Current Drug Targets - Volume 15, Issue 5, 2014

Natural resources are widely used as raw materials by industries. In most cases, abundant byproducts with low economic interest are also generated from agro-industrial supply chains. There are several examples for the rational use of agro-industrial byproducts in the nanobiotechnology field aiming for the development of novel products and high value added processes. Such raw materials include carapaces, pelages, blood, bagasses, and straws. Molecules from such materials (e.g. chitosan, cellulose, and albumin) are used as scaffolds of unprecedented novel nanostructure. Research efforts comprising a combination of sustainability, nanobiotechnology, and nanomedicine have emerged. One major area in nano-biotechnological research of agro-industrial byproducts is represented by the field of drug delivery systems (DDS). Among the main advantages of agro-industrial byproducts used as drug carriers are their abundance; low price; high biocompatibility; good biodegradability; moderate bioresorbability, associated with reduced systemic toxicity or even no toxicity; and often bioactivity. The goal of these efforts includes not only the possibility to characterize and manipulate matter on the nanoscale, but also to develop sustainable products and processes, including the development of platforms for drug delivery aiming for the treatment of pathologies such as cancer and diabetes. Indeed, there is great hope that the use of agro-industrial byproducts in nanobiotechnology will increase not only agricultural and livestock productivity, but will also contribute to other areas such as the development of DDS with new properties and low production costs; and sustainable environmental management due to the reuse of industrial discharged byproducts. This review will compile current findings on the use of byproducts as building blocks for modern drug carrier systems, emphasizing the challenges and promising applications.

Natural polymers are continuously investigated for use in pharmaceutical and tissue engineering applications due to the renewability of their supply. Besides the conventional use of natural materials in dosage form design such as fillers, they are progressively investigated as functional excipients in specialised dosage forms. The hydrophilic nature of natural polymers together with their non-toxic and biodegradable properties make them useful in the design of modified release dosage forms. Matrix type tablets and beads made from natural gums and mucilages often exhibit sustained drug release through erosion in combination with swelling. Natural polymers are used to reach different pharmaceutical objectives, for instance, inulin and pectin are plant derived polymers that have suitable properties to produce colon-specific drug delivery. Alginate is an example of a natural polymer that has been used in the formulation of gastro-retentive dosage forms. Different cellulose derived polymers have been investigated as coating materials for dosage forms. Natural polymers can be chemically modified to produce molecules with specific properties and formation of co-polymers or polymer mixtures provide new opportunities to develop innovative drug delivery systems.

Lipids, one of the major natural products, usually have high biocompatibility and low toxicity. Due to their proper physicochemical properties, they are the most commonly used materials for building modern drug delivery systems, especially nanocarriers. However, to impart new functions or to satisfy special requirements, the lipids can be modified or synthesized. Using lipids or lipid derivatives, various lipid-based drug or gene delivery systems have been developed and show potential in pre-clinical and clinical applications. In this article, the most commonly used lipids are discussed in terms of their properties and functions as drug carrier components, their chemical modifications, the formulation or composition of lipid-based nanocarriers, and their biomedical applications. This article provides a critical view and possible future directions of lipid-based drug delivery strategies.

The ongoing development of manufacturing technologies and of biocompatible and biodegradable polymers have significantly contributed to the progress of drug delivery systems. In the last decades, the knowledge on keratins has significantly increased, regarding their ultrastructure, molecular and cell biology, physiological and pathological roles, as well as their practical applications in the biomedical field. Produced through sustainable, simple and cheap methods, the natural, non-toxic keratin is one of the raw biomaterials frequently used in the pharmaceutical technology for different applications. The purpose of this review is to present the keratins ultrastructure, types, biological distribution, tissue expression profiles, some of their multiple physiological and pathological roles, as well as their practical applications in drug delivery and cellular and tissue engineering.

Excessive production of reactive oxygen species is an important mechanism underlying the pathogenesis of diabetes associated macrovascular and microvascular complications including diabetic nephropathy. Diabetic nephropathy is characterized by glomerular enlargement, early albuminuria and progressive glomerulosclerosis. The pathogenesis of diabetic nephropathy is multi-factorial and the precise mechanisms are unclear. Hyperglycemia-mediated dysregulation of various pathways either enhances the intensity of oxidative stress or these pathways are affected by oxidative stress. Thus, oxidative stress has been considered as a central mediator in progression of nephropathy in patients with diabetes. In this review, we have focused on current perspectives in oxidative stress signaling to determine common biological processes whereby diabetes-induced oxidative stress plays a central role in progression of diabetic nephropathy.

The cdc2-like kinases (CLKs) are an evolutionarily conserved group of dual specificity kinases belonging to the CMGC (cyclin-dependent kinases (CDKs), mitogen-activated protein kinases (MAP kinases), glycogen synthase kinases (GSK) and CDK-like kinases). The CLK family consists of four isoforms namely CLK1, CLK2, CLK3 and CLK4. The human CLK1 encoded protein comprises 454 amino acids and the catalytic domain of CLK1 exhibits the typical protein kinase fold. CLK1 has been shown to autophosphorylate on serine, threonine and tyrosine residues and phosphorylate exogenous substrates on serine and threonine residues. CLK1 plays an important role in the regulation of RNA splicing through phosphorylation of members of the serine and arginine-rich (SR) family of splicing factors. CLK1 is involved in the pathophysiology of Alzheimer’s disease by phosphorylating the serine residue in SR proteins. Nuclear speckles of the nucleoplasm contain the stored form of SR proteins and are moderately responsible for the choice of splicing sites during pre-mRNA splicing. Hence, the inhibition of CLK1 can be used as a therapeutic strategy for Alzheimer’s disease. Many natural and synthetic molecules are reported to possess CLK1 inhibitory activity. Some specific examples are Marine alkaloid Leucettamine B and KH-CB19. Leucettamine B is a potent inhibitor of CLK1 (15 nM), Dyrk1A (40 nM), and Dyrk2 (35 nM) and a moderate inhibitor of CLK3 (4.5 µM) whereas KH-CB19 is a highly specific and potent inhibitor of the CLK1/CLK4. X-ray crystallographic studies have revealed the binding mode of marine sponge metabolite hymenialdisine and a dichloroindolyl enamino nitrile (KH-CB19) to CLK1. This review focuses on the role of CLKs in the pathophysiology of Alzheimer's disease and therapeutic potential of targeting CLK1 in Alzheimer's disease drug discovery and development. In addition, the recent developments in drug discovery efforts targeting human CLK1 are also highlighted.

Inappropriate protein aggregation is a key mechanism in the pathogenesis of several neurodegenerative disorders. One of the main strategies by which cells deal with abnormal protein aggregates is autophagy, a degradation pathway for intracellular aggregate-prone proteins. Trehalose, a non-reducing disaccharide which has been utilized extensively in the food industry, has been recently demonstrated to have a number of unique properties that point to its potential utility in preventing neurodegeneration. First, trehalose may act as a potent stabilizer of proteins and is able to preserve protein structural integrity. Second, it is a chaperone and reduces aggregation of pathologically misfolded proteins. Third, it improves the clearance of the mutant proteins which act as autophagy substrates when aberrant protein deposition occurs. Notably, trehalose is an mTOR-independent inducer of autophagy, and in animal models of neurodegenerative disorders including Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease, has been shown to decrease the levels of toxic protein aggregates, increase autophagy, and improve clinical symptoms and survival. In summary, mounting experimental evidence suggests that trehalose may prevent neurodegenerative disorders by stabilizing proteins and promoting autophagy. Because of the low toxicity profile that allows for administration for extended periods, human studies of trehalose in preventing neurodegeneration are warranted.

Centrosomes are the vital component of cell cycle progression pathway. Recent investigations have suggested their role in regulating the immune response system. Centrosome polarization delivers secretory granules to the immunological synapse (IS). The Cytotoxic T lymphocytes use a specific mechanism, controlled by centrosome delivery to the plasma membrane for delivering the secretory granules to the immunological synapse. Moreover, the polarization of centrioles to the immunological synapse directs secretion from cytolytic cells of innate as well as adaptive immune systems. Although the recent investigations have suggested their strong role in mediating the crucial events of immunological response, there are few discrepancies that are yet to be resolved. Furthermore, a clear picture of their molecular mechanism along with their cellular functions has not been reported. In this manuscript we have reviewed some important points that explain the importance of centrosomes in mediating the immunological signals and the delivery of lytic discharge from the cytotoxic and killer cells.