Journal of Molecular Histology最新文献

Ulcerative colitis (UC) is a long-term inflammatory condition affecting the colon’s lining starting from the rectum and extending throughout the colon. Interplay between UC, diabetes, and a liver complication involves complex interactions between inflammation, the immune system, and metabolic processes, which can complicate their management. Thus, the present study aims to investigate the in vivo effectiveness of sodium orthovanadate (SOV) in attenuating dextran sulfate sodium salt (DSS)-induced colitis and the associated liver injury in diabetic BALB/c mice, with particular emphasis on diabetes-related pathophysiological alterations and the underlying molecular mechanisms. 55 BALB/c male mice were allocated randomly into seven distinct groups (n = 7 − 8. The diabetes was induced with STZ; 40 mg/kg; i.p. for five days successively and UC was instigated using 2.5% w/v DSS in three alternating cycles, each lasting seven days. SOV orally was given at 5 and 10 mg/kg doses, along with the standard 5-aminosalicylic acid at dose 100 mg/kg and metformin at 50 mg/kg dose, in the beginning of the DSS second cycle and continuing until the end of the study. In diabetic mice, DSS-induced colitis was significantly more severe, with elevated glucose levels, worsened disease activity index (DAI) scores, heightened oxidative stress, and altered liver biomarkers, confirming that diabetes exacerbates colitis onset and progression. Oral administration of SOV at 5 and 10 mg/kg, beginning with the second DSS cycle and continuing until the study’s end, significantly mitigated these diabetes-aggravated effects. SOV improved glycemic control, reduced DAI scores, oxidative stress, and normalized liver biomarkers. Histopathological the intervention helped maintain normal pancreatic architecture and mitigate diabetes-induced histological damage. Immunohistochemical analysis revealed that SOV enhanced Nrf2/Keap1 expression while suppressing NF-κB and IL-6, confirming its anti-inflammatory mechanism. The diabetes exacerbated DSS-induced colitis, while SOV (5 and 10 mg/kg) significantly mitigated disease severity, oxidative stress, and metabolic and hepatic disturbances. These findings establish that SOV effectively counteracts the exacerbating impact of diabetes on colitis, highlighting its therapeutic potential in diabetes-associated intestinal inflammation.

Graphical Abstract

Bellidifolin (BEL), the primary active compound in Gentianella acuta, demonstrates significant cardioprotective effects. This study aimed to investigate the protective role of BEL against DOX-induced myocardial injury and its mechanisms. Network pharmacology was utilized to identify possible therapeutic targets of BEL for disease treatment. In vivo, 30 C57BL/6 mice were randomly assigned to three experimental groups: Control, DOX, and BEL treatment (DOX + BEL). Mice were orally administered BEL (30 mg/kg) for 21 days, with a single intraperitoneal injection of DOX (15 mg/kg) on day 14. In vitro, H9c2 cells were used to assess the cardioprotective effects of BEL (50 µM) against DOX-induced toxicity. Cardiac function, myocardial histopathological changes, serum myocardial injury markers, oxidative stress indicators, and apoptosis were evaluated. Western blot analysis was conducted to detect the Nrf2/HO-1 and Galectin-3/NLRP3 pathway proteins. A total of 123 intersection targets were identified between BEL and disease-related proteins, including core targets such as caspase-3, IL-1β, and TNF. GO and KEGG pathway analyses revealed that BEL’s protective effects against DOX-induced myocardial injury were associated with apoptosis, oxidative stress and inflammation. In vivo, BEL treatment improved cardiac function and myocardial histopathological morphology. BEL reduced MDA levels while increasing SOD and GSH-Px activity. Furthermore, BEL alleviated DOX-induced mitochondrial damage. BEL also decreased the apoptosis rate and modulated the expression of Caspase-3, Bax, and Bcl-2. Additionally, BEL activated the Nrf2/HO-1 pathway, as evidenced by increased nuclear translocation of Nrf2, upregulation of Nrf2, HO-1, GCLM, and NQO1 proteins, and a simultaneous decrease in Keap1 levels. BEL also suppressed the Galectin-3/NLRP3 inflammatory pathway, reducing the expression of Galectin-3, NLRP3, ASC, Caspase-1, IL-18, and IL-1β. In vitro, BEL treatment significantly decreased ROS levels induced by DOX. Overall, BEL mitigated DOX-induced cardiotoxicity by inhibiting oxidative stress, inflammation, and apoptosis via the Nrf2/HO-1 and Galectin-3/NLRP3 pathways.

Graphical abstract

Polycystic ovary syndrome (PCOS) is associated with ovarian granulosa cell dysfunction. Ferroptosis, a regulated cell death driven by lipid peroxidation, represents a novel pathological mechanism. Hypermethylation of the glutathione peroxidase 4 (GPX4) promoter may contribute to its suppression. While glucagon-like peptide-1 receptor agonists (GLP-1 RAs) improve metabolic features of PCOS, their direct effects on ovarian ferroptosis and the underlying epigenetic mechanisms are unclear. To explore the therapeutic potential of GLP-1RAs across PCOS phenotypes, we employed a hyperandrogenism-induced rat model and a letrozole plus high-fat diet mouse model, treating them with exenatide or semaglutide, respectively. Phenotypic assessment included estrous cycle monitoring, ovarian histology, and serum hormone profiling. Ferroptosis was evaluated using a multi-parametric approach, including iron deposition (Perls’ staining), lipid peroxidation (MDA), redox status (GSH/GSSG), ultrastructural analysis (TEM), and expression of key regulators. The methylation status of the GPX4 promoter was analyzed by methylation-specific PCR (MSP) and bisulfite sequencing (BSP), alongside the expression of related epigenetic modifiers (DNMTs, TET1). In vitro studies using DHT-stimulated primary granulosa cells further validated the semaglutide effects. GLP-1 RA exenatide alleviated the polycystic ovarian morphology in rats with PCOS, semaglutide treatment not only alleviated PCOS phenotypes but also reversed ovarian ferroptosis markers, restored GPX4 expression, and reduced the GPX4 promoter hypermethylation and DNMTs levels, with efficacy comparable to 5-azacytidine. In vitro, semaglutide corrected DHT-induced GPX4 hypermethylation and ferroptosis in granulosa cells. This study demonstrates that semaglutide alleviates PCOS phenotypes and reverses ovarian granulosa cell ferroptosis. These beneficial effects may be related to the alleviation of GPX4 promoter hypermethylation. Our findings extend the therapeutic rationale for semaglutide in PCOS beyond metabolic benefits, suggesting potential direct ovarian protection via epigenetic modulation.

Graphical abstract

Semaglutide alleviates ovarian ferroptosis in polycystic ovary syndrome and is associated with reduced GPX4 promoter hypermethylation

Adipose-derived stem cell exosomes (ADSCs-Exos) enhance endometrial carcinoma (EC) cell proliferation, migration, and invasion. Mechanistically, ADSCs-Exos downregulate MAGED4B and CDH1, reduce E-cadherin expression, and upregulate vimentin, promoting epithelial-mesenchymal transition (EMT). Overexpression of MAGED4B reverses these effects and inhibits malignant behaviors. Furthermore, ADSCs-Exos increase organoid viability and confirm key protein changes. These findings demonstrate that ADSCs-Exos promote EC progression via the MAGED4B/CDH1/EMT axis.

Melamine, which is used as a chemical in the industry, brings to mind the question of food safety due to its presence in the structure of plates, exposure to insecticides, and, most importantly, its addition to formula and pet foods years ago to provide false high protein positivity. This study aimed to examine the effects of exposure to low-dose melamine from the weaning period on bone development. Eighteen female rats (21 days old) were randomly divided into 3 groups. The first group (n = 6) received 0.1 ml saline, the second group (n = 6) and third group (n = 6) received 50 mg/kg and 75 mg/kg melamine in 0.1 ml saline for 21 days with oral gavage, respectively. After the 21 days application, animals were euthanized under anesthesia on the 45th day and right femur and tibia bones of the rats were taken and placed in 10% buffered formalin for histopathological and micro computed tomography (micro CT) examination. According to histopathologic, morphometric and micro CT analysis, there were not statistically significant differences in the thickness of physis plate (growth plate), compact bone, diaphysis, femur length and bone mineral density (BMD) of tibia between melamine and control groups (p > 0,05). However, the structure of the physis (growth) plates were deterioration in both 50 mg/kg and 75 mg/kg melamine groups. The structural integrity were irregular and even had cartilage areas that advanced towards the trabecular bone area. As a result, melamine exposure from the weaning period, when bone development is important, causes structural disruption of the physis plate (growth plate) with increasing doses.

Graphical Abstract