Toxicology and applied pharmacology最新文献

Worldwide incidence and prevalence of ulcerative colitis (UC) has been rising in recent years, which can occur at any age, with a high frequency seen in young children and people aged 40 to 50. The aryl hydrocarbon receptor (AhR) activation axis is well known for its important role in the regulation of intestinal inflammation, intestinal homeostasis, intestinal immune system and improvement of colitis outcomes. This study investigated the therapeutic efficacy of the thiophene-based styrene derivative (TBSD), a novel AhR agonist against UC in vitro and in vivo. TBSD decreased FITC-dextran hyperpermeability, upregulated the tight junction (TJ)-related protein expression levels and regulated the inflammatory mediators including tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, IL-22 and cyclooxygenase 2 (COX-2) in the Caco-2/RAW264.7 co-culture system and in DSS-induced UC-like mice. Overall, TBSD may be considered as a promising therapeutic agent to improve UC severity through mitigating inflammation, maintaining intestinal mucosal homeostasis and enhancing the intestinal barrier integrity.

Asthma is a heterogeneous disorder driven by inflammatory processes that promote pathogenic airway remodeling. Human umbilical cord mesenchymal stem cell-derived exosomes (hucMSC-Exos) emerge as a compelling therapeutic candidate to disrupt this disease cycle, with potential intergenerational benefits. In a chronic OVA-induced asthma model using C57BL/6 mice, hucMSC-Exos were delivered via serial injections during the sensitization phase. Airway structural changes were evaluated through histological analysis (H&E staining, Masson's trichrome) and immunofluorescence for key remodeling markers including α-SMA, CC-10, and the proliferation marker Ki67. Molecular pathway analyses specifically targeted the TGF-β/Smad and STAT6 signaling cascades. We found that hucMSC-Exos intervention effectively ameliorated the core pathological features of asthma-induced lung injury and significantly reduced the levels of IL-6 and TNF-α in bronchoalveolar lavage fluid (BALF) in a dose-dependent manner. Additionally, this treatment reduced asthma susceptibility in offspring of mothers with chronic asthma. Compared to the OVA group, the Exos group showed restored CC-10 expression and decreased pulmonary Ki67 levels. In offspring, Hopx (but not SPC) expression was significantly elevated at PN1 and PN4 relative to the OVA group, though these differences lost statistical significance at PN14, consistent with Western blotting (WB) validation. Notably, unlike maternal findings, both CC-10 and Ki67 expression in the lungs of treated offspring were lower than in controls. Furthermore, we observed that OVA-induced activation of PECAM-1, α-SMA, p-ROCK1, and Caspase-8 was attenuated by hucMSC-Exos treatment. RNA sequencing of hucMSC-Exos identified asthma-associated miRNAs, including let7a-5p and miR-125a-5p. The therapeutic efficacy of hucMSC-Exos against asthma was partially abolished when these miRNA inhibitors were applied, underscoring their critical regulatory role in exosome-based asthma therapy. In conclusion, hucMSC-Exos have demonstrated significant efficacy in the treatment of asthma, capable of alleviating airway remodeling and related symptoms. What is particularly important is that they have a cross-generational protective effect, which can reduce the asthma susceptibility of children born to asthmatic mothers. Mechanistically, this benefit may be achieved through the transfer of asthma-related miRNAs. These findings elucidate the key molecular pathways of the cross-generational therapeutic effect mediated by hucMSC-Exos, providing a scientific basis for their clinical application in the management of maternal and offspring asthma.

Objective: To investigate the effects of long-term Di(2-ethylhexyl) phthalate (DEHP) exposure on the female reproductive system, employing different dosages and durations of exposure.

Methods: Pregnant female CD-1 mice (F0) were orally exposed to DEHP at doses of 0, 100, and 500 mg/kg/day during gestation. Following birth, the female offspring (F1) were allocated into three groups as F0 mice. Both F0 and F1 mice were consequently subjected to ongoing DEHP exposure until they were sacrificed. Body weight, anogenital distance, anogenital index (AGI), and histopathologic outcomes of the uterus were examined at 21 and 35 weeks for F0 mice and at 10 and 24 weeks for F1 mice.

Results: Both low and high DEHP exposures significantly decreased body weight in F0 at 21 weeks and in F1 at 10 and 24 weeks, while AGI was not significantly changed in response to DEHP exposure in both F0 and F1 mice. DEHP exposure induced endometrial stromal fibrosis, endometrial hyperplasia, and myometrial atrophy in the uterus of F1mice, while cystic hyperplasia and endometrial stromal sarcoma (ESS) were seen in the F0 after DEHP exposure at 35 weeks.

Conclusions: Long-term Exposure to DEHP significantly reduced body weight and induced pathological alterations in the uterus of both F0 and F1 mice. Dams exposed to high doses of DEHP developed ESS, suggesting that DEHP may have carcinogenic potential in the uterus. However, further research is necessary to confirm this finding.

Albumin-bound paclitaxel (Nab-PTX), a nanoparticle albumin-bound formulation in which paclitaxel is conjugated to human serum albumin, has emerged as a pivotal agent in cancer therapy. Its significance stems not only from direct cytotoxic effects on cancer cells but also from multifaceted interactions with angiogenesis, a critical driver of tumor progression and metastasis. Nevertheless, the underlying mechanism of its anti-angiogenesis in breast cancer remains elusive. In the present study, we employed the iTRAQ (isobaric tags for relative and absolute quantification) technique to assess the effect of Nab-PTX on Triple-negative breast cancer cells (MDA-MB-231). A total of 5145 exosomal proteins were identified, of which 941 exhibited significant differences between Nab-PTX-treated cells and the control group (P-value<0.05). Notably, we found that CYR61 (Cysteine-rich angiogenic inducer 61), a secreted matricellular protein belonging to the CCN family, was significantly inhibited by Nab-PTX. Furthermore, our study demonstrated for the first time that Nab-PTX inhibits angiogenesis via the CYR61/Integrin α_vβ₃ signaling pathway. These findings elucidate a potential anti-angiogenesis mechanism of Nab-PTX and highlight CYR61's promise as a therapeutic target in human breast cancer.

Osteoporosis is a prevalent metabolic bone disorder characterized by diminished bone mineral density and elevated fracture susceptibility. Although isoorientin (ISO) has emerged as a promising candidate for osteoporosis treatment, its molecular mechanisms remain unclear. In this study, a comprehensive network pharmacology approach was employed to identify potential therapeutic targets by systematically mining the GeneCards and DisGeNET databases. ISO-target interactions were predicted through an integrated analysis of multiple chemoinformatic platforms, including Super-Pred, SwissTargetPrediction, PharmMapper, and ChemMapper. Hub targets were identified via protein-protein interaction (PPI) network analysis, complemented by functional enrichment assessments and molecular docking simulations. The computational findings were experimentally validated using an ovariectomy (OVX)-induced osteoporotic murine model. Network pharmacological analysis revealed 332 putative ISO targets, 45 of which significantly overlapped with 610 osteoporosis-associated targets. Functional enrichment analysis highlighted the critical involvement of these genes in hormone-mediated signaling pathways and cellular responses to nutrient levels. KEGG pathway analysis further implicated these targets in key regulatory cascades, including the MAPK, relaxin signaling, and lipid metabolism-associated atherosclerosis pathways. Molecular docking simulations demonstrated strong binding affinities between ISO and pivotal targets, including MAPK14, TLR4, and ESR1. In vivo validation using OVX mice confirmed ISO's capacity to attenuate bone loss by suppressing osteoclast activation, as evidenced by micro-CT analysis and histomorphometric quantification. Further in vitro studies demonstrated that ISO inhibits RANKL-induced osteoclastogenesis via suppression of the MAPK pathway. This study elucidates the key targets and pathways through which ISO exerts anti-osteoporotic effects, highlighting its therapeutic potential in osteoporosis management.