Pregnane X receptor (PXR) regulates the expression of drug-metabolizing enzymes and transport enzymes. NF-κB not only plays a role in liver homeostasis and injury-healing processes by regulating inflammatory responses but may also regulate the transcription of PXR. Currently, genetic polymorphisms in PXR are associated with adverse drug effects. Because little is known about the association between NF-κB1 genetic polymorphisms and adverse drug reactions, we explored the association between PXR and NF-κB1 single nucleotide polymorphisms (SNPs) and susceptibility to anti-tuberculosis drug-induced liver injury (ATDILI). A total of 746 tuberculosis patients (118 with ATDILI and 628 without ATDILI) were prospectively enrolled at West China Hospital between December 2014 and April 2018. Nine selected SNPs (rs3814055, rs13059232, rs7643645 and rs3732360 in PXR and rs78872571, rs4647992, rs60371688, rs1598861 and rs3774959 in NF-κB1) were genotyped with a custom-designed 2x48-plex SNP Scan TM Kit. The frequencies of the alleles, genotypes and genetic models of the variants were compared between patients with or without ATDILI, while joint effect analysis of the SNP-SNP interactions was performed using multiplicative and additive models. The odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) were calculated. The T allele of rs3814055 in PXR was associated with a decreased risk for ATDILI (OR 0.61; 95% CI: 0.42–0.89, p = 0.0098). The T alleles of rs78872571 and rs4647992 in NF-κB1 were significantly associated with an increased risk for ATDILI (OR 1.91; 95% CI: 1.06–3.43, p = 0.028 and OR 1.81; 1.06–3.10, p = 0.029, respectively). The allele, genotype and genetic model frequencies were similar in the two groups for the other six SNPs (all P>0.05). There were no multiplicative or additive interactions between the SNPs. Our study is the first to reveal that rs3814055 variants in PXR and rs78872571 and rs4647992 variants in NF-κB1 are associated with susceptibility to ATDILI caused by first-line anti-tuberculosis combination treatment in the Han Chinese population.

Immunoglobulin A nephropathy (IgAN) is characterized by mesangial IgA and IgG co-deposition. As the clinical course of IgAN is highly variable, a lot of patients will eventually develop to end-stage renal disease (ESRD) within years. Hirudin, a potent and specific thrombin inhibitor, has been reported to treat IgAN with hematuria, but the mechanism is unclear. Our study aims to explore the potential of hirudin and the underlying mechanism in the treatment of IgAN. The establishment of IgAN model was set up in rats through oral and intravenous immunization with bovine gamma-globulin (BGG). Results suggested that hirudin could reduce the increased level of proteinuria, serum creatinine and urea nitrogen in IgAN models. Besides that, hirudin ameliorated the elevated number of apoptotic bodies and expressions of apoptosis-related proteins (caspase-3 and caspase-9) in IgAN model. The fibrosis indexes (transforming growth factor β-1 (TGF-β1), Collagen-IV (CoI-IV) and Fibronectin-1) of kidney were remarkably suppressed in IgAN rats treated with hirudin compared with IgAN rats with no further treatment. IgAN rats exhibited remarkably increased inflammatory factors (IL-1β, IL-6, and IL-18), while hirudin treatment significantly alleviated these alterations. Moreover, the reduced levels of CD4⁺CD25⁺Foxp3⁺ Treg and CD4⁺IFN-γ⁺ Th1/CD4⁺IL-4⁺ Th2 could be reversed by hirudin in IgAN model. Furthermore, in the process of IgAN, hirudin could inactivate various pathways (IκBα, NF-κB, TNF-α, and VCAM-1) compared with IgAN model group. Taken together, our study indicated that hirudin could ameliorate IgAN through suppressing fibrosis and inflammatory response. These findings provide a new therapeutic method to treat IgAN.

Thrombocytopenia is a prevalent complication and an adverse prognostic factor in sepsis; however, there is a paucity of studies examining the dynamic changes in platelet counts and their association with the prognosis of sepsis patients with related thrombocytopenia. This study aims to retrospectively to investigate the relationship between the dynamic trajectories of platelet counts and early adverse prognostic outcomes in such patients. A retrospective observational study was conducted using data from 946 sepsis patients with thrombocytopenia extracted from the Medical Information Mart for Intensive Care (MIMIC-IV) database. A joint latent class model (JLCM) was employed to analyze platelet trajectories over time as part of a time series analysis (TSA). Time-dependent piecewise Cox regression models and Kaplan-Meier survival curves were utilized to evaluate the association between trajectory patterns and 60-day mortality. Sensitivity analyses included the Schoenfeld residual test, subgroup analysis and reclassification of groups based on corresponding mortality risks. The platelet trajectories during the first 28 days of hospitalization were classified into four classes, each associated with distinct 60-day mortality risks. Class 1 consistently remained at the lowest level, while Class 2 exhibited a gradual increase, yet still remained below normal levels. Class 3 demonstrated a rapid increase to normal levels, and Class 4 continued to increase closely toward normal level. The multivariable Cox proportional hazards model, with Class 1 as the reference group and adjusted for potential confounders, revealed significant associations between the trajectories and 60-day mortality for Class 3 (HR 0.27, 95% CI 0.08–0.85, P = 0.025) and Class 4 (HR 0.68, 95% CI 0.48–0.96, P = 0.029). Class 2 suggested a non-significant trend toward higher early mortality (HR 1.38, 95% CI 0.85–2.24, P = 0.198). Kaplan-Meier curves from the multivariate analysis indicated that Class 1 had the lowest 60-day survival probability, while Class 3 exhibited the highest, followed by Class 4. After merging Classes 1 and 2 into Group 1 for sensitivity analysis, with Group 1 as the reference, the groups remained significantly associated with 60-day mortality. The Schoenfeld residual test, subgroup analysis, regrouping were performed as sensitivity analyses to ensure the robustness of our study results. This study demonstrates that trajectories of platelet in sepsis patients with thrombocytopenia is clinically significant. Sustained low platelet levels or low amplitude increases that remain below normal levels indicate a higher early mortality rate. Early rapid increase of platelet count is associated with better prognosis.

Background. The accumulation of the hepatotoxic substance protoporphyrin IX (PPIX) induced by aminolevulinate synthase 1 (ALAS1) activation is one of the important mechanisms of antituberculosis drug-induced hepatotoxicity (ATDH). Forkhead box protein O1 (FOXO1) may activate ALAS1 transcription. However, little is known about their roles in ATDH; we performed a study to determine the association between polymorphisms in the two genes and ATDH susceptibility. Then, we verified this possible association by cellular functional experiments. Materials and Methods. Tag single-nucleotide polymorphisms (TagSNPs) in the two genes were genotyped in 746 tuberculosis patients. The frequencies of the alleles, genotypes, genetic models, and haplotype distribution of the variants were compared between the case and control groups. L-02 cells and HepG2 cells were incubated with the indicated concentration of isoniazid (INH) and rifampicin (RIF) for the desired times, and then the expression levels of ALAS1 and FOXO1 mRNAs and proteins were detected. HepG2 cells were transiently transfected with FOXO1 siRNA to observe the effect of changes in the FOXO1 expression on the cell survival rate and ALAS1 expression. Results. The C allele at rs2755237 and the T allele at rs4435111 in the FOXO1 gene were associated with a decreased risk of ATDH. The expression of ALAS1 in both L-02 cells and HepG2 cells was increased by the coadministration of INH/RIF (600/200μM) for 24h. Although FOXO1 expression was reduced slightly by the same treatment, its content in the nucleus was significantly increased. However, the cell survival rate and ALAS1 expression level were not significantly altered by the downregulation of FOXO1 in HepG2 cells. Conclusions. Variants of the rs4435111 and rs2755237 loci in the FOXO1 gene were associated with susceptibility to ATDH. Coadministration of INH/RIF promoted the transfer of FOXO1 from the cytoplasm to the nucleus, but the functional significance of its nuclear translocation requires further verification.