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Background Environmental pollutants can affect N6-methyladenosine (m6A) level in the body, but the change of m6A level in kidney after being exposed to cadmium (Cd) and the molecular mechanism of renal injury need to be further studied. Objective To analyze the associations of m6A modification and methyltransferases/demethylases with microRNA-21 (miR-21) and transforming growth factor- β1 (TGF - β1) in kidney of rats exposed to Cd. Methods Twenty-four SPF male SD rats were divided into 4 groups, with 6 rats in each group, and were exposed to Cd by subcutaneous injection of 2.0, 1.0, and 0.5 mg·kg−1 cadmium chloride (CdCl2) and equal volume of normal saline for 2 weeks, 7 d a week, respectively. The levels of N-acetyl-β-D-glucosidase (UNAG) and albumin (UALB) in urine, and the levels of m6A methylation and TGF-β1 in kidney were detected by enzyme-linked immunosorbent assay (ELISA). The level of blood urea nitrogen (BUN) was measured by urease method. The levels of renal oxidative stress indicators such as malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) were detected by total bile acid method, water-soluble tetrazolium asssay, and colorimetric method respectively. The relative levels of TGF-β1, methyltransferases, and demethylases in kidney were measured by reverse transcription-polymerase chain reaction. The expression of miR-21 in kidney was detected by fluorescent quantitative polymerase chain reaction. Results After 2 weeks of exposure to Cd, the body weights of rats in the 2.0 and 1.0 mg·kg−1 cadmium chloride groups decreased, and the ratio of kidney/body weight and the levels of BUN, UNAG, and TGF-β1 mRNA and protein increased in the 2.0 mg·kg−1 cadmium chloride group (P<0.05). The expression levels of m6A modification, methyltransferases METTL3, METTL14, Wilms’ tumor 1-associated protein (WTAP), and miR-21 were increased both in the 2.0 and 1.0 mg·kg−1 cadmium chloride groups, with significant differences compared with the control group (P<0.05). The results of correlation analysis showed that the m6A modification level was negatively correlated with SOD (r=−0.4489, P<0.05) and GSH-Px (r=−0.4874, P<0.05), METTL3 was negatively correlated with MDA (r=−0.5158, P<0.05), while there was a positive correlation between FTO and GSH-Px (r=0.4802, P<0.05). In addition, miR-21 was positively correlated with METTL3 (r=0.7491), METTL14 (r=0.6157), and WTAP (r=0.6660) (P<0.05), TGF-β1 was positively correlated with METTL3 (r=0.5025, P<0.05) but negatively correlated with FTO (r=−0.5634, P<0.05) . Conclusion Cd can induce m6A methylation and up-regulation of METTL3, METTL14, WTAP, and miR-21 expression levels in rat kidney tissues, indicating that m6A and miR-21 may be associated with Cd-induced renal fibrosis.
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Background Individual lead or cadmium exposure can cause abnormal blood glucose level and changes in telomere length, and the role of telomere length in the relationship between heavy metal joint exposure and blood glucose level is still unclear. Objective To explore the role of telomere length in the relationship between lead and cadmium coexposure and blood glucose. Methods A cross-sectional study was conducted. By convenient sampling method, 600 residents living in two communities in a city in North China were selected as participants from April to June 2016. Face-to-face interviews were performed to collect general demographics and lifestyles of the participants. The peripheral blood samples of the participants were collected for blood glucose and telomere length detection, the urine samples were collected for urinary cadmium, urinary lead, and urinary creatinine measurement, and both urinary cadmium and urinary lead were corrected by urinary creatinine. The included participants were divided into a control group, a high-cadmium and low-lead group, a high-lead and low-cadmium group, and a high-lead and high-cadmium group, according to the median levels of urinary cadmium and urinary lead. A restricted cubic spline model was constructed to analyze the relationship between urinary lead/cadmium levels and blood glucose concentrations in the four groups and the relationship between cadmium exposure and telomere length in the high-lead and high-cadmium group. Intermediary model test was conducted to analyze the effect of telomere length on the relationship between exposures to lead and cadmium and blood glucose. Results The included participants were divided into the control group (n=99), the high-cadmium and low-lead group (n=91), the high-lead and low-cadmium group (n=145), and the high-lead and high-cadmium group (n=265). The differences in age, education level, per capita monthly household income, smoking, blood glucose, and telomere length were statistically significant among the four groups (P＜0.05). The high-lead and high-cadmium group had the highest blood glucose concentration, (5.63±1.68) mmol·L−1, and the shortest telomere length, (2.63±1.05) Kb. The restricted cubic spline results showed that urinary cadmium level was correlated with blood glucose concentration in the high-lead and high-cadmium group (F=3.45, P=0.037), and there was a non-linear association (F=6.91, P=0.002); the association between urinary cadmium level and telomere length was also non-linear (F=5.93, P=0.043). The intermediary model test results showed that telomere length was a mediating variable between urinary cadmium level and blood glucose concentration, and the mediating effect size was 0.0192 (95%CI: 0.0007-0.0563), with a mediation ratio of 15.57%. Conclusion Correlations between urinary cadmium and blood glucose and between urinary cadmium and telomere length were observed in the high-lead and high-cadmium coexposure group, and telomere length may play a mediating role in the relationship between them.
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AlM: To analyze the prescribing of different antiplatelet drugs and clinical conditions of patients with coronary heart disease in department of Geriatrics. METHODS: This study was a single center and cross-sectional study. Patients with coronary heart disease were recruited when hospitalized in the department of Geriatrics department, Xiangya Hospital, Central South University between December 2021 and June 2022. We investigated and analyzed the clinical conditions of patients including the prescribing of the antiplatelet drugs. RESULTS: A total of 347 coronary heart disease patients with a mean age of (65.2 ± 10.1) years were included. The antiplatelet drug clopidogrel was the most commonly prescribed. Among the different dual antiplatelet therapy (DAPT), aspirin combined with clopidogrel was the most widely used. With the increasing of the numbers of target coronary lesions, the prescribing rate of clopidogrel increased significantly (P < 0.05). In three groups with different degrees of target coronary lesions, the prescribing rate of aspirin was higher than that of indobufene (P < 0.05). Compared with patients taking aspirin, the patients taking indobufene were older with a higher blood creatinine level, a higher proportion of chronic gastropathy and the higher level of platelet aggregation rates (P < 0.05). CONCLUSlON: Clopidogrel is the most commonly prescribed antiplatelet drugs in patients with coronary heart disease. Aspirin combined with clopidogrel is the most widely used in DAPT. Compared with aspirin, indobufene is more commonly used in elderly patients with the chronic gastritis and a higher serum creatinine level.
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Background Exposure to environmental lead can cause kidney damage and telomere wear. However, the relationship among lead, peripheral blood telomere length, and glomerular filtration rate (eGFR) are unclear. Objective This study is conducted to investigate the relationships of urinary lead level with peripheral blood telomere length and renal function index eGFR, and further explore whether peripheral blood telomere length plays an intermediary role in the relationship between urinary lead level and eGFR. Methods A case-control study was conducted to select 497 residents from two communities in a city, including 230 in the control group (eGFR≥80 mL·min−1) and 267 in the abnormal eGFR group (eGFR<80 mL·min−1). Basic information and health information of the subjects were collected through a face-to-face questionnaire survey. Fasting morning urine was collected, and urinary lead and urinary creatinine (UCr) were detected. Fasting peripheral venous blood was collected to detect telomere length and serum creatinine (SCr) in peripheral blood leukocytes. eGFR was estimated by the Levey formula. After further adjusting for age, gender, education level, family per capita monthly income, smoking, and drinking the relationship among urinary lead level, peripheral blood telomere length, and renal function index eGFR was evaluated by mediating effect analysis. Results The overall level of creatinine-adjusted urinary lead [M (P25, P75)] in the abnormal eGFR group was 3.85 (1.56, 7.34) μg·g−1 which was higher than that in the control group, 1.57 (0.60, 3.62) μg·g−1(P<0.001). In addition, the overall level of peripheral blood telomere length in the abnormal eGFR group was 2.42 (1.89, 3.10) Kb, lower than that in the control group, 2.69 (2.09, 3.64) Kb (P<0.001). The results of mediating effect analysis showed that the magnitude of mediating effect by peripheral blood telomere length was −0.276 (95%CI: −0.708-−0.001) and it contributed 3.35% to the relationship between urinary lead level and eGFR. In women, the magnitude of mediating effect by peripheral blood telomere length was −0.484 (95%CI: −1.160-−0.023) between urinary lead level and eGFR, and the proportion of the mediating effect was 5.34%. In men, no mediating role of peripheral blood telomere length was found between urinary lead and eGFR. Conclusion Urinary lead level is closely related to renal function index eGFR and telomere length in peripheral blood. Peripheral blood telomere length plays a mediating role in the relationship between female urinary lead and eGFR in women.
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【Objective】 To explore the role of RYBP in activating PARP-1 dependent Parthanatos and promoting response to YM155 in esophageal squamous cell carcinoma. 【Methods】 CCK-8 and flow cytometry were used to analyze the inhibition ratio and cell death percentage after YM155 treatment in both RYBP overexpression group and control group. Western blotting was used to detect the expression of Parthanatos-related proteins. 【Results】 Compared with control group, RYBP overexpression group showed higher inhibition ratio and cell death percentage after YM155 treatment. Overexpression of RYBP activated PARP-1 with or without YM155 treatment. Besides, after YM155 treatment, KYSE170-RYBP showed more PAR accumulation in the nucleus, AIF translocation from mitochondria to the nucleus than control cells. 【Conclusion】 RYBP can activate PARP-1/PAR/AIF-dependent induced Parthanatos in esophageal squamous cell carcinoma and enhance response to YM155.
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Objective To establish a mouse model of kidney-yin and kidney?yang deficiency after oral administra?tion of hydrocortisone, and to explore the related evaluation factors. Methods The model was established by oral adminis?tration of hydrocortisone to induce kidney?yin and kidney?yang deficiency in mice. The survival and body weight of the mice were observed. The serum content of adrenal cortical hormone ( ACTH) , cortisol ( Cor. ) in the hypothalamic?pituitary?ad?renal (HPA) axis, and thyroid stimulating hormone (TSH), triiodothyronine (T3), thyrox (T4) in the hypothalamic?pi?tuitary?thyroid (HPT) axis, follicle?stimulating hormone (FSH), estradiol (E2), testosterone (T) in the hypothalamic?pituitary?gonadal ( HPG) axis were determined by radioimmunoassay. Results The body weight of kidney?yin and kidney?yang mice were decreased, the serum ACTH, Cor, TSH, T3, T4 contents were decreased, the serum FSH, E2, T contents were increased in the kidney?yang deficiency model mce ( P<0. 01 ) , and those parameters in the kidney?yin deficiency model mice were changed in opposite direction. Conclusions It is found that the hormone levels of ACTH, Cor, TSH, T3, T4, FSH, E2 and T in kidney deficiency mice are changed, and cortisol can be used as an important index to evaluate the model of kidney deficiency induced by glucocorticoid.
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γ-Secretase is aⅠtransmembrane protease associated with Alzheimer disease(AD), and including four subunits:presenilin,presenilin enhancer-2,anterior-pharynx-defective1 and nicastrin. In recent studies,the ultra-high-resolution cryo-electron microscope has been used for the first time, revealing the humanγ-secretase″horseshoe″,the three-dimensional structure and the arrangement of the subunits. This technique has shed light on the regulation of the enzyme pathway and mechanism. In addition,the γ-secretase modulators,including non-steroidal anti-inflammatory drugs,have been shown in vitro to inhibit γ-secretase activity and selectively reduce the level of Aβ42 against AD. They have provided an effective approach,with broad prospects for development. Studies in this area have become a hot topic in recent years. Here we summarized the γ-secretase subunits regulatory pathways, humanγ-secretase fine three-dimensional structure andγ-secretase modulators .