Current Pharmacogenomics and Personalized Medicine (Formerly Current Pharmacogenomics) - Volume 16, Issue 3, 2018

Background: Preeclampsia (PE) is a disorder of pregnancy characterised by persistent high blood pressure and proteinuria, which is usually detected after 20 weeks gestation. The pathophysiological mechanisms that underlie the pathogenesis of PE are unclear; although oxidative stress (OS), abnormal placental angiogenesis and endothelial dysfunction are reported to be contributing factors. Despite the synergistic roles OS and placental angiogenesis play in the pathogenesis of PE, very few studies have attempted to integrate both factors in the pathogenesis, diagnosis and treatment of PE. OS also influences placental angiogenesis through redox-sensitive transcription factors; hence understanding how OS influences placental angiogenesis may elucidate potential therapeutic targets for correcting abnormal placental angiogenesis and function in PE. Objective: This article aims to present an insight into the role of OS and angiogenic growth mediators (AGMs) in the pathogenesis of PE. It also provides evidence supporting the fact that OS may directly or indirectly influence placental angiogenesis changes in PE through the expression of a number of reactive oxygen species (ROS)-sensitive transcription factors. Additionally, it covers mainly diagnostic biomarkers of OS and AGMs along with existing biomarkers and treatment options currently available for PE. Conclusion: Understanding the dynamics of preeclampsia will create a window of opportunity for predictive, preventive and personalised medicine (PPPM).

Background: Drug addiction is a major health problem with limited treatment methods. Nowadays, the application of nanotechnology in the diagnosis and treatment of various diseases, such as drug abuse, is increasing. This emerging area of nanotechnology, with its rapid advances in science, opens new horizons in medical science and illness treatment. Nanotechnology research plays an important role in treatment and early diagnosis of pathogens. Objective: Given the severity of the social and economic burden of drug abuse as well as the increasing global rate of death from over-consumption of drugs, in this review, we introduce nanotechnology-based gene therapy strategies for the treatment of drug addiction. Method: A number of relevant published articles 249 were initially collected from three popular databases including Google Scholar, Scopus, and PubMed. Articles that did not have much relevance to this article were deleted from the study process. The present dataset finally included 105 published articles. Results: The results of a close analysis of the articles revealed a paucity of research conducted on the addictive drug-gene therapy by nanoparticles. This was supported by the limited number of articles found for the purpose of the present work. Conclusion: Nanoparticles with low toxicity, high gene transmission efficiency and high bio-compatibility were found to have important application in the combination of diagnosis and treatment in addiction gene therapy, and to cause behavioral changes during drug abuse.

Background: A patient-focused approach to treatment, where individual characteristics provide the selection of optimal medication strategy for a particular patient, is the trend of current clinical therapy. An application of advanced “omics” technologies, which enable to detect the inter-individual variability in genomic, transcriptomic, proteomic, and metabolomic levels is a perspective way to achieve such personalization. Objective: In this review, the advantages of metabolomics-based approach as one of the most promising and perspective for individualization of pharmacotherapy are demonstrated. This approach provides a prediction of the inter-individual variability in drug response and allows monitoring effectiveness of drug treatment, correcting it in account of individual parameters of patients. Method: Comparative analysis of metabolomics-based approach and the current methods of drug treatment personalization are carried out. Results: Advantages and limitations of the metabolomics-based approach were identified and discussed. Conclusion: The perspective ways for solution of limitations of the metabolomics-based approach are considered.

Background: Metformin is recommended in most clinical guidelines as a firstline oral anti-hyperglycemic drug to treat type 2 diabetes. Despite its effectiveness as an anti-hyperglycemic agent, certain genetic variants and conditions may cause metformin accumulation in the body and lead to lactic acidosis- a condition commonly known as Metformin Associated Lactic Acidosis (MALA). Though the incidence of MALA is relatively rare, it is potentially fatal with a mortality rate of 30 to 50%. The mechanism of MALA is not well defined yet. Method: In this study, we explored the molecular mechanism of MALA following an in silico approach. We applied structure modeling and molecular docking tools to predict interactions of metformin with different human Organic Cation Transporters (OCTs) as well as the Complex I of the mitochondrial Electron Transport System (ETS). Results: Molecular docking analyses suggest potential interactions of metformin with the core subunits of the human ETS Complex I that are essential for its function. In silico analyses suggest that metformin can bind to the pores of 8 different OCTs, which are expressed in different organs. Conclusion: Based on these predicted interactions and organ specific gene expression data in the databases, we present here a model to explain the molecular mechanism of MALA.

Background: Tuberculosis is one of the most prevalent infectious diseases. Treatment of tuberculosis requires treatment for a long duration with a combination of drugs such as Isoniazid, Rifampicin, Pyrazinamide and Ethambutol. Certain subsets of the population are more susceptible to adverse effects of treatment with isoniazid. Identification of the related genetic polymorphisms will enable Personalized Medication with optimized combination and dosage of the available drugs for each individual. Objective: Identification of the molecular targets responsible for differences in susceptibility to the adverse effects of isoniazid drug. Method: Inverse docking was used to identify potential molecular targets of isoniazid in the human proteome. The molecular targets and the annotations obtained from inverse docking were compared with those obtained from PharmGKB variant annotations. Results and Conclusion: The results of this study are consistent with and rationalize earlier biochemical, molecular and clinical studies that relate prevalence of isoniazid induced adverse effects to genetic polymorphisms in NAT2, GSTT1, GSTM1 and CYP*. The computational results of this study indicate that MAO, COMT and NNMT are additional potential targets related to variation in isoniazid induced adverse effects.

Background: Paraoxonase is a calcium dependent enzyme which is bound to high density lipoprotein and acts primarily by inhibiting low density lipoprotein oxidation. Its activity is modulated by PON1 polymorphism. Objective: In the present case control study we determined the genotype frequencies of PON1 Q192R and L55M in Indian population and the association between PON activity and lipid markers in patients with coronary artery disease (CAD). Methods: 635 angiographically proven CAD patients from Cardiology & Medicine OPDs of our hospital and 635 age- matched controls were enrolled. Paraoxonase gene polymorphisms were analyzed by PCR-RFLP. Allele frequencies were compared in both patients and controls using Chi-square test. Serum PON1activity towards PON substrates, lipid profile and apolipoprotein A1 was analyzed. Results: Variant allele frequency of R & M in controls and patients was 28% & 37% and 20% & 21% respectively. Phenotypically, Paraoxonase activity was significantly lower in CAD patients as compared to controls, whereas, genotypically, PONase activity was low in all three genotypes in comparison to controls for PON1 polymorphisms. PON1 activity correlated positively with HDLCholesterol and Apo ‘a’ levels (r=0.38 and 0.38). PON1Q192R showed a significantly higher risk for CAD between patients and controls [OR =2.40; CI: 1.58-3.64] for the RR genotype. However, PON1L55M did not show any significant difference between patients and controls. Subgroup analysis showed a significant difference in PON activity and lipid markers between smokers and non-smokers, however, there was no difference among alcoholics & non-alcoholics. Conclusion: The study shows that the PON1-192R allele is strongly associated with CAD patients and affects serum PON1 activity toward paraoxon, implying a higher likelihood of development and/or progression of CAD among Indians.