Multifaceted Effects of Subchronic Exposure to Chlorfenapyr in Mice: Implications from Serum Metabolomics, Hepatic Oxidative Stress, and Intestinal Homeostasis.

As chlorfenapyr is a commonly used insecticide in agriculture, the health risks of subchronic exposure to chlorfenapyr remained unclear. This study aimed to extensively probe the health risks from subchronic exposure to chlorfenapyr at the NOAEL and 10-fold NOAEL dose in mice. Through pathological and biochemical examinations, the body metabolism, hepatic toxicity, and intestinal homeostasis were systematically assessed. After 12 weeks, a 10-fold NOAEL dose of chlorfenapyr resulted in weight reduction, increased daily food intake, and blood lipid abnormalities. Concurrently, this dosage induced hepatotoxicity and amplified oxidative stress in hepatocytes, a finding further supported in HepG2 cells. Moreover, chlorfenapyr resulted in intestinal inflammation, evidenced by increased inflammatory factors (IL-17a, IL-10, IL-1ß, IL-6, IL-22), disrupted immune cells (RORγt, Foxp3), and compromised intestinal barriers (ZO-1 and occludin). By contrast, the NOAEL dose presented less toxicity in most evaluations. Serum metabolomic analyses unveiled widespread disruptions in pathways related to hepatotoxicity and intestinal inflammation, including NF-κB signaling, Th cell differentiation, and bile acid metabolism. Microbiomic analysis showed an increase in Lactobacillus, a decrease in Muribaculaceae, and diminished anti-inflammatory microbes, which further propelled the inflammatory response and leaded to intestinal inflammation. These findings revealed the molecular mechanisms underlying chlorfenapyr-induced hepatotoxicity and intestinal inflammation, highlighting the significant role of the gut microbiota.

LncRNA-PEAK1 promotes neuronal apoptosis after intracerebral hemorrhage by miR-466i-5p/caspase 8 axis.

Background: At present, the treatment of intracerebral hemorrhage (ICH)-induced secondary brain injury (ISB) is limited, and the curative effect is not good. Long noncoding RNAs (lncRNAs) have been reported to play a role in ISB after ICH. We preliminarily monitored the induction effect of lncRNA-pseudopodium-enriched atypical kinase 1 (PEAK1) on neuronal cell apoptosis after ICH through our previous study and further experimental verification. However, the specific role and mechanism of lncRNA-PEAK1 in neuronal cell apoptosis after ICH have not been reported. Methods: ICH cell models were established with hemin. Pro-inflammatory cytokines, cell proliferation, and apoptosis were evaluated by enzyme-linked immunosorbent assay, Cell Counting Kit-8 assay, flow cytometry, and terminal deoxynucleotidyl transferase dUTP nick end labeling, respectively. Moreover, lncRNA expression associated with apoptosis was confirmed by quantitative reverse transcription polymerase chain reaction (qRT-PCR). The biological functions of lncRNA-PEAK1, miR-466i-5p, and caspase8 were conducted in vitro. Further, we used bioinformatics, a dual-luciferase reporter assay, and rescue experiments to understand the mechanisms of competitive endogenous RNAs. Results: qRT-PCR revealed that lncRNA-PEAK1 was markedly upregulated in ICH cell models. LncRNA-PEAK1 knockdown decreased the interleukin-1ß and tumor necrosis factor-alpha levels, promoted cell proliferation, weakened cell apoptosis, and downregulated the key molecular protein levels involved in the cell apoptosis pathway. Bioinformatics analysis and dual-luciferase reporter assay revealed that lncRNA bound to miR-466i-5p, and caspase 8 was a target of miR-466i-5p. The mechanistic analysis demonstrated that lncRNA-PEAK1/miR-466i-5p promoted neuronal cell apoptosis by activating the apoptosis pathway through caspase8 after ICH. Conclusion: Collectively, our investigation identified that the lncRNA-PEAK1/miR-446i-5p/caspase8 axis is closely related to neuronal cell apoptosis after ICH. Additionally, lncRNA-PEAK1 may be a potential target for ICH intervention.

Transvaginal approach for rectovaginal fistula: experience from a single institution.

Transvaginal (TV) repair, featuring its feasibility, effectiveness, safety, and technically less demandingness, is one of the surgical approaches for management of rectovaginal fistula (RVF). However, there are limited numbers of publications available on the transvaginal approach for RVF repair. To this end, the purpose of this study is to evaluate the preliminary outcomes of the transvaginal approach performed by the team, and to further assess its feasibility, safety and effectiveness in the management of RVF. A retrospective analysis was conducted at a single institution. Patients with RVF who had undergone three transvaginal surgical techniques, i.e. transvaginal fistulectomy and stratified suture, transvaginal flip and ligation fistula tract and transvaginal fistula stapled closure were included. Besides, the demographics, operative data, postoperative complications and follow-up outcomes of the patients were collected prospectively. A total of 49 female patients (mean age, 35.76 ± 13.97 years) underwent transvaginal approach, 42 of which were followed up with a median follow-up of 26 months (range 3-82 months), and 29 had closure of the fistula (successful closure rate of 59.1%). The successful closure rates were only significantly different between previous repair times (p = 0.031), and several minor complications including postoperative pain (n = 3), constipation (n = 1), and lower urinary tract infection (n = 1) were observed. Symptomatic improvement was reported in all patients with failed closure. Transvaginal approach for RVF repair is effective, safe, and feasible, and is therefore considered an alternative to transrectal advancement flap for low and mid-level traumatic RVF with normal sphincter function. With the advantage of better surgical access, transvaginal approach is recognized as the initial choice for the surgical repair of RVF.