Current Drug Targets - Volume 18, Issue 16, 2017

Background: Fungal infections have been causing serious problems in all age groups, especially in immune-compromised individuals. Various synthetic agents are in clinical practice for the treatment of these infections, however, resistance to these agents badly affected their therapeutic quality. Objective: This review focuses on the antifungal activity of naturally occurring alkaloids, their source, chemical structure, and potency with a possible mechanism(s) of action. Results: The results of available literature showed that at least 70 different plant derived alkaloids exhibited antifungal activity in vitro. These alkaloids are isolated from different plants and families showing their diverse distribution in plant kingdom. Additionally, the alkaloid from various classes depicted antifungal effects against a variety of fungi. Conclusions: Alkaloids could be a better therapeutic alternative to available therapies with fewer chances of resistance but more research and clinical trials are needed before final recommendations. Additionally, the details provided in this review will offer greater awareness of the excellent promise that natural alkaloids exhibit as antifungal agents.

Background: Prohibitin (PHB) is overtly conserved evolutionarily and ubiquitously expressed protein with pleiotropic functions in diverse cellular compartments. However, regulation and function of these proteins in different cells, tissues and in various diseases is different as evidenced by expression of these proteins which is found to be reduced in heart diseases, kidney diseases, lung disease, Crohn's disease and ulcerative colitis but this protein is highly expressed in diverse cancers. The mechanism by which this protein acts at the molecular level in different subcellular localizations or in different cells or tissues in different conditions (diseases or normal) has remained poorly understood. There are several studies reported to understand and decipher PHB's role in diseases and/or cancers of ovary, lung, stomach, thyroid, liver, blood, prostrate, gastric, esophagus, glioma, breast, bladder etc. where PHB is shown to act through mechanisms by acting as oncogene, tumor suppressor, antioxidant, antiapoptotic, in angiogenesis, autophagy etc. Objective: This review specifically gives attention to the functional role and regulatory mechanism of PHB proteins in cardiovascular health and diseases and its associated implications. Various molecular pathways involved in PHB function and its regulation are analyzed. Conclusion: PHB is rapidly emerging as a critical target molecule for cardiovascular signaling. Progress in delineating CVD and mechanisms of PHB in diverse molecular pathways is essential for determining when and how PHB targeted therapy might be feasible. In this regard, new therapies targeting PHB may best be applied in the future together with molecular profiling of CVD for clinical stratification of disease diagnosis and prognosis.

Background: The thromboembolic risk of atrial fibrillation (AF) is significantly mitigated by oral anticoagulation (OAC) therapy, albeit at an increasing bleeding risk. The general principle is that the potential harm conferred by possible bleeding must not exceed the expected protective benefit of OAC. Over the recent years, the CHA2DS2-VASc score has been proven to be superior to other scores in identifying ‘low risk’ AF patients. However, even this latest score does not incorporate all possible risk factors causing a high thromboembolic risk, while the individual components of the CHA2DS2-VASc score do not seem to carry equal thromboembolic risk. Thus, the quest for more reliable risk stratification schemes and identification of “truly low-risk” patients has been continued. Objective: In this article, data concerning the risk stratification schemes and particularly the CHA2DS2-VASc score of 1 and 0, are critically reviewed and a practical algorithm is proposed for all and more specifically for the “low-risk” patients. Results: A variety of clinical, echocardiographic, genetic and biochemical or coagulation parameters can also predict adverse thromboembolic events in AF patients. Nevertheless, the addition or adoption of more complex schemes may defeat the purpose of simplicity and practicality, demanding more extensive and costly assessments to decide on a relatively simple question, that of the need for anticoagulation. In the era of non-vitamin K oral anticoagulants (NOACs) proven equivalent or superior to vitamin K antagonists (VKAs), this may not be necessary any more, and a simple recommendation of dispensing OAC therapy almost to every patient afflicted by AF may prove to be a more practical and a ubiquitous approach, as long as safety is ensured by these newer agents. Conclusion: The accumulated evidence appears compelling that at least those with a CHA2DS2- VASc score of ≥1, should receive OAC. With regards to those with a CHA2DS2-VASc score of 0, one may wish to consider additional risk factors (Figure 1) beyond those in scores to decide whether there is a need for thromboembolic protection that outweighs the bleeding risk, preferably with use of NOACs. Finally, an individualized strategy and clinical judgement may be necessary by assessing patient's clinical and financial status, preferences and choices in a shared decision-making or participatory medicine approach.

Background: The lack of an outright treatment for Parkinson’s disease (PD) is a pivotal concern in medicine and has driven the search for novel alternatives for treating the disease. Among the proposed approaches, small interfering RNA (siRNA)-based therapy is attracting significant attention as a potential method for the treatment of PD; however, siRNAs delivery possesses potential drawbacks, such as reduced stability in blood circulation and low capacity for reaching the target site. Objective: This review aims to explore siRNA-based approaches to PD and the latest advances for designing nanoparticles that effectively target siRNAs to the action site and that protect these against degradation in blood circulation. Results: siRNA-based approaches provide an interesting option for designing new strategies for treating PD through the silencing of genes, whose abnormal expressions contribute to the pathophysiology of the disease; however, siRNA delivery to the brain is a key issue that remains unsolved to date. Current research efforts are focused on designing vectors that effectively transport and protect siRNAs. In this regard, nanoparticles are being developed as carriers for siRNAs with controlled delivery efficiency and low toxicity profiles, and these represent an alternative to common vectors. Conclusion: Identification of putative gene targets for siRNA therapy of PD has set the pace for researching non-viral vectors; however, the technological aspects for tackling the challenge that siRNAs targeting to the brain represents are essentials. In this respect, the formulation of siRNAs in nanoparticles would avoid harmful side effects, such as immunogenic and oncogenic drawbacks.

Background: The incidence of lung cancers has increased globally. Increased exposure to tobacco, passive smoking, less consumption of vegetables and fruits and occupational exposure to asbestos, arsenic and chromium are the main risk factors. The pathophysiology of lung cancer is complex and not well understood. Various microRNAs, genes and pathways are associated with lung cancers. The genes involved in lung cancers produce proteins involved in cell growth, differentiation, different cell cycles, apoptosis, immune modulation, tumor spread and progression. The Hippo pathway (also known as the Salvador-Warts-Hippo pathway) is the latest emerging concept in cancers. The Hippo pathway plays an important role in controlling the size of the tissue and organ by virtue of its action on cell proliferation and apoptosis. Objective: In the present review, we highlight the mammalian Hippo pathway, role of its core members, its upstream regulators, downstream effectors and the resistance cases in lung cancers. Results: Specific interaction of Mer with cell surface hyaluronan receptor CD44 is vital in cell contact inhibition, thereby activating Hippo pathway. Both transcription co-activators YAP and TAZ (also known as WWTR1, being homologs of Drosophila Yki) are important regulators of proliferation and apoptosis, and serve as major downstream effectors of the Hippo pathway. Mutation of NF2, the upstream regulator of Hippo pathway is linked to the cancers. Conclusion: Targeting YAP and TAZ may be important for future drug delivery and treatment.

Background: Electrochemotherapy (ECT) is a combination of electroporation (EP) and chemotherapy and has been reported as a potential radiosensitizing agent for radiation therapy. Objective: The main objective of this study was to systematically review of the literature to evaluate the effectiveness of ECT in sensitization of tumors to ionization radiation. In addition, the clinical considerations and mechanisms of action of radiosensitizing effect are discussed. Results: Nine studies were included in this review. Bleomycin and cisplatin showed radiosensitizing effects in combined protocols with EP. EP enhances the cytotoxicity of bleomycin and cisplatin by factor of 1000 and 100, respectively. The mechanism of action of these drugs is induction of single and double strand breaks in DNA molecule. Moreover, the two main mechanisms of EP are increasing drug uptake in the tumor cells and generating reactive oxygen species. A single session ECT before radiotherapy can significantly enhance the tumor response. Conclusion: ECT is effective for different cell lines and tumors with different levels of radiosensitivity. Our findings show that ECT can be further translated into the clinic and can be matched by singledose irradiation as well as in the fractionated regime.

Background: Mycobacteria genus is responsible for deadly diseases like tuberculosis and leprosy. Cell wall of bacteria belonging to this genus is unique in many ways. It plays a major role in the pathogenesis and intracellular survival inside the host. In intracellular pathogens, their cell wall acts as molecular shield and interacts with host cell milieu to modulate host defense responses. Objectives: In this review, we summarize the factors that participate in the biosynthesis of unique mycobacterial cell wall, understand their potential as drug targets and the recent developments where they have been evaluated as possible drug targets. Results: Several cell wall associated factors that play crucial roles in the synthesis of cell wall components like Antigen 85 complex, Glycosyltransferases (GTs), LM (lipomannan) and LAM (lipoarabinomannan), mAGP Complex, lipolytic enzyme have been categorically documented. Most of the presently used anti TB regimens interrupted cell wall synthesis, but the emergence of drug resistant strains made it mandatory to identify new drug targets. Novel drug candidates which could inhibit the synthesis of cell wall components have been thoroughly studied worldwide. Conclusion: Studies demonstrated that the cell wall components are unique in terms of their contribution in mycobacterium pathogenesis. Targeting these can hamper the growth of M. tuberculosis. In this study, we scrutinize the drugs under trials and the potential candidates screened through in silico findings.