Current Signal Transduction Therapy - Volume 13, Issue 2, 2018

Background: Signal transduction is a process where a chemical or physical signal is transmitted from extracellular to the intracellular nuclear matrix as a series of molecular events, most commonly protein phosphorylation which ultimately result in a response. At the molecular level, such responses include changes in the transcription or translation of genes, and posttranslational and conformational changes in proteins, as well as changes in their location. These molecular events are the basic mechanisms of controlling cell growth, proliferation, metabolism and many other processes. In multi-cellular organisms, signal transduction pathways evolve to regulate cell communication in various ways. One of the important signal transduction occurs through JAK-STAT and NF-ΚB regulated Pim-1 kinase expression. Methods: Major pathways such as JAK-STAT and NF-ΚB signaling are involved as the targets of Pim-1 kinase activities including cell cycle progression, mitotic cell division, oncogenic transcription, apoptosis and metastatic invasion. There are three target points in JAK –STAT systems including the inhibition of activated JAK via phosphorylation, STAT –STAT dimerization and the entry of activated STAT components for nuclear binding. NF-ΚB signaling is regulated by IKK enzyme proteasomal degradation and translocation of activated NF-ΚB complex into nuclear domain for DNA transcription and cellular expression. A number of inhibitors were designed to inhibit these major drug target points of activated JAK-STAT and NF-kB signaling cascades. Results: Pim denotes Proviral insertion in murine. It was reported that a wide range of human cancers including bladder cancer, colorectal cancer, head and neck cancer and hematological malignancies such as leukemia and lymphomas form due to over-expression of PIM1 via JAK-STAT and NF-ΚB signaling cascades. An attempt has been made in the present review to focus various potent inhibitors for the inhibition of JAK-STAT and NF-ΚB signaling targets. These inhibitors are in clinical trials or to be progressed in the clinical investigation. Conclusion: Incorrect regulation of cytokine-mediated activation of JAK-STAT and NF-ΚB produces abnormal expression of Pim -1 kinase and solid cancer. Phosphorylated JAKs can induce transcription of target genes and NF-ΚB acts as a regulator of a gene that can control cell proliferation and cell survival. Therefore, JAK-STAT and NF- ΚB regulated Pim-1 kinase is a novel target for anticancer leads and these leads can be used to design a template as an anticancer agent. Further clinical studies can be carried out to discover new novel congeneric entities.

Background: Complex integrin molecules, composed of eighteen α and eight β subunits, are responsible for modulating different signal transduction mechanisms across the plasma membrane. Two heterodimeric integrins, α4β7 and α4β1 are in the interest of researchers due to their immense importance in regulating a variety of inflammatory diseases such as asthma, rheumatoid arthritis (RA), inflammatory bowel disease (IBD), atherosclerosis and multiple sclerosis (MS). Small molecules α4β7 antagonists selective over α4β1 may be a safe and effective remedy for autoimmune disorders. Therefore, designing new small molecule selective α4β7 antagonists should have immense importance in anti-inflammatory and anti-cancer drug discovery. Materials and Methods: Integrins are discussed in terms of their structural point of view along with their signaling mechanisms. A brief description of the α4β7 and α4β1 antagonists in clinical trials in process or terminated was also highlighted. Firategrast and SB-683698 as dual integrin α4β7 and α4β1 antagonists having N-benzoyl-L-biphenylalanine moiety showed some positive response in clinical trials initially. However, this molecule failed in evaluation due to adverse effects. Hence, compounds with this scaffold may be clinically effective as a drug candidate in future. Therefore, detailed structural analysis of the N-benzoyl-L-biphenylalanines was provided in this study. Conclusion: The Open3DQSAR models on both integrins α4β7 and α4β1 were statistically significant. For integrin α4β7 antagonists, the best 3D-QSAR model resulted in an LOO-Q2 of 0.6240 and an R2 Pred of 0.7366 whereas, for integrin α4β1 antagonists, the best model yielded an LOO-Q2 of 0.7487 and an R2 Pred of 0.5366. Important structural features required for higher α4β7 and α4β1 antagonistic activity of N-benzoyl-L-biphenylalanines were highlighted. This study may provide useful information regarding the overall structural aspects of integrins along with better α4β7 antagonists designing approaches in future.

Background: Parkinson's disease commonly characterised as a neurodegenerative disease affecting the global population in the upper age limit affecting movement and is identified by stopped posture, shaking hands and frequent tremors. The difficulty in the treatment of the disease arises due to the fact that a considerable time lag exists between the onset of the disease internally and appearance of the disease symptoms. The symptoms of Parkinson's disease are caused by reduction in the levels of dopamine neurotransmitter in the brain due to nerve cell damage in the brain. Objective: The primary treatment of the disease aims to restore the proper balance of the neurotransmitters acetylcholine and dopamine by increasing dopamine levels. In addition to the dopamine agonists, several mono amino oxidase B (MAO-B) inhibitors, anticholinergics and Catechol- O-methyltransferase (COMT) inhibitors have also been proposed for the treatment of the disease. Method: Based on the need for searching target specific drug molecules with potential therapeutic efficacy, design of new chemical entities using recent approaches in the field of drug discovery has drawn attention of a wide group of medicinal chemist. In this aspect, chemometrics proposing the concept of computer-aided drug design (CADD) has been adopted widely for the purpose of database searching and design of molecules with improved anti-parkinsonian potential. Results: In the current review, an attempt has been made to explore the CADD methodology in the field of drug discovery related to identification of molecules that may be utilised for alleviating symptoms related to Parkinson's disease. Conclusion: The works reported by the different groups of authors further help in the identification of the biological pharmacophore of the anti-parkinsonian agents and determine their degree of interaction with the corresponding receptor. However, the literature search made in this review is an exhaustive one and other additional works have also been performed by other different groups of researchers in this field.

Background: Cancer is a complicated genetic disorder which is a major global health issue. The complexities of several cancer therapies are due to heterogenic nature of tumor and its microenvironment that is highly inflammatory and acidic. Thus, cancer related inflammation (CRI) is responsible for metastasis, resistance and recurrence of cancer. Although, several researches are being investigated, still emphasis is being made extensively on targeting the acidic and heterogenic inflammatory conditions in the tumor microenvironment. The present review article has focused on the different aspects of cancer to advanced strategies in cancer therapy. Objective: The review majorly focused on several molecules that are reported for preliminary, preclinical and clinical trials. Some important aspects are discussed in detail. Method: Several research findings were carefully reviewed and the conclusion made is based on the strong evidences that have been reported. Exclusively, the molecules targeting cellular signalling pathways of the different compartments of tumor microenvironment and inflammatory state are also reported. Results: Based on the strong evidences, we were able to document few molecules of natural and synthetic origin for cancer therapy targeting an important aspect of cancer. In this review, we have focused on the molecules that target the important cellular signalling pathways especially with respect to photodynamic and multi-targeted therapies that are in preliminary, preclinical and clinical trials. Conclusion: Although, the advanced cancer therapeutics have been established but the combination of different strategies is very important. The efficiency of the treatments depends on the stage of cancer and response of patients. Search for closely defined and selective molecular targets for a particular therapy is very complicated due to heterogenic nature of tumor environment, different therapeutic agents, incubation time, exposure doses and selectivity of therapy. The most promising photodynamic therapy (PDT) and multi- targeted therapies are being established but the question whether the cellular proteins that are most susceptible to the therapies has to be addressed. An important aspect that needs to be addressed is whether cancer is vulnerable to the particular therapy that selectively induces cell death in the cancerous tissue and inflammatory cells in tumor microenvironment that is a very challenging aspect of research in cancer treatment strategies. Hence, in this review, we focused on different therapeutic strategies for targeting multi- components of the fumigating inflammatory tumor environment.

Crossing the threshold in clinical activity, chimeric antigen receptor-modified T cells have emerged as a new effective therapeutic regimen against various types of cancer both in adults and pediatric oncology. Currently available CARs are designed in a manner so that that they are capable of recognizing MHC independent antigen and incorporate costimulatory signal, converting the transduced T cells with potent activity. They have higher efficacy than monoclonal antibody and antibody-drug conjugate. There are various generations of CAR-T cells depending upon intracellular signalling domain number. CAR therapy maintained especial status as cancer immunotherapeutic agent, after targeting the CD19 cell surface molecules expressed in various types of cancers and are successfully transforming into clinic practice. Standing on the pillars of genetic engineering, T cell biology, molecular biology, tumor biology, target identification, CAR-T therapy holds great promise as off the shelf cancer therapeutic agent. Several unresolved concerns are still prevailing. Various issues with regard to safety, efficacy and their preparation, quality control issues, are still hampering our way. Cytokine release syndrome, neurological toxicities are few major side effects of the therapy blocking the successful development of CAR-T cells in the clinical trials. Aim: Current review is dealing with structural aspects of CAR T cells, target and signalling, their toxicity perspectives and current status and futuristic scope. Method: By undertaking structured search approach, we had gone through various bibliographic databases for peer-reviewed research literature on the focused research topic. Results: The review identifies various issues with regard to safety, efficacy and their preparation, structural aspects of CAR T cells, target and signalling, their toxicity perspectives and current status and futuristic scope. Conclusion: Amongst the most novel approaches, the CAR based research should be focussed on effective tumor targeting with limited toxicity in normal tissues, to improve efficacy with modulation of cell products or host cell products for rapid in vivo expansion.

Background: The whole thought is to demonstrate the parallel parking framework for self-ruling robots with the help of real-time embedded boards. Autonomous systems are outlined and developed by considering the non-holonomic requirements. PID controller is used to accomplish the servo reaction. The path planning scheme is created for parallel stopping of self-ruling vehicles by gaining data from the sensor. Methods: The three vital stages engaged in safety parking are scanning, positioning and maneuvering. The scanning stage filters the stopping condition by ultrasonic separation estimating sensors. The positioning stage advances the vehicle and in reverse. It is mostly used to alter the appropriate separation from the begin point to turn point before moving. The parallel stopping of self-ruling robots with non-holonomic requirements are mimicked through MATLAB environment and prototype implementation is carried out through embedded platform. Results: Initially, open loop response of the non-holonomic vehicle is unstable and nonlinear in nature. Therefore the PID controller is used to control the response of the non-holonomic vehicle with minimum error based on the set point. The goal of this research is to attain the parallel parking scheme for non-holonomic vehicles, which is attained with the help of real time implementation. This implementation has been carried out using embedded processor with PID algorithm, sensors and actuators. Conclusion: Hence the paper depicts the structure of non-holonomic robotic vehicle and control with the help of PID controller. The parallel parking scheme has established using MATLAB programming and verified with the help of real time prototype. The paper proposed an idea of automated parking system in contrast to manual parking by the driver. The consumption of space, energy and time are minimized due to the automated parking scheme. Due to human error and negligence, harms such as collisions and accidents are occurred. These harms are reduced by implementing the parallel parking scheme in an intelligent manner. In future, Fuzzy based PD controller will be developed and implemented for the enhancement of parallel parking algorithm in robots.

Background: Since surface electromyogram (SEMG) signal plays a vital role in prosthetic designs, hence the evaluation of these signals for identifying the upper arm motions leading to myoelectric control based design of artificial devices is presented. Methods: A total of two upper limb locations were chosen for recording of data, thereafter the evaluation and interpretation of signal was done for the estimation of extracted parameters using simulated algorithm (four arm activities were performed). A statistical algorithm of two way ANOVA for estimating the effectiveness of recorded signal followed by a discriminant classifier for pattern recognition task was investigated. Results: Outcome of the proposed study after analyzing the effectiveness of recorded data supports the formularize reparability of the classification approach for signal accuracies (97.50%). Conclusion: Finally, the simulation study based on muscle modeling allowed us to explore the parameters that affect the muscle-force relationship prior to prostheses design. Further, the proposed study will also help researchers in understanding the nature of these complex signals particularly in biomedical applications.