Association of ABCG2 polymorphisms with susceptibility to anti-tuberculosis drug-induced hepatotoxicity in the Chinese population.

The accumulation of endogenous hepatotoxin protoporphyrin IX (PPIX) in the liver was proposed to be a novel mechanism of anti-tuberculosis drug-induced hepatotoxicity (ATDH). ATP-binding cassette transporter G2 (ABCG2) plays an important role in modulating PPIX concentrations. This study aimed to explore the role of ABCG2 genetic polymorphisms in the risk of ATDH in Chinese patients.A 1:4 matched case-control study was performed among 202 ATDH cases and 808 controls. Conditional logistic regression model was used to estimate the association between genotypes and the risk of ATDH by odds ratios (ORs) with 95% confidence intervals (CIs).Male patients with CC genotype of rs2622605 had an increased risk of ATDH (adjusted OR = 1.615, 95% CI: 1.119-2.332, p = 0.011). The peak value of alkaline phosphatase (ALP) was significantly higher in male patients with CC genotype of rs2622605 than in those with TT + TC genotype during antituberculosis treatment (102.0 U/L vs. 98.0 U/L, p = 0.029).This is the first attempt to evaluate the association between ABCG2 genetic variants and the risk of ATDH. Based on the 1:4 matched case-control study, the polymorphism at rs2622605 in the ABCG2 gene may be associated with the susceptibility to ATDH in Chinese male patients.

Ecological and health risk assessment of heavy metals in soil and Chinese herbal medicines.

As medicinal plants can accumulate harmful metals from the native soil, people's consumption of these materials may cause the human body to accumulate toxic metal elements. This has given rise to people's concerns about the quality and safety of Chinese medicinal materials. This research aims to determine the levels of Cr, Ni, Cu, Zn, As, Cd, Hg and Pb in four medicinal plant species (Aster tataricus L.f., Salvia miltiorrhiza Bge, Radix Aucklandiae, Scutellaria baicalensis Georgi) and their native soil. All samples were collected from Qian'an city, beside Yanshan Mountain Range in Tangshan city, east Hebei Province, north China. The contents of heavy metals we detected in the soil conformed to the current limits. However, the Cd and Hg in the soil had a very high potential ecological risk because of their contents higher than the base level of local soil. The contents of Cu, Cd, Hg and Pb in some medicinal herbs exceeded the standards. The content of Cu in Radix Aucklandiae exceeded the standard by 3 times, and others exceeded the standard by less than one time. The comprehensive health risk assessment of heavy metals with chronic non-carcinogenic effects for human body showed that none of the four medicinal herbs can create a health risk. Thus, there is no strong positive correlation between heavy metal pollution in medicinal herbs and that in the native soil. Further research should be investigated to the connection between the heavy metal levels in the soil and plants, and the comprehensive effects of soil, air and irrigation water on heavy metal pollution of Chinese herbal medicines. We also recommend that Chinese herbal medicines should be cultivated and gathered only from controlled or uncontaminated areas.

Changing Trajectories of Alanine Aminotransferase and Risk of Antituberculosis Drug-Induced Liver Injury in Chinese Patients: A Cohort Study.

Antituberculosis drug-induced liver injury (ATLI) is a major adverse effect during antituberculosis treatment. Early detection or prediction is essential to prevent ATLI in antituberculosis treatment patients. The purpose of this work is to explore the relationship between alanine aminotransferase (ALT) trajectories within 15 days of initial treatment and the risk of ATLI. Based on a historical cohort of patients hospitalized for antituberculosis treatment and group-based trajectory modeling analysis, ALT trajectories within 15 days of initial treatment were determined. Conditional logistic regression model was used to estimate the association between different ALT trajectories and the risk of ATLI, and the corresponding odds ratios (ORs) and their 95% confidence intervals (CIs) were calculated with covariates. Based on the ALT levels within 15 days of initial treatment, a total of 853 patients were divided into four ALT trajectories. The incidence of ATLI significantly increased with the increase of ALT trajectories (2.33%, 4.38%, 5.90%, and 2.44%, respectively). Compared with trajectory 1, the adjusted OR for ATLI in trajectory 2, trajectory 3, and trajectory 4 were 2.448 (95% CI: 0.302-19.856, P = 0.402), 5.373 (95% CI: 0.636-45.411, P = 0.123), 11.010 (95% CI: 0.720-168.330, P = 0.085), respectively, and there was an increasing trend of ATLI risk (Ptrend = 0.015). Different ALT trajectories within 15 days of initial treatment were associated with different risk of ATLI, and it is necessary to pay attention to the ALT trajectory within 15 days of initial treatment to predict the occurrence of ATLI.

Genetic Polymorphisms of UDP-Glucuronosyltransferases and Susceptibility to Antituberculosis Drug-Induced Liver Injury: A Systematic Review and Meta-Analysis.

Methods: The PRISMA statement was strictly followed, and the protocol was registered in PROSPERO (CRD42022339317). The PICOS framework was used: patients received antituberculosis treatment, UGTs polymorphisms (mutants), UGTs polymorphisms (wild), AT-DILI, and case-control studies. Eligible studies were searched through nine databases up to April 27, 2022. The study's qualities were assessed by the revised Little's recommendations. Meta-analysis was conducted with a random-effects model using odds ratios (ORs) with 95% confidence intervals (95% CIs) as the effect size. Results: Twelve case-control studies with 2128 cases and 4338 controls were included, and 32 single nucleotide polymorphisms (SNPs) in the seven UGT genes have been reported in Chinese and Korean. All studies were judged as high quality. The pooled results indicated that UGT1A1 rs3755319 (AC vs. AA, OR = 1.454, 95% CI: 1.100-1.921, P = 0.009), UGT2B7 rs7662029 (G vs. A, OR = 1.547, 95% CI: 1.249-1.917, P < 0.0001; GG + AG vs. AA, OR = 2.371, 95% CI: 1.779-3.160, P < 0.0001; AG vs. AA, OR = 2.686, 95% CI: 1.988-3.627, P < 0.0001), and UGT2B7 rs7439366 (C vs. T, OR = 0.585, 95% CI: 0.477-0.717, P < 0.0001; CC + TC vs. TT, OR = 0.347, 95% CI: 0.238-0.506, P < 0.0001; CC vs. TC + TT, OR = 0.675, 95% CI: 0.507-0.898, P = 0.007) might be associated with the risk of AT-DILI. Conclusions: The polymorphisms of UGT1A1 rs3755319, UGT2B7 rs7662029, and UGT2B7 rs7439366 were significantly associated with AT-DILI susceptibility. However, this conclusion should be interpreted with caution due to the low number of studies and the relatively small sample size.

SLCO1B1 variants and the risk of antituberculosis drug-induced hepatotoxicity: a systematic review and meta-analysis.

Aims: To evaluate the association between SLCO1B1 gene polymorphisms and susceptibility of antituberculosis drug-induced hepatotoxicity (ATDH). Methods: We searched the PubMed, Cochrane Library, Embase, Web of Science, Wan Fang and China National Knowledge Infrastructure database from inception to 2022. Results: Nine case-control studies with 1129 cases and 2203 controls were included. Among four SNPs reported in two or more studies, the final results indicated that SNP rs4149014 was significantly associated with decreased ATDH risk (dominant model, odds ratio: 0.73; 95% CI: 0.55-0.97; p = 0.03; allele model, odds ratio: 0.69; 95% CI: 0.55-0.86; p = 0.001), and the trial sequential analysis also confirmed this significant association. Conclusion: SLCO1B1 gene SNP rs4149014 was significantly associated with lower risk of ATDH susceptibility.

Genetic variants of the nuclear factor erythroid 2-related factor 2/antioxidant reaction element pathway on the risk of antituberculosis drug-induced liver injury: a systematic review.

Aim: To evaluate the effects of genetic variants in the nuclear factor erythroid 2-related factor 2/antioxidant reaction element signaling pathway on antituberculosis drug-induced liver injury (AT-DILI) susceptibility. Methods: The PubMed, Embase, Cochrane, Web of Science, China National Knowledge Infrastructure and Wanfang databases were searched from inception to April 2022. Results: Seven case-control studies with 4676 patients were included. Six genes with 35 SNPs in the pathway have been reported. Among 17 SNPs reported in two or more studies, the meta-analysis indicated that only one SNP (rs3735656 in MAFK) was significantly associated with a decreased risk for AT-DILI under the dominant model (odds ratio: 0.636; 95% CI: 0.519-0.780; p < 0.001). Conclusion: SNP rs3735656 in the MAFK gene was significantly associated with the risk of AT-DILI.

Transcriptomics-based investigation of manganese dioxide nanoparticle toxicity in rats' choroid plexus.

Manganese dioxide nanoparticles (MnO2-NPs) have a wide range of applications in biomedicine. Given this widespread usage, it is worth noting that MnO2-NPs are definitely toxic, especially to the brain. However, the damage caused by MnO2-NPs to the choroid plexus (CP) and to the brain after crossing CP epithelial cells has not been elucidated. Therefore, this study aims to investigate these effects and elucidate potential underlying mechanisms through transcriptomics analysis. To achieve this objective, eighteen SD rats were randomly divided into three groups: the control group (control), low-dose exposure group (low-dose) and high-dose exposure group (high-dose). Animals in the two treated groups were administered with two concentrations of MnO2-NPs (200 mg kg-1 BW and 400 mg kg-1 BW) using a noninvasive intratracheal injection method once a week for three months. Finally, the neural behavior of all the animals was tested using a hot plate tester, open-field test and Y-type electric maze. The morphological characteristics of the CP and hippocampus were observed by H&E stain, and the transcriptome of CP tissues was analysed by transcriptome sequencing. The representative differentially expressed genes were quantified by qRT-PCR. We found that treatment with MnO2-NPs could induce learning capacity and memory faculty decline and destroy the structure of hippocampal and CP cells in rats. High doses of MnO2-NPs had a more obvious destructive capacity. For transcriptomic analysis, we found that there were significant differences in the numbers and types of differential genes in CP between the low- and high-dose groups compared to the control. Through GO terms and KEGG analysis, high-dose MnO2-NPs significantly affected the expression of transporters, ion channel proteins, and ribosomal proteins. There were 17 common differentially expressed genes. Most of them were transporter and binding genes on the cell membrane, and some of them had kinase activity. Three genes, Brinp, Synpr and Crmp1, were selected for qRT-PCR to confirm their expression differences among the three groups. In conclusion, high-dose MnO2-NPs exposure induced abnormal neurobehaviour, impaired memory function, destroyed the structure of the CP and changed its transcriptome in rats. The most significant DEGs in the CP were within the transport system.

Relationship between common telomere length-related genetic variations, telomere length, and risk of antituberculosis drug-induced hepatotoxicity in Chinese Han population: As assessed for causality using the updated Roussel Uclaf Causality Assessment Method.

Antituberculosis drug-induced hepatotoxicity (ATDH) is a significant threat to tuberculosis control, and two recent studies indicated that leukocyte telomere length (LTL) might be a potential biomarker for ATDH. This study aimed to investigate the relationship between common telomere length-related genetic variations, LTL, and risk of ATDH in Eastern Chinese antituberculosis treatment patients. A 1:4 matched case-control study was conducted among 79 ATDH cases assessed for causality using the updated RUCAM and 316 controls. LTL was determined by quantitative real-time PCR, and nine SNPs involved in telomere biology reported by previous GWAS were assessed. Conditional logistic regression model was used to estimate the association between genotypes and risk of ATDH with odds ratios (ORs) and 95% confidence intervals (CIs). The average RUCAM score of cases was 7.1. The average LTL in cases was significantly shorter than that in controls (median = 1.239 vs. 1.481, P = 0.032). Differences in the distribution of LTL were statistically significant among three genotypes of SNP rs2736098 (CC vs. CT vs. TT, median = 1.544 vs. 1.356 vs. 1.337, P = 0.026) and rs2853677 (AA vs. AG vs. GG, median = 1.511 vs. 1.544 vs. 1.159, P = 0.005) in TERT. SNP rs7675998 in NAF1 was statistically associated with the risk of ATDH under the dominant model (adjusted OR = 1.725, 95% CI: 1.021-2.913, P = 0.042). This is the first study to investigate the relationship of LTL, common telomere length-related variations, and risk of ATDH. SNP rs2736098 and rs2853677 in TERT were significantly associated with LTL, and SNP rs7675998 in NAF1 may be associated with ATDH in Chinese population.

Incidence and Temporal Trend of Antituberculosis Drug-Induced Liver Injury: A Systematic Review and Meta-Analysis.

Methods: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses standards were followed, and the protocol was registered in PROSPERO (CRD42020200077). Five electronic databases were searched to identify eligible studies published between 1990 and 2022. Search terms included anti-TB treatment and drug-induced liver injury. Studies that reported the incidence of ATLI or provided sufficient data to calculate the incidence of ATLI were included, and duplicate studies were excluded. Meta-analysis was conducted on the basis of logit-transformed metrics for the incidence of ATLI with 95% confidence intervals (CIs), followed by a predefined subgroup meta-analysis. Temporal trend analyses were performed to describe the change in pooled incidence over time. A random effects metaregression was conducted to explore the source of heterogeneity. All statistical analyses were carried out using R 4.0.1. Results: A total of 160 studies from 156 records with 116147 patients were included in the meta-analysis. Based on the random effects model, the pooled incidence of ATLI was 11.50% (95% CI: 10.10%-12.97%) and showed an upward trend over time (P < 0.001). Patients who received first-line anti-TB drugs, patients in South America, and patients with hepatitis B and C virus coinfection had a higher incidence of ATLI (13.66%, 18.16%, and 39.19%, respectively). Sensitivity analyses also confirmed this robust incidence after the exclusion of some studies. The metaregression showed that different anti-TB regimens and geographical regions were important explanatory factors of the heterogeneity between studies. Conclusions: The present systematic review provided a basis for estimating the incidence of ATLI worldwide, which varied among patients with different anti-TB regimens in different geographical regions and with different coinfections and had an upward trend. Regular liver function monitoring is imperative for patient safety during the anti-TB treatment course.