scholarly journals Essential role of DNA-PKcs and plasminogen for the development of doxorubicin-induced glomerular injury in mice

2021 ◽  
Vol 14 (9) ◽  
Author(s):  
Bernhard N. Bohnert ◽  
Irene Gonzalez-Menendez ◽  
Thomas Dörffel ◽  
Jonas C. Schneider ◽  
Mengyun Xiao ◽  
...  
Keyword(s):  
Essential Role ◽  
Mendelian Inheritance ◽  
Glomerular Injury ◽  
Nucleotide Polymorphism ◽  
Repair Enzyme ◽  
Gene Encoding ◽  
Single Nucleotide ◽  
Genetic Deficiency ◽  
Glomerular Damage

ABSTRACT Susceptibility to doxorubicin-induced nephropathy (DIN), a toxic model for the induction of proteinuria in mice, is related to the single-nucleotide polymorphism (SNP) C6418T of the Prkdc gene encoding for the DNA-repair enzyme DNA-PKcs. In addition, plasminogen (Plg) has been reported to play a role in glomerular damage. Here, we investigated the interdependence of both factors for the development of DIN. Genotyping confirmed the SNP of the Prkdc gene in C57BL/6 (PrkdcC6418/C6418) and 129S1/SvImJ (PrkdcT6418/T6418) mice. Intercross of heterozygous 129SB6F1 mice led to 129SB6F2 hybrids with Mendelian inheritance of the SNP. After doxorubicin injection, only homozygous F2 mice with PrkdcT6418/T6418 developed proteinuria. Genetic deficiency of Plg (Plg−/−) in otherwise susceptible 129S1/SvImJ mice led to resistance to DIN. Immunohistochemistry revealed glomerular binding of Plg in Plg+/+ mice after doxorubicin injection involving histone H2B as Plg receptor. In doxorubicin-resistant C57BL/6 mice, Plg binding was absent. In conclusion, susceptibility to DIN in 129S1/SvImJ mice is determined by a hierarchical two-hit process requiring the C6418T SNP in the Prkdc gene and subsequent glomerular binding of Plg. This article has an associated First Person interview with the first author of the paper.

scholarly journals Metalaxyl Resistance in Phytophthora infestans: Assessing Role of RPA190 Gene and Diversity Within Clonal Lineages

2015 ◽  
Vol 105 (12) ◽  
pp. 1594-1600 ◽  
Author(s):  
Michael E. H. Matson ◽  
Ian M. Small ◽  
William E. Fry ◽  
Howard S. Judelson
Keyword(s):  
Phytophthora Infestans ◽  
Nucleotide Polymorphism ◽  
High Resolution Melt ◽  
Gene Encoding ◽  
Single Nucleotide ◽  
Metalaxyl Resistance ◽  
The Us ◽  
Polymerase I ◽  
Late Blight Pathogen

Prior work has shown that the inheritance of resistance to metalaxyl, an oomycete-specific fungicide, is complex and may involve multiple genes. Recent research indicated that a single nucleotide polymorphism (SNP) in the gene encoding RPA190, the largest subunit of RNA polymerase I, confers resistance to metalaxyl (or mefenoxam) in some isolates of the potato late blight pathogen Phytophthora infestans. Using both DNA sequencing and high resolution melt assays for distinguishing RPA190 alleles, we show here that the SNP is absent from certain resistant isolates of P. infestans from North America, Europe, and Mexico. The SNP is present in some members of the US-23 and US-24 clonal lineages, but these tend to be fairly sensitive to the fungicide based on artificial media and field test data. Diversity in the level of sensitivity, RPA190 genotype, and RPA190 copy number was observed in these lineages but were uncorrelated. Controlled laboratory crosses demonstrated that RPA190 did not cosegregate with metalaxyl resistance from a Mexican and British isolate. We conclude that while metalaxyl may be used to control many contemporary strains of P. infestans, an assay based on RPA190 will not be sufficient to diagnose the sensitivity levels of isolates.

scholarly journals Genetic polymorphism for IFNγ +874T/A in patients with acute toxoplasmosis

2012 ◽  
Vol 45 (6) ◽  
pp. 757-760 ◽  
Author(s):  
Elizabeth de Souza Neves ◽  
André Luis Land Curi ◽  
Maira Cavalcanti de Albuquerque ◽  
Cassius Schnel Palhano-Silva ◽  
Laura Berriel da Silva ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphism ◽  
Case Control Study ◽  
Severe Disease ◽  
Clinical Manifestations ◽  
Nucleotide Polymorphism ◽  
Gene Encoding ◽  
Single Nucleotide ◽  
Duration Of Disease ◽  
Acute Toxoplasmosis ◽  
Control Study

INTRODUCTION: A single nucleotide polymorphism (SNP) in the gene encoding gamma interferon influences its production and is associated with severity of infectious diseases. This study aimed to evaluate the association of IFNγ+874T/A SNP with duration of disease, morbidity, and development of retinochoroiditis in acute toxoplasmosis. METHODS: A case-control study was conducted among 30 patients and 90 controls. RESULTS: Although statistical associations were not confirmed, A-allele was more common among retinochoroiditis cases and prolonged illness, while T-allele was more frequent in severe disease. CONCLUSIONS: Despite few cases, the results could indicate a relation between IFNγ+874T/A single nucleotide polymorphism and clinical manifestations of toxoplasmosis.

scholarly journals Prevalence of ACSL (rs6552828) polymorphism among runners

2019 ◽  
Vol 24 ◽  
pp. 121-128
Author(s):  
Sigal Ben-Zaken ◽  
Yoav Meckel ◽  
Dan Nemet ◽  
Alon Eliakim
Keyword(s):  
Single Nucleotide Polymorphism ◽  
Genetic Basis ◽  
Maximal Oxygen Consumption ◽  
Professional Athletes ◽  
Distance Runners ◽  
Nucleotide Polymorphism ◽  
Long Distance ◽  
Single Nucleotide ◽  
The Common

The ACSL A/G polymorphism is associated with endurance trainability. Previous studies have demonstrated that homozygotes of the minor AA allele had a reduced maximal oxygen consumption response to training compared to the common GG allele homozygotes, and that the ACSL A/G single nucleotide polymorphism explained 6.1% of the variance in the VO2max response to endurance training. The contribution of ACSL single nucleotide polymorphism to endurance trainability was shown in nonathletes, however, its potential role in professional athletes is not clear. Moreover, the genetic basis to anaerobic trainability is even less studied. Therefore, the aim of the present study was to examine the prevalence of ACSL single nucleotide polymorphism among professional Israeli long distance runners (n=59), middle distance runners (n=31), sprinters and jumpers (n=48) and non-athletic controls (n=60). The main finding of the present study was that the ACSL1 AA genotype, previously shown to be associated with reduced endurance trainability, was not higher among sprinters and jumpers (15%) compared to middle- (16%) and long-distance runners (15%). This suggests that in contrast to previous studies indicating that the ACSL1 single nucleotide polymorphism may influence endurance trainability among non-athletic individuals, the role of this polymorphism among professional athletes is still not clear.

scholarly journals A ROLE OF POLYMORPHONUCLEAR LEUKOCYTES AND COMPLEMENT IN NEPHROTOXIC NEPHRITIS

1965 ◽  
Vol 122 (1) ◽  
pp. 99-116 ◽  
Author(s):  
Charles G. Cochrane ◽  
Emil R. Unanue ◽  
Frank J. Dixon
Keyword(s):  
Polymorphonuclear Leukocytes ◽  
Basement Membranes ◽  
Ultrastructural Changes ◽  
Glomerular Injury ◽  
Large Numbers ◽  
Secondary Stage ◽  
Vascular Beds ◽  
Nephrotoxic Nephritis ◽  
Glomerular Damage

In acute nephrotoxic nephritis, polymorphonuclear leukocytes (polymorphs) accumulated in large numbers in the glomeruli in the first 12 hours. The endothelial cells were dislodged by the polymorphs which then came to lie immediately adjacent to the glomerular basement membranes. Ultrastructural changes in neither polymorphs nor basement membranes were observed. Depletion of polymorphs in both rats and rabbits prevented the development of proteinuria. This occurred when doses of nephrotoxic globulin were employed that produced proteinurias of as much as 1800 mg/kg/24 hours in intact rabbits, or enough to yield near maximal immediate proteinuria in intact rats. In addition, measurable glomerular damage was frequently averted until the onset of the secondary stage of NTN. Controls indicated that the polymorph depleted animals exhibited minimal non-specific changes in the blood, that the ability of their vascular beds to react to stimuli was not affected, and that deposition of nephrotoxic antibody and C' in the glomeruli was not inhibited. Elimination of polymorphs from the circulation was only partially effective in preventing glomerular damage when large doses of nephrotoxic globulin were used. This indicated that under these circumstances, a polymorph independent glomerular injury may also take place in first stage nephrotoxic nephritis. An indirect role of C', i.e., the accumulation of polymorphs, in bringing about glomerular injury in first stage nephrotoxic nephritis was apparent. When rabbit nephrotoxic globulin was injected into rats depleted of C', or when duck nephrotoxic globulin that fixed C' poorly was injected into normal rats, C' failed to bind with the antibody along glomerular basement membranes and polymorphs did not accumulate.

PERSONALIZED APPROACH TO THE USE OF MACROLIDES IN THE TREATMENT OF COMPLICATED FORMS OF ACUTE BACTERIAL RHINOSINUSITIS

2019 ◽  
Vol 25 (3) ◽  
pp. 60-72
Author(s):  
A.P. Smirnov ◽  
◽  
P.A. Shamkina ◽  
A.A. Krivopalov ◽  
Yu.K. Yanov ◽  
...  
Keyword(s):  
Protein Function ◽  
English Language ◽  
Nucleotide Polymorphism ◽  
Gene Encoding ◽  
Single Nucleotide ◽  
Homozygous Genotype ◽  
Major Allele ◽  
Acute Bacterial Rhinosinusitis ◽  
Personalized Approach ◽  
Genetically Determined

The purpose was to assess the possibilities of applying a personalized approach to the appointment of macrolides in acute bacterial rhinosinusitis, depending on the carrier of single-nucleotide polymorphism genes. Materials and methods. An analysis of Russian and English-language publications was conducted with a search depth of 30 years. Results. The main enzymes involved in macrolide pharmacokinetics are P-gp, OATP1B1, OATP1B3, CYP3A4, MRP2. P-gp activity is higher in carriers of the homozygous genotype in the major allele C (3435CC, 48.33%) and the heterozygous genotype (3435CT, 45.90%) of the SNPs rs1045642, whereas the lowest activity was detected in the carriers of the homozygote genotype in the minor allele T (3435 TT, 31.62%), P = 0.02. SNPS 521 T> C (rs4149056) in the SLCO1B1 gene, encoding because of the need for OATP1B1*5, associated with changes in the activity of the protein that carries and erythromycin metabolizing, respectively, in homozygous carriers of the major T allele (P = 0.0072). The activity of the 3A4 isoenzyme in the liver in homozygous carriers of negative T (CC) alleles was 1.7 and 2.5 times higher than in heterozygous (ST) and homozygous (TT) carriers of the minor T allele (rs35599367). The homozygous carriage of the G major allele (rs717620) is associated with a reduced protein function, the homozygous carriage of the minor A allele is associated with an increase in the activity of the MRP2 protein. Conclusion. Genetically determined differences in the pharmacokinetics and pharmacodynamics of macrolides were detected depending on the gene carrier of the SNP ABCB1, SLCO1B1, CYP3A4, АВСС2. Knowledge of the genetically determined metabolism of macrolides in humans can provide new insights into the systemic effects that are available and clinically interesting from their appointment.

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