Phosphodiesterases (PDEs) from Snake Venoms: Therapeutic Applications.

BACKGROUND: Snake venom, a highly poisonous and active venomous snake's secretion, is a complex mixture of inorganic cations, carbohydrates, lipids, proteins, peptides, toxins and hydrolytic enzymes of importance including Phosphodiesterases (PDEs). These snake venom hydrolytic enzymes interfere in different physiological processes. Snake venom PDEs have several roles to metabolize extracellular nucleotides and to regulate nucleotide based intercellular signalling mechanisms including platelet aggregation, which can lead to death and debilitation in cardiac arrest and strokes in patients having cerebro-vascular and cardiovascular diseases, hypertension and atherosclerosis which is the primary cause of life-threatening diseases such as, stroke and myocardial- infarction. CONCLUSION: PDEs are used to synthesize modified oligonucleotides, which are useful in potential therapeutic applications. Characterization of PDEs from different snake venoms has potential in identifying new anticoagulants that target specific active sites, which leads to the treatment of haemostatic disorders. Here, we review the snake venom PDEs potential therapeutic activity against platelet aggregation which could provide ideal platforms to design drugs for treatment or to fight against unwanted clots formation.

Genetic variants in LEP, LEPR, and MC4R explain 30% of severe obesity in children from a consanguineous population.

OBJECTIVE: Single gene mutations leading to severe obesity have so far been identified in 3-5% cases in European populations. However, prevalence of these pathogenic mutations has not systematically been examined in specific consanguineous populations. Here we describe the incidence of obesity-associated mutations through a step-wise sequence analysis, in a cohort of 73 Pakistani children with severe obesity from consanguineous families. METHODS: Initially, all subjects were screened for mutations in coding regions of leptin (LEP) and melanocortin 4 receptor (MC4R) genes by direct sequencing. Subjects negative for mutation in these genes were screened using microdroplet PCR enrichment and NGS. Genomic structural variation was assessed by genotyping. Serum leptin, insulin, and cortisol were determined by ELISA. RESULTS: Among 73 children with severe obesity (BMI SDS > 3.0), we identified 22 probands and 5 relatives, carrying 10 different loss-of-function homozygous mutations in LEP, leptin receptor (LEPR), and MC4R genes, including 4 novel variants. Hypercortisolemia was significantly emphasized in LEP mutation carriers. CONCLUSIONS: The prevalence of pathogenic mutations in genes known to directly influence leptin-melanocortin signaling is 30% in our cohort. The results of this study emphasize the desirability of undertaking systematic and in-depth genetic analysis of cases with severe obesity in specific consanguineous populations.