Abstract: Developing effective therapies for serious neurological insults remains a major challenge for biomedical research. Despite intense efforts, the ability to promote functional recovery after contusion injuries, ischemic insults, or the onset of neurodegenerative diseases in the brain and spinal cord remains very limited even while the need for such therapies is increasing with an aging population. Recent studies suggest that cellular therapies utilizing mesenchymal stem cells (MSCs) may provide a functional benefit in a wide range of neurological insults. MSCs derived from a variety of tissue sources have been therapeutically evaluated in animal models of stroke, spinal cord injury, and multiple sclerosis. In each situation, treatment with MSCs results in substantial functional benefit and these pre-clinical studies have led to the initiation of a number of clinical trials worldwide in neural repair. ... Read more

Abstract: The idea of promoting angiogenesis in ischemic tissues remains an undisputed therapeutic approach for the treatment of myocardium and skeletal muscles that lack sufficient blood supply. However, clinical experiences from several large trials indicated that delivery of proangiogenic factors to patients suffering from myocardial infarction and leg ischemia has not shown significant benefits. Despite continuous success in various animal disease models, why has this simple principle not shown proof of concept in patients? What has been missing in the trial deign? What are the differences between animal models and patients? What are the optimal components for promoting functional collateral networks? This brief review discusses molecular mechanisms underlying arteriogenesis and proposes novel approaches for improvement of therapeutic outcomes. ... Read more

Abstract: The dynamic and multiple functions of p53, together with its involvement in the most common non-infectious diseases, underscore the need to elucidate the complexity of the p53 regulatory networks. Pathological conditions such as cancer, neurodegeneration, ischemia, cholestasis, and atherosclerosis are all strongly associated with deregulated levels of apoptosis in which p53 dysfunction has a prominent role. We will highlight recent developments of p53-induced apoptosis in human diseases, with a focus on modulation of liver cell apoptosis. In addition, we will discuss controversies arising from widespread p53 activation as a therapeutic approach to cancer. Recent studies have provided relevant and unprecedented information about mechanistic antiapoptotic functions of the endogenous bile acid, ursodeoxycholic acid (UDCA), suggesting that the finely tuned, complex control of p53 by Mdm-2 (mouse double minute-2, an oncoprotein) is a key step in UDCA modulation of p53-triggered apoptosis. We will also review recent therapeutic strategies and clinical applications of targeted agents, their safety, and efficacy, with particular emphasis on potential benefits of UDCA. ... Read more

Abstract: Anti-epileptic drugs (AEDs) have a variety of mechanisms of action which are reflected through different anticonvulsant activities and behavioral effects. Two categories of AEDs are considered based on psychotropic profile. The first group is characterized by potentiation of gamma-aminobutyric acid (GABA) inhibitory neurotransmission, and comprises of agents such as vigabatrin, tiagabine, and gabapentin. These agents are noted to have sedating effects ranging from cognitive slowing to anti-manic effects. On the other hand, the second group is typified by attenuation of glutamate excitatory neurotransmission and has activating effects including anxiogenic and antidepressant actions. Lamotrigine and felbamate feature in this latter group. Mechanisms of action, chief clinical indications, as well as behavioral profile including comment on chief cognitive effects of the newer AEDs are reviewed in accordance with this dual categorization. In clinical practice, assessment of an individual patient alongside consideration of AED behavioral profile primes for appropriate prescription according to patient mood profile, also permitting exposure of AED-induced behavioral disturbance. ... Read more

Abstract: Glioblastoma is the most common and most lethal primary brain tumor. While small progress has been made in treating this cancer in recent years, glioblastoma remains largely resistant to all existing therapies. It has been hoped that dissection of the genetics of this cancer would lead to more targeted and effective treatments, and new advances may finally be bringing this closer to fruition. Within the last few years, high-throughput efforts such as The Cancer Genome Atlas and a massive sequencing project have yielded novel insights and classifications of this dreaded cancer. The likely impact on care delivery in the clinic may only be a few years away. The rapid and exciting pace of advances in glioblastoma genetics has prompted this up-to-date review. ... Read more

Abstract: Human gene therapy has made substantial progress since the initiation of the first clinical trials 20 years ago. Here, we summarized important applications of gene transfer protocols in the treatment of various human diseases using different viral vectors. Recent successful trials on the treatment of ocular diseases and inherited immune deficiencies are particularly encouraging and have raised hopes that human gene therapy as a standard treatment option will finally become a reality. While immune responses and insertional mutagenesis pose obstacles for this novel form of molecular medicine, continuous progress suggests that a wider range of diseases can be treated with gene therapy in the future. ... Read more

Abstract: If those of us privileged enough to have the opportunity to work towards curing human diseases had the power to design the ideal therapeutic molecule, the question would be what selection criteria would we choose? Arguably, at the top of the list would be four mandatory properties: specificity, potency, tolerability, and universality. So it should come as no surprise the momentum associated with the field of small interfering RNA (siRNA)-induced RNA Interference (RNAi) therapeutics has gained strength, as these molecules have shown exceptional promise in fulfilling all of these requirements. Unfortunately, siRNAs are too large, too charged, and too rigid to passively diffuse across the cellular membrane and thereby require a delivery system to enter cells. Thus, since its conception of working in human cells, siRNA delivery remains THE 800 Pound Gorilla in the room. The main complication yet to overcome is engineering delivery systems that are safe and efficient in systemically delivering siRNA molecules to the diseased tissue and across the cellular membrane of target cells. Currently, encapsulating the siRNA in nanoparticle and liposomal systems has risen to become the standard of delivery approaches. While generally speaking these delivery platforms offer significant advancements, our laboratory is committed to generating alternative siRNA delivery technologies that avoid nanoparticle packaging and allow siRNA molecules to be delivered as single, soluble entities. This brief review discusses the first of these technologies, a Peptide Transduction Domain-dsRNA Binding Domain (PTD-DRBD) fusion protein that avidly binds to the siRNA backbone to mask the negative charge and uses the PTD for macromolecular cellular delivery. ... Read more

Abstract: Carbohydrates are ubiquitous and represent the most abundant class of molecules in nature. All cell surfaces are coated with complex carbohydrates where they act as recognition molecules for other cells, functional molecules, and pathogens. Consequently, they are involved in disease indications as diverse as inflammation, cancer, and infectious disease. In general, native carbohydrates lack the properties necessary for efficacious drugs and historically have not been successful candidates to capitalize on these applications. Understanding the bioactive conformation and molecular interactions of functional carbohydrates, however, allows the rational design of small molecule glycomimetics that exhibit improved drug-like properties such as increased affinity, serum half-life, stability, and bioavailability. Recent advances in analytical techniques (i.e., NMR, x-ray crystallization), molecular modeling, and synthetic organic chemistry allow the design of potent glycomimetic compounds, which opens the door to a new class of therapeutic drugs to target molecular mechanisms that can address many of the current unmet needs in the treatment of disease. ... Read more

Abstract: Platelets are key players in hemostasis, but are also involved in fundamental processes of vascular biology such as angiogenesis, tissue regeneration, and tumor metastasis. Microparticles (MP) are small plasma membrane vesicles shed from cells upon their activation or apoptosis. Platelet-derived microparticles (PMP) constitute the majority of the pool of MP circulating in the blood. In this review we will summarize some possible roles of PMP other than participation in blood coagulation. PMP can express and transfer functional receptors from platelet membranes, increase expression of adhesion molecules on cells, stimulate the release of cytokines, activate intracellular signaling pathways, alter vascular reactivity, induce angiogenesis, and are involved in cancer metastasis. The role of PMP in cancer development is unknown but a high PMP level is highly correlated with aggressive tumors and a poor clinical outcome. It has been reported that PMP can stimulate proliferation and adhesion of cancer cells. Given their documented association with pathological conditions, PMP may serve as biomarkers for disease status or as a possible new target for anti-platelet drugs to treat cancer or inflammation. On the other hand, local PMP application may be found useful for developing novel therapeutic strategies targeting angiogenesis-related conditions. ... Read more

Abstract: Increasing evidence suggests an important role for programmed cell death (PCD) pathways in aging phenotypes across species. PCD is critical to the homeostasis of tissues maintained by cell division, for example, the blood and the lining of the gut. During aging, accumulated cellular damage and non-optimal systemic signaling can cause too little cell death (hyperproliferation and cancer), or too much cell death (tissue atrophy and ectopic cell death), thereby limiting tissue function and life span. For these reasons PCD pathways are promising targets for interventions in aging and aging-related diseases: reactivation of PCD may be beneficial in clearing cancerous and senescent cells, whereas inhibiting PCD may help prevent muscle atrophy and nervous system degeneration. ... Read more