Current Pharmacogenomics and Personalized Medicine (Formerly Current Pharmacogenomics) - Volume 13, Issue 2, 2015

Background: Obsessive-compulsive disorder (OCD) is a common mental illness and a ubiquitous cause of disability. Approximately half of the patients with OCD only partially respond or do not respond at all to current ways of treatment. Even patients responding to treatment usually need high doses of medication and/or intense psychotherapy for a long time. It is obvious that therapeutic approaches to OCD need improving. In this article, we review the modalities of personalized medicine in OCD. Methods: We conducted a search in PubMed (until June 2015) and Scopus (until June 2015) by using the following terms: “obsessive-compulsive disorder,” “personalized medicine,” “response prediction,” “pharmacogenetics,” “therapeutic drug monitoring,” “EEG,” “neuroimaging” and “serotonin.” The literature about neuroimaging including radiological techniques (positron emission tomography, single-photon emission tomography, functional and morphometric magnetic resonance imaging and magnetic resonance spectroscopy) and electroencephalography, therapeutic drug monitoring (measuring the plasma levels of drugs), pharmacogenetics (genes encoding cytochrome P450 enzymes, serotonin transporter, serotonin receptors, norepinephrine transporter, dopamine receptors, brain-derived neurotrophic factor [BDNF] and catechol-O-methyltransferase) and biochemistry (whole blood serotonin levels and neuroendocrine challenge tests) is investigated. Results: Pre-treatment changes in glucose metabolism shown by radiological instruments might be related to response to medication. Increased alpha in EEG is predictive of good response whereas increased theta forecasts a poor response. BDNF, serotonin receptors and glutamatergic and serotonergic transmission have been found to be somewhat related to treatment response in OCD. Few studies on whole blood serotonin levels and hormone response to challenge with a serotonergic medication in patients seem to have a predictive value in OCD treatment. Conclusion: Although the studies to elaborate a personalized treatment of OCD have produced some promising results, much more work is required to provide clinician with a reliable decision tree.

Background: There is a plethora of studies indicating temporal relationship between utilization of Omega-3-fatty acids and amelioration of emotional distress including depression. Some studies have also emerged to indicate the role of fish oil (FO) as adjunct therapy for depressive symptoms in clinical literature. In order for such view to have heuristic value, pre-clinical behavioral paradigms are needed to scrutinize whether FO has efficacy as adjunct therapy for depressive symptoms. In order to fill the gap in the literature, this study examined the effects of FO on behavior in untreated mice, and mice treated with the antidepressant drug fluoxetine. Method: Male/female mice were randomly grouped and orally treated for 28 days with saline (control), FO (0.05 or 0.1 mL/day), fluoxetine alone (10 mg/kg), and fluoxetine (1 or 10 mg/kg) given with FO (0.05 or 0.1 mL / day). After 28 days, the mice were subjected to two indices of despair and helplessness, viz forced swimming test (FST), and tail suspension test (TST) along with motor activity. Results: In the FST, FO at two different doses (0.05mL or 0.1 mL) decreased the immobility time and this effect was not potentiated by combining fluoxetine. In TST, FO significantly decreased the immobility time compared to control (saline) at same doses and this effect that was not potentiated by adding fluoxetine. Motor activity was not significantly affected by any of the treatments. Conclusion: FO displayed anti-depressant - like action suggested by the FST and TST. Combined treatment with fluoxetine and FO did not significantly affect the performance of mice on these two tests. This suggest FO has direct bearing on the present reported behavioral paradigm of despair and helplessness. Future studies to explore molecular the molecular mechanisms behind the presently observed behavioral effect of FO in this animal model.

Background: The survival of all biological systems depends on a series of complex pathways of maintenance and repair systems, which are the crucial components of the homeodynamic space of an individual. A progressive failure of maintenance and the consequent shrinkage of the homeodynamic space are the fundamental basis of ageing, age-related diseases and eventual death. Mechanisms: Although longevity assurance genes do affect the essential lifespan of a species, there are no gerontogenes with the specific function to cause ageing and to limit the lifespan of an individual. Approaches: Age-related diseases and other health problems may be better tackled by abandoning the futile hope of discovering the one-shot age-reversing or anti-ageing treatments. Developing realistic, practical and wholistic methods, such as mild stress-induced hormesis by physical, nutritional and mental hormetins, for maintaining health for a longer period are more likely to succeed.

Background: Mitochondria are critically important in providing cellular energy ATP. They also play important roles in anti-oxidant defense, fat oxidation, intermediary metabolism and cell death processes. It is well-established that mitochondrial functions are suppressed through nitroxidative stress when living cells or organisms are exposed to potentially toxic agents including alcohol, high fat diets, smoking and certain drugs or in many pathophysiological states. Under elevated nitroxidative stress, cellular macromolecules proteins, DNA, and lipids can undergo different types of modification, usually leading to disruption of their normal, sometimes critical, physiological functions. Recent reports have also indicated that many mitochondrial proteins are suppressed through various post-translational modifications (PTMs), contributing to mitochondrial dysfunction and cell death, as observed in many distinct neurodegenerative diseases including Alzheimer’s Disease (AD), Parkinson’s Disease (PD), Huntington’s Disease (HD), alcoholic dementia, and ischemia-reperfusion related brain injury (stroke). Methods: In this review article, we have described an overview of the sensitive methods we developed for the detection of PTMs of mitochondrial proteins. And by using in vitro AD mouse model, we demonstrated that dietary supplements can alleviate the disease condition by inhibiting pro-inflammatory cytokines and mediating protective effects. Results: Here, we have discussed the simple methods that we developed in our lab for the detection of PTMs of mitochondrial proteins, and have shown that how PTMs affect the normal cellular functions. Secondly, we have also discussed the role of natural antioxidants, including plant flavonoids and polyphenols that can inhibit or delay the formation of reactive oxygen/nitrogen species, prevent the mitochondrial dysfunction and apoptosis in various neurodegenerative diseases. Conclusion: In conclusion, we made an attempt to give an overview on the PTMs of mitochondrial proteins and their importance in understanding the role of mitochondrial dysfunction and apoptosis in neurodegenerative diseases. Furthermore, we described the PTMs (oxidation, nitration, phosphorylation, etc.) of mitochondrial proteins that may play an important role in mitochondrial dysfunction and promote neuro-degeneration. We also concluded that ingesting healthy diets combined with physical exercise may restore normal mitochondrial functions (Fig. 1). Furthermore, a better understanding of the mitochondrial dynamics as well as nitroxidative stress may lead to the development of new translational approaches for the prevention and treatment of mitochondria-related neurodegenerative diseases.

Background: Since the last decade, the therapeutic potentials of natural phenolic antioxidants in human diseases associated with oxidative damage have received great attention. Within the last few years, a rapidly growing number of natural compounds with neuro-protective effects have been described. Many efforts have been made to explore the mechanisms for the neuro-protective properties of natural compounds. This review focuses on the beneficial effects of natural products in treating traumatic brain injury (TBI). Numerous epidemiological studies have shown consistent health benefits through the consumption of fruits, vegetables and nuts. In this review, we have summarized the protective effects of natural compounds [apocynin, (-)-epigallocatechin Gallate (EGCG), baicalein, caffeic acid, caffeic acid phenethyl ester, hydroxysaffloryellow A, osthole, oxy-resveratrol, pycnogenol, resveratrol, salvianolicacid B, triptolide and wogonin], and omega-3 fatty acid, particularly docosahexaenoic acid and its metabolites, may be used as personalized medicine against TBI and we have also discussed some of the barricades in translating these biofunctional compounds into relevant therapeutics for TBI. Conclusion: The benefits of natural products for traumatic brain injury show high inter-individual variability in their therapeutic effects and thus, this article addresses the intersection between novel therapeutics for traumatic brain injury and personalized medicine that will allow a broader range of interventions including the evidence-based natural products.

Acute myeloid leukemia (AML) is the most common leukemia diagnosed in adults and curative treatments remain currently a great challenge. AML occur in about 60% of patients over 60 years with unsatisfactory survival results, which have not improved significantly over the last two decades, in spite of improved supportive care. Global genomic instability is the hallmark of the disease, leading to chromosomal/molecular alterations, proliferative advantage and clonal heterogeneity. Epigenetic deregulation of gene expression is considered as a consequence and/or the initiating cause of this instability and DNA methylation is one of the most commonly occurring epigenetic events in this setting. The plasticity of the epigenome, compared to the conserved status of the genome, designed it as a therapeutic target especially in AML. Among novel therapeutic agents, the availability of compounds targeting epigenetic modifiers offers the opportunity to have new therapeutic insights with improvement of outcome, especially in older patients, while reducing toxicity. We reviewed herein some of the epigenetic mechanisms involved in normal hematopoiesis, which may be deregulated in AML, and therapeutic potentials of cell re-programming.