Previous investigations on chronic kidney disease of unknown etiology characterized by tubulointerstitial damages (CKDu) in the North Central Region (NCR) of Sri Lanka have supported the involvement of social, environmental and genetic factors in its pathogenesis.We conducted a social-environmental-and-genetic epidemiology study on a male population in NCR to investigate the genetic and environmental contributors. We recruited 311 case-series patients and 504 control candidates. Of the 504 control candidates, 218 (43%) were eliminated because of the presence of hypertension, proteinuria, high HbA1c, high serum creatinine or high alpha-1 microglobulin in urine.None of 18 metals measured (μg//) in urine, including Cd, As and Pb, showed significantly higher concentrations in cases compared with controls. As speciation results showed that 75-80% of total urinary As was in the form of arsenobetaine, which is non-toxic to humans. None of the metal concentrations in drinking water samples exceeded guideline values. A genome-wide association study (GWAS) was conducted to determine the genetic contributors. The GWAS yielded a genome-wide significant association with CKDu for a single nucleotide polymorphism (SNP; rs6066043; p=5.23 × 10(-9) in quantitative trait locus analysis; p=3.73 × 10(-9) in dichotomous analysis) in SLC13A3 (sodium-dependent dicarboxylate transporter member 3). The population attributable fraction and odds ratio for this SNP were 50% and 2.13. Genetic susceptibility was identified as the major risk factor for CKDu. However, 43% of the apparently healthy male population suffers from non-communicable diseases, suggesting their possible influence on CKDu progression.
RNF213/Mysterin has been identified as a susceptibility gene for moyamoya disease, a cerebrovascular disease characterized by occlusive lesions in the circle of Willis. The p.R4810K (rs112735431) variant is a founder polymorphism that is strongly associated with moyamoya disease in East Asia. Many non-p.R4810K rare variants of RNF213 have been identified in white moyamoya disease patients, although the ethnic mutations have not been investigated in this population. In the present study, we screened for RNF213 variants in 19 Slovakian and Czech moyamoya disease patients. A total of 69 RNF213 coding exons were directly sequenced in 18 probands and one relative who suffered from moyamoya disease in Slovakia and the Czech Republic. We previously reported one proband harboring RNF213 p.D4013N. Results from the present study identified four rare variants other than p.D4013N (p.R4019C, p.E4042K, p.V4146A, and p.W4677L) in four of the patients. P.V4146A was determined to be a novel de novo mutation, and p.R4019C and p.E4042K were identified as double mutations inherited on the same allele. P.W4677L, found in two moyamoya disease patients and an unaffected subject in the same pedigree, was a rare single nucleotide polymorphism. Functional analysis showed that RNF213 p.D4013N, p.R4019C and p.V4146A-transfected human umbilical vein endothelial cells displayed significant lowered migration, and RNF213 p.V4146A significantly reduced tube formation, indicating that these are disease-causing mutations. Results from the present study identified RNF213 rare variants in 22.2% (4/18 probands) of Slovakian and Czech moyamoya disease patients, confirming that RNF213 may also be a major causative gene in a relative large population of white patients.
Perfluorooctanoic acid (PFOA) is one of the major per- and polyfluoroalkyl substances. The role of ATP-binding cassette (ABC) transporters in PFOA toxicokinetics is unknown.
Molnupiravir is a prodrug of the antiviral ribonucleoside analogue N4-hydroxycytidine (NHC), for use in treatment of coronavirus disease 2019 (COVID-19). However, it is generally considered that NHC-triphosphate is incorporated into the host genome to induce mutations. In our previous preliminary report, we proposed oxidative DNA damage by NHC via cytidine deaminase (CDA)-mediated ROS formation. In the present study, we investigated cell viability using the HL-60 human leukemia cell line and its H2O2-resistant clone, HP100 cells. The survival rate was significantly reduced in HL-60 cells treated with NHC, but not in HP100 cells. LC-MS analysis revealed that uridine formation occurred from CDA-treated NHC, suggesting that CDA metabolizes NHC to uridine and hydroxylamine. We clarified mechanisms of CDA-mediated reactive oxygen species (ROS) generation and DNA damage by NHC using isolated DNA. CDA-treated NHC induced DNA damage in the presence of Cu(II). The DNA damage was enhanced by NADH addition and piperidine treatment. CDA-treated NHC and Cu(II) caused piperidine-labile sites at thymine, cytosine, and guanine, and the DNA cleavage pattern was similar to that of hydroxylamine. Catalase and bathocuproine inhibited the DNA damage, indicating the involvement of H2O2 and Cu(I). An indicator of oxidative DNA damage, 8-oxo-7,8-dihydro-2′-deoxyguanosine formation by CDA-treated NHC, was lower under hypoxic conditions than under normal conditions. Therefore, hydroxylamine, possibly produced from NHC treated with CDA, could induce metal-dependent H2O2 generation during the redox reactions, suggesting that oxidative DNA damage induced by ROS plays an important role in molnupiravir-related cytotoxicity and mutagenicity.
Background and purpose: RNF213 is a susceptibility gene for moyamoya disease (MMD) and over 90% of Japanese patients with MMD have the RNF213 p.R4810K variant. Recent studies have reported that 20 - 25% of East Asian patients with intracranial arterial stenosis also have the p.R4810K variant, while only about 2% of healthy Japanese population have the variant. In this study, we examined the prevalence of this variant in patients with juvenile-onset ischemic stroke. Methods: This single-center cross-sectional study was completed at the National Cerebral and Cardiovascular Center, Osaka, Japan. We analyzed 70 Japanese patients who suffered ischemic stroke or TIA with intracranial arterial stenosis before their 60 th birthday. Patients with cardioembolic stroke or definite/probable MMD were excluded. Results: The RNF213 p.R4810K variant was found in 24.2% of juvenile-onset stroke patients with intracranial arterial stenosis. This variant was found more often in women than in men (38% vs. 16%, OR 3.3, 95% CI 1.1-10.2, p=0.045). The variant was identified in 35% of the patients with stenosis in the M1 segment of the middle cerebral artery or the A1 segment of the anterior cerebral artery (OR 25.0, 95% CI 1.4-437.8, p<0.01), but in only one patient with intracranial posterior circulation stenosis (Table 1). When restricted to patients with multiple M1 or A1 stenoses, the variant prevalence increased to 56%. Conventional risk factors for stroke, such as smoking, hypertension, diabetes mellitus, dyslipidemia, and family history did not differ between patients with and without the variant. Conclusion: The RNF213 p.R4810K variant is common for juvenile-onset ischemic stroke with M1 or A1 stenosis.
Sucrose and high-fructose corn syrup comprise nearly equal amounts of glucose and fructose. With the use of high-fructose corn syrup in the food industry, consumption of fructose, which may be a tumor promoter, has increased dramatically. We examined fructose-induced oxidative DNA damage in the presence of Cu(II), with or without the addition of H2O2. With isolated DNA, fructose induced Cu(II)-mediated DNA damage, including formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), to a greater extent than did glucose, and H2O2 enhanced the damage. In cultured human cells, 8-oxodG formation increased significantly following treatment with fructose and the H2O2-generating enzyme glucose oxidase. Fructose may play an important role in oxidative DNA damage, suggesting a possible mechanism for involvement of fructose in carcinogenesis.
◼ moyamoya disease ◼ RING finger domains ◼ stroke I schemic stroke (IS) is the leading cause of disability and early death in Asia, where large-artery atherosclerosis (LAA) attributable to intracranial stenosis is the predominant etiology.Recently, a large transethnic genome-wide association study identified 32 loci associated with IS 1 ; however, Asian-specific genetic determinants remain unknown.Moyamoya disease (MMD), a rare cerebrovascular disease endemic in East Asia, is associated with a susceptibility gene RNF213, and its dysregulation experimentally impairs cerebral perfusion. 2,3We hypothesized a more general role of RNF213 in IS and examined the association of the p.R4810K variant of the RNF213 gene, the founder variant for MMD for Japanese, Korean, and Chinese, 2 with IS and its subtypes.In this 2-stage case-control study, we analyzed data from 3 independent Japanese population studies with a total of 46 958 individuals of East Asian ancestry (17 752 cases and 29 206 controls).All study participants provided written informed consent, and the responsible ethics committees and the local ethics committee of the National Cerebral and Cardiovascular Center approved the study.Variables were compared by using the Student t test and χ 2 test as appropriate.Stroke subtypes were classified according to TOAST criteria (Trial of Org 10172 in Acute Stroke Treatment).In the primary stage, we examined the p.R4810K genotype using a single hospital-based population with clinical and radiological data (NCVC Biobank: 383 noncardioembolic stroke cases and 1011 controls), excluding patients with MMD (n=12).The RNF213 p.R4810K variant was found in 5.2% of patients with noncardioembolic stroke and in 2.1% of controls (odds ratio [OR], 2.60 [95% CI, 1.39-4.85],P=0.0019).When stratified by subtypes, only LAA was significantly associated with the variant (OR, 5.19 [95% CI, 2.53-10.64],P=2.6×10 -6 ).The mean age of stroke onset was lower in the variant carriers than noncarriers (58.1±15.5 years versus 69.1±13.2years, P=0.0003).The variant carriers included more women (55.0%versus 27.3%, P=0.011), and showed greater frequency of intracranial anterior circulation stenosis (60.0%versus 27.3%, P=0.004).We investigated whether the significant association was replicable.The p.R4810K genotypes were derived from genome-wide genotyping data in Biobank-Japan (16 256 IS cases and 27 294 controls), and the Hisayama and the Fukuoka Stroke Registry (FSR) study (1113 cases and 901 controls).We investigated the association between RNF213 R4810K and IS by imputed allele dosage of R4810K and fitted to logistic regression model with additive genetic model. 1 In the replication stage, the variant was found in 2.3% and 3.8% of patients with ischemic stroke and in 1.3% of both controls in the Biobank-Japan and Hisayama-FSR.In comparison with controls, the carrier frequency was significantly higher in all IS cases (OR, 1.77 [95% CI, 1.40-2.24],P=1.6×10 -6 in Biobank-Japan; OR, 2.90 [95% CI, 1.39-6.04],P=0.0045 in Hisayama-FSR), especially in those with LAA (OR, 3.10 [95% CI, 1.98-4.84],P=6.9×10 -7 in Biobank-Japan; OR, 4.20 [95%
Alzheimer’s disease (AD) is the most common form of dementia among older people. Amyloid β (Aβ) aggregation has been the focus for a therapeutic target for the treatment of AD. Naturally occurring polyphenols have an inhibitory effect on Aβ aggregation and have attracted a lot of attention for the development of treatment strategies which could mitigate the symptoms of AD. However, considerable evidence has shown that the pro-oxidant mechanisms of polyphenols could have a deleterious effect. Our group has established an assay system to evaluate the pro-oxidant characteristics of chemical compounds, based on their reactivity with DNA. In this review, we have summarized the anti-Aβ aggregation and pro-oxidant properties of polyphenols. These findings could contribute to understanding the mechanism underlying the potential risk of polyphenols. We would like to emphasize the importance of assessing the pro-oxidant properties of polyphenols from a safety point of view.
