Metformin is one of the first-line and most widely prescribed drugs to treat type 2 diabetes (T2D). Its clearance from circulation is mostly facilitated by SLC22A2 (OCT2) in the renal cells. SLC22A2 is a polyspecific organic cation transporter and mediate transport of structurally unrelated endogenous and exogenous compounds including many drugs. rs316019 (p.270A > S) is the most common variant of SLC22A2 with a frequency as high as 15% or more in many populations. The 270S form of SLC22A2 clears metformin from circulation at much reduced level compared to the 270A form. If accumulated, metformin increases plasma lactate level in a concentration-dependent manner which can lead to a condition known as metformin-associated lactic acidosis (MALA). MALA is a potentially life-threatening complication with a mortality rate of 30–50%. Pre-existing clinical conditions, such as renal impairment, sepsis, anoxia, etc may make individuals more prone to MALA. In this study, we used computational approaches to investigate the effect of 270A > S change in SLC22A2 on interaction with metformin and other drugs. Based on the structural models, all substrates bind to the same pocket of SLC22A2. The substrates fit better to the binding site of 270A form of SLC22A2. The binding site has a few core interacting residues, among which SER358 appears to be the most important. It is an in silico prediction that the T2D patients, who are under metformin regimen, should be cautious in taking ranitidine (an over-the-counter sold drug) on a regular basis as it may lead to metformin associated lactate accumulation in blood.
Background: Leishmaniasis is a disease caused by the Leishmania sp. and can be classified into two major types: cutaneous and visceral leismaniasis. Visceral leishmaniasis is the deadlier type and is mediated by Leishmania donovani and involves the establishment of persistent infection and causes damage to the liver, spleen and bone marrow. With no vaccine yet available against leishmaniasis and the current therapeutic drugs of leishmaniasis being toxic and expensive; an alternative treatment is necessary. Objective: Surface glycocalyx protein gp63, plays a major role in the virulence and resulting pathogenicity associated with the disease. Henceforth, silencing the gp63 mRNA through the RNA interference system was the aim of this study. Methods: In this study two competent siRNAs and three miRNAs have been designed against gp63 for five different strains of L. donovani by using various computational methods. Target specific siRNAs were designed using siDirect 2.0 and to design possible miRNA, another tool named IDT (IntegratedDNA Technology). Screening for off-target similarity was done by BLAST and the GC contents and the secondary structures of the designed RNAs were determined. RNA-RNA interaction was calculated by RNAcofold and IntraRNA, followed by the determination of heat capacity and the concentration of duplex by DNAmelt web server. Results: The selected RNAi molecules; two siRNA and three miRNA had no off-target in human genome and the ones with lower GC content were selected for efficient RNAi function. The selected ones showed proper thermodynamic characteristics to suppress the expression of the pathogenic gene of gp63.
Background: Metformin is prescribed as a first-line drug to treat type 2 diabetes. It is excreted directly and primarily through the SLC22A2 gene-encoded OCT2 transporter in the kidney. rs316019 (c.808G>T, p.270A>S) is the most common variant of SLC22A2, which affects its capacity to clear metformin from the body. Metformin increases the plasma lactate level in a concentration-dependent manner by inhibiting mitochondrial respiration and may lead to a condition known as metformin-associated lactic acidosis (MALA). MALA is a potentially life-threatening complication that can occur within the clinical doses of metformin. Therefore, dose adjustments based on the SLC22A2 rs316019 variants may be beneficial to maximize the efficacy and minimize the toxicity of metformin. Objective: This study was carried out to develop a simple and fast method to define genotype at the rs316019 locus. This method was applied to estimate the rs316019 allele frequencies in the Bangladeshi population. Methods: We designed allele-specific primers to determine genotype at the rs316019 locus using allele-specific polymerase chain reaction (AS-PCR). AS-PCR data were confirmed by targeted sequencing of randomly selected samples. Results: The DNA sequence chromatograms showed the exact genotypes predicted through the AS-PCR method. A proportion of 79.62, 18.01, and 2.37% of Bangladeshi individuals have GG, GT, and TT genotypes, respectively. Conclusion: We report here a simple and fast method to define genotypes at the rs316019 locus in diabetic patients who are under metformin regimen. Allele frequencies at the rs316019 locus in the Bangladeshi population are close to those reported in other populations.
Porteresia coarctata (Roxb.) Tateoka is an endemic halophyte growing all over the coastal belt of Bangladesh, propagating through rhizomes and setting a few ricelike grains. So exploiting the genetic potential of this wild rice as salt tolerant donor in possible wide crosses with rice (2n = 24) could be useful. We attempted intergeneric hybridization between Oryza sativa L. and P. coarctata. The survival rate of hybrid progenies in embryo culture was low but among them 2 hybrid plants were successfully matured from the intergeneric cross between the cultivated induced tetraploid of rice, Latisail (2n = 4x = 48) and P. coarctata (2n = 48). The hybrid plants could be successfully established in soil and were not like either of the parents in morphology although some of their features were similar to their maternal parent, Latisail (4x). Both of the hybrids were investigated through physiological analysis under salinity stress and molecular analyses with rice specific SSR markers. Molecular analysis of the F 1 DNA with only 3 SSR markers, RM581, RM20224 and RM25271, out of 36 others tested, showed bands specific to both of the parents, while all had common bands with the maternal parent. Dendrogram analysis of the hybrids with the 36 SSR markers, show that P. coarctata forms a different clade and is clearly separated from Latisail and the hybrids. The putative hybrids however made a subgroup with Latisail. These observations could be possibly explained if chromosome loss of the paternal
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