Current Drug Targets - Volume 15, Issue 9, 2014

microRNAs (miRNAs) are a class of small non-coding RNAs that are 18-25 nucleotides (nt) in length and negatively regulate gene expression post-transcriptionally. miRNAs are known to mediate myriad processes and pathways. While many miRNAs are expressed ubiquitously, some are expressed in a tissue specific manner. miR-133 is one of the most studied and best characterized miRNAs to date. Specifically expressed in muscles, it has been classified as myomiRNAs and is necessary for proper skeletal and cardiac muscle development and function. Genes encoding miR-133 (miR-133a-1, miR-133a-2 and miR-133b) are transcribed as bicistronic transcripts together with miR-1-2, miR-1-1, and miR-206, respectively. However, they exhibit opposing impacts on muscle development. miR-133 gets involved in muscle development by targeting a lot of genes, including SFR, HDAC4, cyclin D2 and so on. Its aberrant expression has been linked to many diseases in skeletal muscle and cardiac muscle such as cardiac hypertrophy, muscular dystrophy, heart failure, cardiac arrhythmia. Beyond the study in muscle, miR-133 has been implicated in cancer and identified as a key factor in cancer development, including bladder cancer, prostate cancer and so on. Much more attention has been drawn to the versatile molecular functions of miR-133, making it a truly valuable therapeutic gene in miRNA-based gene therapy. In this review, we identified and summarized the results of studies of miR-133 with emphasis on its function in human diseases in muscle and cancer, and highlighted its therapeutic value. It might provide researchers a new insight into the biological significance of miR-133.

Melanoma is a life threatening disease with a growing incidence rate. It is estimated that 9840 patients will die from melanoma in 2014. Despite numerous attempts for treating metastatic melanoma, conventional therapies including systemic chemotherapy or immunotherapy, either as single agents or combined, have not been promising. The most cytotoxic agents have low molecular weight, which leads to rapid excretion, nonspecific distribution, and poor therapeutic index. Therefore, they may even increase toxicity due to their non-specific action on healthy tissue that can exacerbate the malady. To provide optimum effective concentration, multiple-dose drug administration is required, which again can increase the incidence of adverse effects. Recent developments in drug delivery systems are able to improve the drug efficacy and safety, and offer more promising approaches in treating melanoma. Recent researches have shed more light on the advantages of novel drug loaded carrier systems versus free drugs. Most of these animal studies, reported improvement in treatment efficacy and survival rate using novel carrier systems. This is related to the ability of these systems in enhancing the anticancer effect by modifying drug pharmacokinetics and biodistribution, selective target delivery of the agents to the diseased tissue and their ability to cross the biological barriers. In this paper, it is attempted to illustrate the potentials of novel strategies in treatment of melanoma incorporating drug delivery systems versus conventional therapies.

During the last decade research is gradually repositioning the antimalarial drug chloroquine, and certain related quinoline derivatives, as anticancer agents. Chloroquine and hydroxychloroquine, in particular, have relatively wellcharacterized toxicity profiles due to several decades of use for treatment of malaria. Previously published review articles provide an excellent overview of the diversity of chloroquine effects on cancer cells, both in the cell culture as well as on human tumors grafted into mice; and an account of the increasing pace of incorporation of hydroxychloroquine in combination treatment schemes for clinical studies. In this review we present some features that are common between cancers that are sensitive to quinoline derivatives, in particular features that are amenable to pharmaceutical intervention.

Schistosomiasis sometimes referred to as bilharzia ranks high among the common neglected human tropical diseases. Parasitic trematode flatworm belonging to the genus Schistosoma is responsible for this acute and chronic disease. Its prevalence is rapidly increasing in the tropical regions worldwide; however, its economic and global health impact is grossly underestimated. There are five recognized species of schistosome parasitizing humans but the common species causing the disease are S. haematobium, S. japonicum and S. mansoni. Over the years, praziquantel, due to its advantage over other drugs employed in the treatment of schistosomiasis especially because of its effectiveness against all schistosoma species has remained the drug of choice. Unfortunately, due to drug pressure, some reports of praziquantel resistance in the treatment of some strains of S. haematobium and S. mansoni have been documented in literature. This has necessitated the search for novel anti-schistosomal agents as alternatives to praziquantel treatment. Currently, antimicrobial peptides are gaining prominence as possible sources of novel drugs in the control and treatment of schistosomiasis. A major driving force for evaluating antimicrobial peptides is their general diverse therapeutic applications, basically due to their size and properties as well as their broad spectrum of activities. Therefore, antimicrobial peptides are attractive candidates with promising results that may overcome drug resistance problems in search for novel therapeutic agents for the control and treatment of schistosomiasis.

Abdominal aortic aneurysm (AAA) is an important cause of mortality in older adults. Most AAAs are asymptomatic and screening programs have been introduced to identify AAAs at an early stage in some countries. There is currently no accepted therapy for early stage or small AAAs, which are frequently identified by such programs. In this review, we discuss work underway to identify targets for medical treatments to limit progression of small AAAs. Specifically we discuss studies, which have examined the potential of targeting inflammation, proteolysis, the renin-angiotensin system, the coagulation system and sex hormones as approaches to limiting AAA pathogenesis. As yet, none of the treatment targets have translated into an agent, which can effectively reduce AAA progression in clinical practice.

NF-κB essential modulator (NEMO), the non-catalytic regulatory subunit of the IκB kinase (IKK) complex, is essential for the canonical NF-κB activation pathway. It has been identified as a molecular platform for assembling the IKK complex and recruiting upstream IKK activators. However, the exact mechanism for regulating IKK activity has still remained elusive. This review describes structural and functional characteristics of NEMO protein, covers the feasible polyubiquitin-mediated NEMO-dependent IKK complex activation mechanism, and briefly summarizes some proteins that bind to NEMO for enhancing or suppressing IKK complex activity. Furthermore, it also discusses several bioactive compounds that disrupt the protein-protein interactions (PPI) involving NEMO, as these PPI may act as alternative routes to develop novel pharmacological agents for inflammation and cancer therapy.

As the most common form of arthritis, osteoarthritis (OA) is prevalent in the elderly, bringing patients pain and functional limitations of joints. Current medication treatments of OA mainly consist of oral and intra-articular administration. Despite the undeniable advantages over oral administration, the efficacy of intra-articular therapy is still limited by the rapid clearance of drugs. To guarantee the efficacy and avoid frequent injections, rationally designed intra-articular drug delivery systems (DDSs), which may remain in OA joints for a long time and sustainedly release drugs, are clinically in need. In this article, we present a review of the novel intra-articular DDSs for OA treatment reported recently, especially in the last five years. Factors influencing the biocompatibility and efficacy of such systems are also addressed. Moreover, the potential fate of different systems in joints is highlighted. Future innovations in this field may lie in the discovery of effective DMOADs and the development of novel biomaterials as carriers of bioactivity substances.

International interest on the benefits of using the steroid hormone Dehydroepiandrosterone (DHEA) on various aspects of human health, including the regulation of mood, is increasing. This study aimed to review the scientific literature on the use of DHEA in the treatment of depression and depressive symptoms in other psychiatric and medical illnesses. PubMed, ISI Web of Knowledge and Virtual Health Library (VHL) databases were independently searched by two researchers using the following terms: depression, treatment, DHEA, and mood. Clinical studies were considered eligible when subjects were treated with DHEA and psychological assessments of depression were conducted. No time limits or language for this research were imposed. One 183 references were identified, and 22 references were selected to compose this review. Significant improvements related to the use of DHEA in patients with depression were observed, in addition to improvements in depressive symptoms in patients with schizophrenia, anorexia nervosa, HIV and adrenal insufficiency. No significant improvements were observed regarding depressive symptoms in patients with fibromyalgia; the results observed in patients with autoimmune diseases and healthy individuals remain contradictory. Although the selected studies demonstrated good methodological applications, most studies consisted of small samples, and only 3 studies were conducted in a young population. Therefore, we concluded that the studies published to date indicate promising results regarding the use of DHEA in the treatment of depression and depressive symptoms, especially in depression that is mild or resistant to conventional therapy.