Current Medicinal Chemistry (v.24, #7)

Meet Our Editorial Board Member by Carmelo Puglia (653-653).

Human Host Defense Peptides - Role in Maintaining Human Homeostasis and Pathological Processes by Malgorzata Anna Dawgul, Katarzyna E. Greber, Wieslaw Sawicki, Wojciech Kamysz (654-672).
The human body expresses over 100 host defense peptides and proteins (antimicrobial peptides, AMPs). The compounds are produced by tissues and mucosal surfaces, e.g. skin, the digestive and urinary tract, the ocular surface and neutrophils, and are believed to play a crucial role in defense from microbial infection. They are considered to protect the human body against microbial infections due to their antimicrobial and immunomodulatory activities. As well as having strong antimicrobial activity towards a broad spectrum of microorganisms, AMPs have been found to interact with neutrophils, monocytes and T-cells and promote the production of cytokines. They also neutralize the action of lipopolysaccharide (LPS) and play a crucial role in wound healing processes.

In response to the microbial stimuli the AMPs are released in order to fight the infection, however there are several microorganisms evading the human immune system by downregulation of AMPs. Decreased or elevated expression of AMPs is associated also with several non-infectious diseases. Despite numerous studies conducted in the field of AMPs over the last few decades, their exact role in physiological and pathological processes remains to be explained. In this paper, we review the most significant human AMPs and their potential roles in maintaining human homeostasis as well as in pathological processes.


PDE7-Selective and Dual Inhibitors: Advances in Chemical and Biological Research by Agnieszka Jankowska, Artur Swierczek, Grazyna Chlon-Rzepa, Maciej Pawlowski, Elzbieta Wyska (673-700).
Phosphodiesterase 7 (PDE7) is an intracellular enzyme that specifically hydrolyzes the second messenger, cyclic-3',5'-adenosine monophosphate (cAMP), into inactive noncyclic nucleotide, 5'-AMP. To date, many structurally diverse compounds with PDE7 inhibitory properties have been described, including selective PDE7 inhibitors, dual PDE4/PDE7, PDE7/PDE8, and PDE7/GSK-3 inhibitors, and non-selective PDE inhibitors with high affinity for PDE7. Inhibitors of PDE7 have provided beneficial effects in animal models of inflammatory and neurological disorders, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, and many others. This review is a comprehensive summary of the current state-of-the-art in the field of design and synthesis of PDE7 inhibitors, their physicochemical properties, biological evaluation, and structure-activity relationships as well as it highlights the updated evidence for a potential therapeutic utility of these compounds. Moreover, new approaches to obtain more effective and safer PDE7 inhibitors than those available now are presented.

Human African Trypanosomiasis (HAT), a neglected disease endemic in Sub- Saharan Africa, is usually fatal if left untreated. It is caused by the parasite Trypanosoma brucei, and is spread by the tsetse fly. The drugs currently available to treat HAT are few, and limited in efficacy. Furthermore, resistance towards these drugs is beginning to grow. In the last 25 years, only one advance has been made into HAT treatment and consequently, there is an increasing need for new drugs to be sought that are able to effectively treat this disease. This review provides a brief overview of drug discovery research for HAT, focusing on research published in the last four years, identifying new molecules with the potential to be developed into anti-HAT agents. The methods of drug discovery have been grouped into three key areas; new molecules inspired by known antitrypanosomal agents, target-based screening, and phenotypic screening.

Neuroinflammation plays an important role in different brain diseases including acute brain injuries such as cerebral ischemic stroke and chronic neurodegenerative diseases e.g. Alzheimer's disease etc. The central player in this is the activated microglia, which produce substantial amounts of proinflammatory mediators that may exacerbate the disease. Associated with microglia activation is astrogliosis characterized by hypertrophic astrocytes with increased expression of proinflammatory cytokines, neurotrophic factors, stem cell, neuronal and proliferation markers, all these are crucial for reconstruction of damaged tissue and ultimate restoration of neurological functions.

Here, we review the roles of activated microglia and reactive astrocytes in brain diseases with special reference to cerebral ischemia, and the effects of scutellarin, a Chinese herbal extract on both glial cells. We first reviewed the close spatial relation between activated microglia and reactive astrocytes as it suggests that both glial cells work in concert for tissue reconstruction and repair. Secondly, we have identified scutellarin as a putative therapeutic agent as it has been found to not only suppress microglial activation thus ameliorating neuroinflammation, but also enhance astrocytic reaction. In the latter, scutellarin amplified the astrocytic reaction by upregulating the expression of neurotrophic factors among others thus indicating its neuroprotective role. Remarkably, the effects of scutellarin on reactive astrocytes were mediated by activated microglia supporting a functional “cross-talk” between the two glial types. This review highlights some of our recent findings taking into consideration of others demonstrating the beneficial effects of scutellarin on both glial cell types in cerebral ischemia as manifested by improvement of neurological functions.


Current Strategies in the Modification of PLGA-based Gene Delivery System by Mohammad Ramezani, Mahboubeh Ebrahimian, Maryam Hashemi (728-739).
Successful gene therapy has been limited by safe and efficient delivery of nucleic acid to the target cells. Poly (d,l-lactide-co-glycolide) (PLGA) nanoparticles (NPs) are able to deliver drugs and genes efficiently. This formulation has several advantages in comparison with other formulations including improvement in solubility, stability, controlling of degradation and release of the entrapped agents. For application of PLGA as a gene carrier, there exist many challenges. PLGA NPs could protect the encapsulated DNA from in vivo degradation but the DNA release is slow and the negative charge acts as a barrier to DNA incorporation and delivery. Also, during the preparation process, DNA could be exposed to high shear stress and organic solvents which could result in its inactivation. Moreover, PLGA NPs could be modified with different agents to reduce cytotoxicity, to enhance delivery efficiency and to target specific tissues/cells. This review summarizes different methods used for the preparation of PLGA NPs as gene carriers and recent strategies for the modification of PLGA particles applied in gene therapy.