Clinical and Experimental Pharmacology and Physiology最新文献

Epigenetic dysregulation plays a critical role in colorectal cancer (CRC) progression. Our study investigated the role of FAM111B in tumorigenic phenotypes and ferroptosis in CRC and the mechanisms by which epigenetic alterations influence FAM111B expression. Bioinformatics analyses revealed FAM111B expression and predicted the association between IGF2BP2 and FAM111B or ELF1. The influence on cell phenotypes was determined by assessing cell proliferation, migration, apoptosis and ferroptosis. Mechanism analyses were performed using luciferase reporter and ChIP assays. Subcutaneous xenografts were used to evaluate the role in vivo. FAM111B, IGF2BP2 and ELF1 were upregulated in CRC tumours and cell lines. FAM111B downregulation inhibited cell proliferation and migration while inducing apoptosis and ferroptosis. IGF2BP2 increased FAM111B expression by stabilising its mRNA, and ELF1 transcriptionally upregulated IGF2BP2. Moreover, ELF1 modulated FAM111B expression through IGF2BP2. ELF1 knockdown suppressed cell proliferation and migration while triggering apoptosis and ferroptosis, which could be abolished by reintroduction of IGF2BP2 or FAM111B. Additionally, ELF1 depletion diminished the in vivo tumorigenicity of HCT116 cells. The ELF1/IGF2BP2/FAM111B cascade drives CRC progression and ferroptosis resistance. Targeting this cascade may provide a therapeutic avenue for CRC treatment.

Venous thromboembolism (VTE) is a complication of head and neck cancer (HNC). However, the effectiveness of routine anticoagulation as a preventive measure and its impact on patient outcomes is unclear. The purpose of this study was to evaluate the association between long-term systemic anticoagulation and in-hospital outcomes of patients with HNC. Data of patients ≥ 20 years old with HNC treated from 2005 to 2018 were extracted from the US Nationwide Inpatient Sample (NIS) database. Associations between long-term systemic anticoagulation and in-hospital outcomes were assessed by the univariate and multivariable regression analyses. The study included 20 312 patients with a mean age of 63 years, and 72% were males. Among them, 5078 (25.0%) were on long-term systemic anticoagulation. After adjustment, the multivariable analysis indicated long-term systemic anticoagulation was significantly associated with decreased odds for in-hospital mortality (adjusted odds ratio [aOR] = 0.64, 95% confidence interval [CI]: 0.54–0.76, p < 0.001), overall life-threatening events (aOR = 0.84, 95% CI: 0.78–0.92, p < 0.001), acute myocardial infarction (aOR = 0.76, 95% CI: 0.59–0.97, p = 0.026), sepsis (aOR = 0.80, 95% CI: 0.71–0.90, p < 0.001) and acute kidney injury (aOR = 0.86, 95% CI: 0.76–0.97, p = 0.015). Long-term systemic anticoagulation was significantly associated with elevated overall bleeding risk (aOR = 1.34, 95% CI: 1.17–1.54, p < 0.001) but not intracerebral haemorrhage (ICH) (aOR = 1.65, 95% CI: 0.90–3.04, p = 0.107). In conclusion, in patients with HNC, long-term anticoagulation is associated with better in-hospital outcomes, and does not increase the risk of ICH; however, there is an increased risk of overall bleeding.

Nitroimidazole antibiotics, including metronidazole, tinidazole, and ornidazole, are widely used to treat anaerobic infections and parasitic diseases. Although their efficacy is well established, comprehensive safety profiles—particularly concerning rare adverse events—remain incompletely elucidated. This study aimed to systematically evaluate the safety signals of these drugs using the FDA adverse event reporting system (FAERS) database from 2014 to 2024. Disproportionality analyses were performed at the system organ class (SOC) and standardised MedDRA queries (SMQ) levels to identify associations between nitroimidazole antibiotics and adverse events. A total of 17,631 adverse event reports were analysed for metronidazole, tinidazole, and ornidazole, respectively. Females comprised the majority of reports (57.35%, 51.70%, and 61.11%, respectively), which may reflect the common use of these agents in gynaecological infections. Metronidazole was associated with the shortest median time to onset of adverse events (2.5 days), while tinidazole had the longest (5.5 days). At the SOC level, all three drugs showed positive associations with gastrointestinal, nervous system, and cardiac disorders. Ornidazole showed strong disproportionality signals for vascular (IC₀₂₅ = 18.46) and skin disorders (IC₀₂₅ = 17.46), while tinidazole was associated with weaker but notable signals for skin and blood disorders. Notably, SMQ-level analysis uncovered significant safety signals not currently emphasised in drug labelling, including acute pancreatitis, hepatic failure, fibrosis/cirrhosis, and tachyarrhythmias for tinidazole and ornidazole. These findings highlight the potential need for intensified clinical monitoring of hepatic and cardiac function during treatment with these antibiotics. Although limited by the nature of spontaneous reporting data, this study offers important insights into both established and emerging risks associated with nitroimidazole antibiotics, reinforcing the value of continuous pharmacovigilance to optimise patient safety.

In this study, we found that PDZK1, a scaffold protein, interacts with the β₂-adrenergic receptor (ADRB2) through its PDZ domains, stabilising ADRB2 by inhibiting its ubiquitination and proteasomal degradation. This study explored the PDZK1–ADRB2 interaction and its role in hypertension-induced vascular remodelling. Using PDZK1 knockout mice infused with angiotensin II, we found that PDZK1 deficiency further exacerbates angiotensin II-induced hypertension, vascular dysfunction, and vascular remodelling. Mechanistically, PDZK1 stabilises ADRB2 protein by preventing its ubiquitination and proteasomal degradation, thereby maintaining ADRB2-mediated vasodilation. Additionally, PDZK1 prevents ADRB2 internalisation and its interaction with β-arrestin, thereby inhibiting β-arrestin–mediated ERK activation and suppressing vascular smooth muscle cell (VSMC) phenotypic switching. This mechanism contributes to vascular protection under hypertensive conditions. Targeting the PDZK1/ADRB2 interaction may provide a novel therapeutic strategy for hypertension-related vascular complications.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are life-threatening conditions that involve severe lung inflammation leading to respiratory failure. Tanshinone IIA (TIIA) and Matrine (MAT), two herbal medicinal compounds, have been reported to exhibit several similar pharmacological properties including anti-inflammatory, antioxidant, and anticancer effects. Although previous studies have reported the combined therapeutic efficacy of using two drugs in treating ALI, it remains unknown whether TIIA and MAT have any synergistic effect in alleviating ALI/ARDS. Therefore, this study investigated whether a combined therapy of TIIA and MAT has protective effects against lipopolysaccharide (LPS)-induced ALI and its mechanism of action using mouse and cell models. The results showed that the TIIA + MAT combination ameliorated ALI by reducing edema, tissue injury, and proinflammatory cytokine secretion. This therapy enhanced antioxidant defences, as indicated by upregulated GPX4 and SLC7A11 levels, decreased 4-HNE and ROS levels, and ferroptosis inhibition. Furthermore, TIIA + MAT promoted Nrf2 nuclear translocation, leading to increased HO-1 expression and an anti-oxidative response. These findings suggest that the combination of TIIA and MAT alleviates LPS-induced ALI by inhibiting ferroptosis via activation of the Nrf2/HO-1 pathway. Thus, the co-administration of TIIA and MAT may be an effective therapeutic strategy for ALI, potentially offering a novel clinical approach to mitigate ferroptosis and inflammation.

Although antibiotics can effectively control infectious diseases, overuse of antibiotics can cause problems such as drug resistance. Pulpitis and apical periodontitis are among the most common infectious diseases in humans. To alleviate the intense tooth pain, patients often self-administer antibiotics. To guide patients in managing pulpitis and apical periodontitis more effectively, we designed a Root Canal Treatment Health Education Form and provided personalised guidance on antibiotic use during the treatment period. From January 2024 to March 2025, a total of 272 patients participated in this project. Benefiting from health education, the proportion of antibiotic use was significantly lower compared to the control group. Both patients and healthcare professionals involved in this health education program held positive attitudes towards the intervention. Our experience suggested that health education should be actively promoted in the treatment of pulpitis and apical periodontitis.