Current Medicinal Chemistry - Volume 23, Issue 16, 2016

Stroke is the most common neurological cause of morbidity and mortality in industrialized countries, afflicting 15 million people every year. The numbers are expected to increase, mostly due to aging populations. One in five stroke patients dies, and one in three are left with permanent disabilities. Although some acute phase therapies such as intravenous recombinant tissue plasminogen activator (rt-PA) andendovascular treatment have been shown to improve ischemic stroke outcome, these therapies are available only for a small proportion of patients. The use of stem cells to replace brain cells lost during stroke is a long-term goal, and one which is difficult to achieve given that transplanted cells must integrate and restore neural pathways to regain function of damaged parts of the brain. Over the past decade the use of mesenchymal stromal cells (MSCs) as therapy has emerged as a particularly attractive option. MSCs are a class of multipotent, self-renewing cells that give rise to differentiated progeny when implanted into appropriate tissues. Herein, we present a review of the application of MSCs in ischemic stroke, including the source of MSCs, the route and timing of their delivery into the brain and the endpoints measured. Experimental data of transplantation of MSCs in animal stroke models suggest an improved functional recovery. The transplantation of MSCs influences a wide range of events by modulating the inflammatory environment, stimulating endogenous neurogenesis and angiogenesis and reducing the formation of glial scar, although the precise, underlying mechanism of this phenomenon remains unknown. The results from early clinical trials highlight the need to optimize variables such as cell selection and route of administration in order to translate these results into safe and successful clinical applications.

Onychomycosis (fungal nail infections) is very common worldwide but is fortunately not often lethal. Several powerful drugs have been introduced into clinical practice in recent years, but these infections remain difficult to cure primarily due to the difficulty of penetration of drug to the site of the infection in therapeutic concentrations. The nature of the disease, the causative fungi, and the characteristics of the drugs employed to treat this condition are discussed in this review.

Nitric Oxide, synthesized from L-arginine by the nitric oxide synthases, has a complex role within the human body. It contributes to almost every physiological system and has been found to be both protective and toxic in disease states. An aging population faces an increasing incidence of neurodegenerative disease and the pathological action of nitric oxide in Alzheimer’s and Parkinson’s diseases may be important therapeutic targets for the future. Nitric oxide’s protective effects are also important to consider, through inhibition of caspase-3, nitrosylation of NMDA and increased activation of protein kinase B and CREB transcription factor. Nitric oxide has been shown to play a part in long term potentiation, revealing its importance in synaptic plasticity. Due to nitric oxide’s mixed effects it is an exciting and varied therapeutic target. Currently, the impact of these therapies has been explored and developed in animal studies, but is yet to be fully realized in human trials. This paper outlines both the pathological and protective roles of nitric oxide in the central nervous system and the potential pharmacological therapies and targets these indicate.

G-protein-coupled receptors (GPCRs) are physiologically important transmembrane proteins that sense signaling molecules such as hormones, neurotransmitters, and various sensory stimuli; GPCRs represent major molecular targets for drug discovery. Although GPCRs traditionally have been thought to function as monomers or homomers, in the recent years these proteins have also been shown to function as heteromers. Heteromerization among GPCRs is expected to generate potentially large functional and physiological diversity and to provide new opportunities for drug discovery. However, due to the existence of numerous combinations, the larger universe of possible GPCR heteromers is unknown, and thus its functional significance is still poorly understood. The oligomerization of GPCRs in living cells now has been demonstrated in mammalian cells and in native tissues by using genetic, biochemical, and physiological approaches, as well as various resonance energy transfer (RET) technologies. In addition, the yeast Saccharomyces cerevisiae, which can serve as a biosensor for monitoring eukaryotic biological processes, can also be used for the identification of functionally significant heteromer pairs of GPCRs. In this review, we focus on studies of GPCR oligomers, and summarize the technologies used to evaluate GPCR oligomerization. We additionally consider the potential limitations of these methods at present, and envision the possible future applications of these techniques.

Inflammation generates a systemic response against injury or infection from bacteria, viruses, and other pathogens. The welfare of host is the primary target of this process. However, uncontrolled or inadequate regulation of the inflammatory response produces detrimental effects leading to the generation of various chronic disorders including atherosclerosis, type-2 diabetes, neurodegenerative disease, cancer and Alzheimer’s disease with severe tissue damage. The exact identity of the inflammatory stimuli is still elusive as they function in multiple pathways; therefore targeting a particular pathway does not resolve the problem. Existing therapeutics targeting the inflammatory responses include steroidal antiinflammatory drugs (SAIDs) and nonsteroidal antiinflammatory drugs (NSAIDs). In spite of their numerous beneficial effects, both SAIDs as well as NSAIDs have their independent, unavoidable side effects, which discourage their prolonged therapeutic applications. Since the management of uncontrolled inflammation is critical for the general wellbeing, therefore an alternative source of multi-targeted non-toxic therapeutic intervention is mandatory. Plant-derived phenols constitute such a group of molecules that can be utilised to manage inflammation. They synergistically modulate several important components involved in multiple signalling pathways that regulate uncontrolled inflammation to exhibit their beneficial health effects. This review discusses the recent advances in structure-function activity of some antiinflammatory polyphenols, their bioavailability enhancement, clinical/ preclinical findings with a view to provide knowledge for developing novel antiinflammatory drugs by following system biology of proinflammatory responses with minimal side effects.