Journal of Biomedical Research最新文献

Interferon-related genes are involved in antiviral responses, inflammation, and immunity, which are closely related to sepsis-associated acute respiratory distress syndrome (ARDS). We analyzed 1972 participants with genotype data and 681 participants with gene expression data from the Molecular Epidemiology of ARDS (MEARDS), the Molecular Epidemiology of Sepsis in the ICU (MESSI), and the Molecular Diagnosis and Risk Stratification of Sepsis (MARS) cohorts in a three-step study focusing on sepsis-associated ARDS and sepsis-only controls. First, we identified and validated interferon-related genes associated with sepsis-associated ARDS risk using genetically regulated gene expression (GReX). Second, we examined the association of the confirmed gene (interferon regulatory factor 1, IRF1) with ARDS risk and survival and conducted a mediation analysis. Through discovery and validation, we found that the GReX of IRF1 was associated with ARDS risk (odds ratio [OR _MEARDS] = 0.84, P = 0.008; OR _MESSI = 0.83, P = 0.034). Furthermore, individual-level measured IRF1 expression was associated with reduced ARDS risk (OR = 0.58, P = 8.67 × 10 ^-4), and improved overall survival in ARDS patients (hazard ratio [HR _28-day] = 0.49, P = 0.009) and sepsis patients (HR _28-day = 0.76, P = 0.008). Mediation analysis revealed that IRF1 may enhance immune function by regulating the major histocompatibility complex, including HLA-F, which mediated more than 70% of protective effects of IRF1 on ARDS. The findings were validated by in vitro biological experiments including time-series infection dynamics, overexpression, knockout, and chromatin immunoprecipitation sequencing. Early prophylactic interventions to activate IRF1 in sepsis patients, thereby regulating HLA-F, may reduce the risk of ARDS and mortality, especially in severely ill patients.

Clostridioides difficile ( C. difficile) is one of the major causes of nosocomial infections. Pregnant women, who are generally considered at low risk for C. difficile infection (CDI), have attracted attention because of an increasing number of reports. Oral vancomycin, the only first-line treatment for pregnant women infected with C. difficile, has been associated with increasing strain resistance, leading to decreased efficacy. Fecal microbiota transplantation (FMT) is recommended for severe, fulminant, and recurrent CDI; however, it is generally avoided in pregnant women because of safety concerns. We report a case of a pregnant woman with a primary ribotype 027 CDI who experienced a successful outcome with washed microbiota transplantation (WMT), an improved form of FMT, via enema. The specific strain of ribotype 027 is related to severe outcomes but has not previously been reported in pregnant women. The follow-up lasted for two years, during which the patient's diarrhea was fully alleviated without recurrence. The baby showed normal growth and development, and no adverse events were recorded for either. This case provides evidence for the efficacy and safety of WMT in pregnant women infected with C. difficile, indicating that WMT via enema may be a viable therapeutic strategy for this population for treating CDI.

Bone metastasis is the primary cause of mortality in breast cancer (BC) patients. The present study elucidates the functional role of the differentiated embryonic chondrocyte-expressed gene 1 (DEC1) in promoting BC-related bone metastasis. Analysis of patient-derived samples and public databases revealed a significant upregulation of DEC1 and CXCR4 in breast tumors compared with adjacent normal tissues, with elevated levels correlating with increased metastatic potential, suggesting their synergistic involvement in BC progression. Intracardiac injection experiments demonstrated that Dec1-WT 4T1 cells induced more severe osteolysis and larger metastatic lesions than Dec1-KD 4T1 cells. In MDA-MB-231 cells, DEC1 overexpression (OE) upregulated CXCR4 and proliferation/migration-related genes, whereas DEC1 knockdown reversed these effects. Notably, AMD3100, a specific CXCR4 antagonist, partially reversed the DEC1-OE-induced upregulation of CXCR4 and associated pro-metastatic genes. Mechanistically, DEC1 bound to the CXCR4 promoter region (-230 to -326) and activated its transcription, corroborated by ChIP-seq data. Furthermore, pharmacological inhibition of AKT (LY294002) or JAK2 (AZD1480), but not ERK (PD98059), attenuated DEC1-mediated CXCR4 upregulation, although all three inhibitors mitigated DEC1-driven migration-related gene expression. Additionally, DEC1 enhanced CXCL12 secretion from mesenchymal stromal cells and osteoblasts, amplifying the CXCR4/CXCL12 axis within the bone microenvironment. Collectively, our findings demonstrate that DEC1 promotes BC bone metastasis by directly transactivating CXCR4 expression, providing a molecular basis for targeting DEC1 to prevent and treat BC bone metastasis.

Dent disease is a rare X-linked recessively inherited renal tubulopathy, caused by variants in the CLCN5 (Dent disease type 1, DD1) and OCRL (Dent disease type 2, DD2) genes, and characterized by low molecular weight proteinuria, hypercalciuria, microscopic hematuria, or nephrocalcinosis. In the current study, we collected and analyzed clinical data and genetic testing results of 21 children diagnosed with Dent disease, who were hospitalized at the Department of Nephrology, Children's Hospital of Nanjing Medical University between January 2014 and August 2023, aiming to assist in the early diagnosis and treatment of these patients. Among the 21 patients, 16 (76.19%) had CLCN5 variants, and five (23.81%) had OCRL variants, and four of the variants were novel. All patients presented with low molecular weight proteinuria, 14 (66.67%) of whom had nephrotic-range proteinuria. Eight patients underwent renal biopsies because of diagnostic uncertainty. We transfected the novel CLCN5 missense variant (p.G222R) and OCRL missense variant (p.I371T) plasmids into both HEK293 and HK-2 cells and found a significantly lower expression of the OCRL1 protein in the transfected cells than in the wild-type cells ( P < 0.05). Moreover, we observed an extremely skewed X-chromosome inactivation pattern in a female patient carrying the same novel CLCN5 variant, as assessed by the human androgen receptor gene assay. These findings provide insight into the clinical characteristics of Dent disease in Chinese patients and may shed light on its pathogenesis.

It is often challenging to diagnose acute myocardial infarction (AMI) in patients with elevated high-sensitivity cardiac troponin T (hs-cTnT) before a significant rise and/or fall of hs-cTnT can be observed. This study aimed to find an optimal cut-off to rule in AMI. A total of 76411 patients with elevated hs-cTnT were included. The predictive cut-off values for diagnosing ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation myocardial infarction (NSTEMI) were assessed by the area under the receiver operating characteristic curves (AUC). Among the patients, 50466 (66.0%) had non-cardiac diseases, 25945 (34.0%) had cardiac diseases, and 15502 (20.3%) had AMI, including 816 (1.1%) with STEMI and 14686 (19.2%) with NSTEMI. The median hs-cTnT level was 3788.0 ng/L in STEMI patients and 67.2 ng/L in NSTEMI patients. The optimal cut-off for diagnosing STEMI was 251.9 ng/L, with a sensitivity of 90.7%, specificity of 86.5%, and an AUC of 0.942; the optimal cut-off for diagnosing NSTEMI was 130.5 ng/L, with a sensitivity of 40.9%, specificity of 83.8%, and an AUC of 0.638. In patients with elevated hs-cTnT, optimizing the cut-off values for diagnosing STEMI and NSTEMI to 251.9 ng/L and 130.5 ng/L, respectively, demonstrated high accuracy in a large cohort of Chinese patients.

The OPTIMA-5 study demonstrated that a single bolus of half-dose recombinant staphylokinase (r-SAK) before primary percutaneous coronary intervention (PCI) significantly improved the patency of infarct related artery in patients with ST-elevation myocardial infarction (STEMI) expected to undergo PCI within 120 minutes. This study aimed to investigate the 1-year clinical outcome and the effect of the r-SAK antibody on a second r-SAK thrombolysis in OPTIMA-5 patients. The clinical outcome was major adverse cardiovascular events (MACE) within 360 days. Patients' r-SAK antibodies were determined on days 90 ± 7, 180 ± 7, and 360 ± 14 after thrombolysis, and in-vitro r-SAK antibody neutralization experiments were performed to explore an optimal interval for a second r-SAK thrombolysis. Results showed that the MACE incidence was numerically lower in r-SAK group compared with normal saline (NS) group (14.0% vs. 20.0%, HR 0.67, 95% CI: 0.34-1.32; log-rank P=0.245). The r-SAK antibody levels in r-SAK group decreased by time, but kept significantly higher than those in NS group on days 90 ± 7 (2.96 ± 0.68 vs. 0.22 ± 0.53, P<0.001), 180 ± 7 (2.19 ± 0.74 vs. 0.44 ± 0.65, P<0.001) and 360 ± 14 (1.73 ± 0.97 vs. 0.37 ± 0.71, P<0.001). The in-vitro r-SAK antibody neutralization experiments illustrated that the thrombolysis rate decreased exponentially as the antibody titer increased from 1.90 to 2.20 (67.80 ± 14.19% vs. 44.32 ± 21.54%, P< 0.0001). Therefore, for STEMI patients expected to undergo PCI within 120 minutes, a single bolus of half-dose r-SAK before primary PCI may reduce 1-year MACE risk. The r-SAK antibody lasts over 1 year, and a second r-SAK thrombolysis may not be indicated until 1 year after the first r-SAK thrombolysis if necessary.

Silicosis is an occupational lung disease caused by prolonged exposure to silica dust in the workplace. It has a complex pathogenesis and currently lacks effective treatments. Homoharringtonine(HHT), a natural compound approved for the treatment of acute myeloid leukemia, but its effects on silicosis are unclear. In the present study, we constructed a mouse model of silica (SiO ₂)-induced pulmonary fibrosis and evaluated the preventive and therapeutic capacity of HHT. The results showed that HHT attenuated the progression of SiO ₂-induced pulmonary fibrosis in mice. We then used MRC-5, a human lung fibroblast cell line to explore the mechanisms underlying HHT's inhibitory effects in vitro and found that HHT significantly inhibited the activation and migratory capacity of MRC-5 cells. Mechanistically, the effects were mediated by enhanced ubiquitination and degradation of the CCR1 protein. Furthermore, HHT exhibited favorable biocompatibility in vivo, and its preventive and therapeutic effects were validated in SiO ₂-treated mice. This study demonstrates that HHT holds significant potential as a therapeutic agent for silicosis by targeting CCR1 and the PI3K/AKT/mTOR signaling pathway, highlighting it as a promising candidate for clinical development in silicosis treatment.

Mutation in oxysterol-binding protein-like 2 ( OSBPL2) has been identified as the genetic cause of autosomal dominant nonsyndromic hearing loss (DFNA67, OMIM No. 616340). However, the pathogenesis of the OSBPL2 mutation in DFNA remains unclear. Our previous work showed that OSBPL2 deficiency impaired cell adhesion in auditory HEI-OC1 cells. In addition, loss of hair cells (HCs) and morphological abnormalities of HC stereocilia were detected in OSBPL2-disrupted pigs, suggesting that OSBPL2 plays an important role in the regulation of the actin cytoskeleton in auditory cells. In the present study, we found that OSBPL2 deficiency inhibited the Rho/ROCK2 signaling pathway and downregulated phosphorylated Ezrin-Radixin-Moesin (p-ERM), resulting in abnormal F-actin morphology in HEI-OC1 cells and stereociliary defects in mouse HCs. The present study demonstrates the underlying mechanism of OSBPL2 in the regulation of the actin cytoskeleton in HCs, which contributes to a deeper understanding of the pathogenesis of OSBPL2 mutations in DFNA.

Prenatal maternal psychological distress, particularly depression, has been increasingly recognized as a factor that influences fetal growth; however, its impact on early childhood development remains less well understood. The present study investigated the association between prenatal depression and children's growth trajectories, as well as the odds of overweight and obesity from 1 to 36 months, while also accounting for maternal anxiety and stress. We analyzed data from 4710 mother-child dyads in the Jiangsu Birth Cohort, assessing maternal psychological distress across trimesters and categorizing participants into groups with mild, moderate, and severe depressive symptomatology. Children's weight-for-length z-scores (WLZ) were used to assess overweight/obesity prevalence, and growth patterns were identified through trajectory models. The results from the generalized estimating equations analysis showed that greater depressive symptomatology during pregnancy was associated with a 28% to 41% increase in the odds of childhood overweight/obesity across all three trimesters, compared with mild depressive symptomatology. We identified five distinct WLZ growth trajectory patterns, and found that mothers with greater depressive symptomatology were 39%-47% more likely to have children who followed a very-high-stable growth trajectory, compared with mothers with mild depressive symptomatology. These findings highlight the significant impact of prenatal depression on adverse growth patterns and childhood overweight/obesity, underscoring the need for early intervention.