites of plants, present in a large number of species mostly from the Asteracea family, are used in the traditional medicine of many countries for the treatment of various pathological conditions. They exert a broad range of activities, including antiinflammatory, anti-bacterial and anti-cancer properties. The best-known sesquiterpene lactones which are already used as drugs or are used in clinical trials are artemisinin, thapsigargin and parthenolide. Yet another sesquiterpene lactone, helenalin, an active component of Arnica montana, known for its strong anti-inflammatory activity, has been used for centuries in folk medicine to treat minor injuries. Unfortunately, helenalin's ability to cause allergic reactions and its toxicity to healthy tissues prevented so far the development of this sesquiterpene lactone as an anticancer or anti-inflammatory drug. Recently, the new interest in the biological properties, as well as in the synthesis of helenalin analogs has been observed. This review describes helenalin's major biological activities, molecular mechanisms of action, its toxicity and potential for further research.

Photopolymerizable Resins for 3D-Printing Solid-Cured Tissue Engineered Implants.

Abstract: With the advent of inexpensive and highly accurate 3D printing devices, a tremendous flurry of research activity has been unleashed into new resorbable, polymeric materials that can be printed using three approaches: hydrogels for bioprinting and bioplotting, sintered polymer powders, and solid cured (photocrosslinked) resins. Additionally, there is a race to understand the role of extracellular matrix components and cell signalling molecules and to fashion ways to incorporate these materials into resorbable implants. These chimeric materials along with microfluidic devices to study organs or create labs on chips, are all receiving intense attention despite the limited number of polymer systems that can accommodate the biofabrication processes necessary to render these constructs. Perhaps most telling is the limited number of photo-crosslinkable, resorbable polymers and fabrication additives (e.g., photoinitiators, solvents, dyes, dispersants, emulsifiers, or bioactive molecules such as micro-RNAs, peptides, proteins, exosomes, micelles, or ceramic crystals) available to create resins that have been validated as biocompatible. Advances are needed to manipulate 4D properties of 3D printed scaffolds such as pre-implantation cell culture, mechanical properties, resorption kinetics, drug delivery, scaffold surface functionalization, cell attachment, cell proliferation, cell maturation, or tissue remodelling; all of which are necessary for regenerative medicine applications along with expanding the small set of materials in clinical use. This manuscript presents a review of the foundation of the most common photopolymerizable resins for solidcured scaffolds and medical devices, namely, polyethylene glycol (PEG), poly(D, L-lactide) (PDLLA), poly-e-caprolactone (PCL), and poly(propylene fumarate) (PPF), along with methodological advances for 3D Printing tissue engineered implants (e.g., via stereolithography [SLA], continuous Digital Light Processing [cDLP], and Liquid Crystal Display [LCD]).

Cdk9 as an Appealing Target for Therapeutic Interventions

Abstract: Cyclin Dependent Kinase 9 (CDK9) as a serine/threonine kinase belongs to a great number of CDKs. CDK9 is the main core of PTEF-b complex and phosphorylates RNA polymerase (RNAP) II besides other transcription factors which regulate gene transcription elongation in numerous physiological processes. Multi-functional nature of CDK9 in diverse cellular pathways proposes that it is as an appealing target. In this review, we summarized the recent findings on the molecular interaction of CDK9 with critical participant molecules to modulate their activity in various diseases. Furthermore, the presented review provides a rationale supporting the use of CDK9 as a therapeutic target in clinical developments for crucial diseases; particularly cancers will be reviewed.

Functional Diversity of Quorum Sensing Receptors in Pathogenic Bacteria: Interspecies, Intraspecies and Interkingdom Level.

Abstract: The formation of biofilm by pathogenic bacteria is considered as one of the most powerful mechanisms/modes of resistance against the action of several antibiotics. Biofilm is formed as a structural adherent over the surfaces of host, food and equipments etc. and is further functionally coordinated by certain chemicals produced itself. These chemicals are known as quorum sensing (QS) signaling molecules and are involved in the cross talk at interspecies, intraspecies and interkingdom levels thus resulting in the production of virulence factors leading to pathogenesis. Bacteria possess receptors to sense these chemicals, which interact with the incoming QS molecules. It is followed by the secretion of virulence molecules, regulation of bioluminescence, biofilm formation, antibiotic resistance development and motility behavioral responses. In the natural environment, different bacterial species (Gram-positive and Gram-negative) produce QS signaling molecules that are structurally and functionally different. Recent and past research shows that various antagonistic molecules (naturally and chemically synthesized) are characterized to inhibit the formation of biofilm and attenuation of bacterial virulence by blocking the QS receptors. This review article describes about the diverse QS receptors at their structural, functional and production levels. Thus, by blocking these receptors with inhibitory molecules can be a potential therapeutic approach to control pathogenesis. Furthermore, these receptors can also be used as a structural platform to screen the most potent inhibitors with the help of bioinformatics approaches.

Inhibition of RAGE Axis Signaling: A Pharmacological Challenge

Abstract: The Receptor for Advanced Glycation End Products (RAGE) is an important cell surface receptor, which belongs to the IgG super family and is now considered as a pattern recognition receptor. Because of its relevance in many human clinical settings, it is now pursued as a very attractive therapeutic target. However, particular features of this receptor such as a wide repertoire of ligands with different binding domains, the existence of many RAGE variants as well as the presence of cytoplasmatic adaptors leading a diverse signaling, are important limitations in the search for successful pharmacological approaches to inhibit RAGE signaling. Therefore, the present review aimed to display the most promising approaches to inhibit RAGE signaling, and provide an up to date review of progress in this area.

Silicon Quantum Dots: Promising Theranostic Probes for the Future

Abstract: Nanotechnology has emerged as one of the leading research areas involving nanoscale manipulation of atoms and molecules. During the past decade, the growth of nanotechnology has been one of the most important developments that have taken place in the biomedical field. The new generation nanomaterials like Quantum dots are gaining much importance. Also, there is a growing interest in the development of nano-theranostics platforms in medical diagnostics, biomedical imaging, drug delivery, etc. Quantum dots are also known as nanoscale semiconductor crystals, with unique electronic and optical properties. Recently, silicon quantum dots are being studied extensively due to their less-toxic, inert nature and ease of surface modification. The silicon quantum dots (2-10nm) are comparatively stable, having optical properties of silicon nanocrystals. This review focuses on silicon quantum dots and their various biomedical applications like drug delivery regenerative medicine and tissue engineering. Also, the processes involved in their modification for various biomedical applications along with future aspects are discussed.

Heat Shock Proteins (HSPs): A Novel Target for Cancer Metastasis Prevention

Abstract: Background Heat shock proteins (HSPs) are predominant molecular chaperones which are actively involved in the protein folding; which is essential in protecting the structure and functioning of proteins during various stress conditions. Though HSPs have important physiological roles, they have been well known for their roles in various pathogenic conditions such as carcinogenesis; however, limited literature has consolidated its potential as an anti-metastatic drug target. Objectives The present review outlines the role of different HSPs on cancer progression and metastasis; possible role of HSP inhibitors as anti-neoplastic agents is also discussed. Methods The data were collected from PubMed/Medline and other reputed journal databases. The literature that was too old and had no significant role to the review was then omitted. Results Despite their strong physiological functions, HSPs are considered as good markers for cancer prognosis and diagnosis. They have control over survival, proliferation and progression events of cancer including drug resistance, metastasis, and angiogenesis. Since, neoplastic cells are more dependent on HSPs for survival and proliferation, the selectivity and specificity of HSP-targeted cancer drugs remain high. This has made various HSPs potential clinical and experimental targets for cancer prevention. An array of HSP inhibitors has been in trials and many others are in experimental conditions as anticancer and anti-metastatic agents. Several natural products are also being investigated for their efficacy for anticancer and anti-metastatic agents by modulating HSPs. Conclusion Apart from their role as an anticancer drug target, HSPs have shown to be promising targets for the prevention of cancer progression. Extensive studies are required for the use of these molecules as anti-metastatic agents. Further studies in this line may yield specific and effective antimetastatic agents.

MicroRNAs as Potential Diagnostic and Prognostic Biomarkers in Hepatocellular Carcinoma.

Abstract: Hepatocellular carcinoma (HCC) is a common cancer, and the second most common cause of cancer-associated death globally. One of the major reasons for this high rate of mortality is a failure to make an early diagnosis. The average survival in untreated HCC patients is estimated to be approximately three months. The 5-year overall survival rate after radical resection is about 15-40% and within two years, more than two third of patients experience a relapse. To date, the most common biomarker which has been used for the diagnosis of HCC is serum alpha-fetoprotein (AFP). However, there is a lack of sensitive and specific tumor biomarkers for the early diagnosis of HCC. MicroRNAs are a class of short endogenous RNA with crucial role in many biological activities and cellular pathways and can be found in various tissues and body fluids. The aim of this review was to summarize the results of recent studies investigating miRNAs as novel biomarkers for the early diagnosis and prognostic risk stratification of patients with this type of liver cancer.

Diversity of Bacteria and Bacterial Products as Antibiofilm and Antiquorum Sensing Drugs Against Pathogenic Bacteria.

Abstract: The increase in antibiotic resistance of pathogenic bacteria has led to the development of new therapeutic approaches to inhibit biofilm formation as well as interfere quorum sensing (QS) signaling systems. The QS system is a phenomenon in which pathogenic bacteria produce signaling molecules that are involved in cell to cell communication, production of virulence factors, biofilm maturation, and several other functions. In the natural environment, several non-pathogenic bacteria are present as mixed population along with pathogenic bacteria and they control the behavior of microbial community by producing secondary metabolites. Similarly, non-pathogenic bacteria also take advantages of the QS signaling molecule as a sole carbon source for their growth through catabolism with enzymes. Several enzymes are produced by bacteria which disrupt the biofilm architecture by degrading the composition of extracellular polymeric substances (EPS) such as exopolysaccharide, extracellular- DNA and protein. Thus, the interference of QS system by bacterial metabolic products and enzymatic catalysis, modification of the QS signaling molecules as well as enzymatic disruption of biofilm architecture have been considered as the alternative therapeutic approaches. This review article elaborates on the diversity of different bacterial species with respect to their metabolic products as well as enzymes and their molecular modes of action. The bacterial enzymes and metabolic products will open new and promising perspectives for the development of strategies against the pathogenic bacterial infections.

Application of Machine Learning Approaches for the Design and Study of Anticancer Drugs.

Abstract: Background Globally the number of cancer patients and deaths are continuing to increase yearly, and cancer has, therefore, become one of the world's highest causes of morbidity and mortality. In recent years, the study of anticancer drugs has become one of the most popular medical topics. Objective In this review, in order to study the application of machine learning in predicting anticancer drugs activity, some machine learning approaches such as Linear Discriminant Analysis (LDA), Principal components analysis (PCA), Support Vector Machine (SVM), Random forest (RF), k-Nearest Neighbor (kNN), and Naive Bayes (NB) were selected, and the examples of their applications in anticancer drugs design are listed. Results Machine learning contributes a lot to anticancer drugs design and helps researchers by saving time and is cost effective. However, it can only be an assisting tool for drug design. Conclusion This paper introduces the application of machine learning approaches in anticancer drug design. Many examples of success in identification and prediction in the area of anticancer drugs activity prediction are discussed, and the anticancer drugs research is still in active progress. Moreover, the merits of some web servers related to anticancer drugs are mentioned.

Toll-like Receptor as a Molecular Link between Metabolic Syndrome and Inflammation: A Review.

Abstract: Metabolic Syndrome (MetS) involves a cluster of five conditions, i.e. obesity, hyperglycaemia, hypertension, hypertriglyceridemia and low High-Density Lipoprotein (HDL) cholesterol. All components of MetS share an underlying chronic inflammatory aetiology, manifested by increased levels of pro-inflammatory cytokines. The pathogenic role of inflammation in the development of MetS suggested that toll-like receptor (TLR) activation may trigger MetS. This review summarises the supporting evidence on the interactions between MetS and TLR activation, bridged by the elevation of TLR ligands during MetS. The regulatory circuits mediated by TLR activation, which modulates signal propagation, leading to the state of chronic inflammation, are also discussed. Taken together, TLR activation could be the molecular basis in the development of MetS-induced inflammation.

Nanonetworks in Biomedical Applications

Abstract: By interconnecting nanomachines and forming nanonetworks, the capacities of single nanomachines are expected to be enhanced, as the ensuing information exchange will allow them to cooperate towards a common goal. Nowadays, systems normally use electromagnetic signals to encode, send and receive information, however, in a novel communication paradigm, molecular transceivers, channel models or protocols use molecules. This article presents the current developments in nanomachines along with their future architecture to better understand nanonetwork scenarios in biomedical applications. Furthermore, to highlight the communication needs between nanomachines, two applications for nanonetworks are also presented: i) a new networking paradigm, called the Internet of NanoThings, that allows nanoscale devices to interconnect with existing communication networks, and ii) Molecular Communication, where the propagation of chemical compounds like drug particles, carry out the information exchange.

A Review of Preclinical Experiments Toward Targeting M2 Macrophages in Prostate Cancer.

Abstract: Prostate cancer is malignant cancer leading to high mortality in the male population. The existence of suppressive cells referred to as tumor-associated macrophages (TAM) is a major obstacle in prostate cancer immunotherapy. TAMs contribute to the immunosuppressive microenvironment that promotes tumor growth and metastasis. In fact, they are main regulators of the complicated interactions between tumor and surrounding microenvironment. M2 macrophages, as a type of TAMs, are involved in the growth and progression of prostate cancer. Recently, they have gained remarkable importance as therapeutic candidates for solid tumors. In this review, we will discuss the roles of M2 macrophages and worth of their potential targeting in prostate cancer treatment. In the following, we will introduce important factors resulting in M2 macrophage promotion and also experimental therapeutic agents that may cause the inhibition of prostate cancer tumor growth.

Molecular aspects of melatonin treatment in tinnitus: A review

Abstract: Tinnitus is a hearing disorder characterized by the perception of sound without external acoustic stimuli, which is caused by damage to the auditory system in response to excessive levels of noise, ototoxic agents and aging. Neural plasticity, oxidative/nitrosative stress and apoptosis play important roles in the pathogenesis of tinnitus. The expression of neural plasticity related to excessive glutamatergic neurotransmission leads to generation of abnormal sound in one's ears or head. Furthermore, hyperactivation and over-expression of NMDA receptors in response to excessive release of glutamate contribute to the calcium overload in the primary auditory neurons and subsequent cytotoxicity. Reactive oxygen/nitrogen species are endogenously produced by different type of cochlear cells under pathological conditions, which cause direct damage to the intracellular components and apoptotic cell death. Cochlear hair-cell death contributes to the progressive deafferentation of auditory neurons, which consequently leads to the aberrant activity in several parts of the auditory pathway. Therefore, targeting neural plasticity, oxidative/nitrosative stress, apoptosis and autophagy may ameliorate tinnitus. Melatonin is an endogenously produced indoleamine synchronizing circadian and circannual rhythms. Based on laboratory studies indicating the protective effect of melatonin against cochlear damage induced by acoustic trauma and ototoxic agents, and also clinical studies reporting the ability of melatonin to minimize the severity of tinnitus, melatonin is suggested to be a treatment option for the patient with tinnitus. Herein, we describe the ameliorative effect of melatonin on tinnitus, focusing on neural plasticity, oxidative/nitrosative stress, apoptotsis and autophagy.