To investigate the effects of ursolic acid (UA) on glomerular mesangial cell behavior and ferroptosis in lupus nephritis (LN) and to determine the involvement of the dipeptidyl peptidase-4 (DPP4)-protease-activated receptor-2 (PAR2) pathway. SV40-MES-13 cells were exposed to LPS and treated with UA, ferrostatin-1 (Fer-1), or linagliptin, with DPP4 or PAR2 overexpression as appropriate. Cell viability, migration, apoptosis, iron accumulation, oxidative stress, and lipid peroxidation were assessed using CCK-8, Transwell, and TUNEL assays, biochemical measurements, and BODIPY 581/591 C11 staining. Bioinformatics analysis and molecular docking were used to identify candidate targets of UA. qRT-PCR and western blotting were used to examine DPP4-PAR2 signaling, the ferroptosis regulators SLC7A11 and GPX4, and proteins associated with apoptosis, proliferation, and migration. MRL/lpr mice were used to evaluate renal function, histopathological injury, apoptosis, Fe2+ accumulation, and renal DPP4 and PAR2 expression in vivo. LPS reduced cell viability and migration and increased apoptosis, Fe2+ accumulation, ROS, MDA, 4-HNE, and lipid peroxidation. UA significantly attenuated these LPS-induced alterations. Fer-1 and UA both improved cell viability and reduced the BODIPY 581/591 C11 green-to-red fluorescence intensity ratio, although Fer-1 produced a greater recovery of viability. UA and linagliptin increased SLC7A11 and GPX4 expression; these effects were reversed by DPP4 and PAR2 overexpression, respectively. UA also decreased cleaved caspase-3 and Bax expression and increased Bcl-2, MMP2, and MMP9 expression, whereas PCNA was not significantly restored. In MRL/lpr mice, UA and linagliptin improved renal function, attenuated histopathological injury, reduced apoptosis and Fe2+ accumulation, and decreased renal DPP4 and PAR2 expression. UA protects glomerular mesangial cells and attenuates LN in MRL/lpr mice, at least in part, by suppressing the DPP4-PAR2 axis and restoring SLC7A11/GPX4-mediated antioxidant defense. The findings support the coexistence of ferroptotic and apoptotic injury in this model, both of which were attenuated by UA.
Tributyltin (TBT) is a persistent environmental organotin compound and endocrine-disrupting chemical that has been associated with inflammation, oxidative stress, and cellular injury. Although the toxic effects of high-dose TBT exposure have been extensively investigated, the renal effects of prolonged exposure to low doses remain insufficiently characterized. Fucoxanthin (Fx), a marine carotenoid with anti-inflammatory and anti-apoptotic properties, may attenuate toxicant-associated tissue injury. This study investigated the effects of prolonged low-dose TBT exposure on renal tissue and to evaluate whether fucoxanthin attenuates TBT-associated histopathological alterations and inflammation- and apoptosis-related immunoreactivity in female rats. Seventy-two female Wistar rats were randomly allocated to nine groups (n = 8/group): control, vehicle control, TBT at 50, 100, or 300 ng/kg/day, TBT at each corresponding dose combined with Fx, and Fx alone. Treatments were administered orally by gavage once daily for four weeks (28 days). Renal tissues were examined histopathologically, and immunohistochemistry was performed to evaluate cleaved Caspase − 3, tumor necrosis factor-alpha (TNF-α), and nuclear factor-kappa B p65 (NF-κB p65) immunoreactivity. TBT exposure was associated with renal histopathological alterations that increased in severity with TBT dose, including tubular degeneration, glomerular structural changes, vascular alterations, hemorrhage, and interstitial inflammatory cell infiltration. These changes were accompanied by increased cleaved Caspase − 3, TNF-α, and NF-κB p65 immunoreactivity, particularly in tubular and interstitial compartments. Compared with the corresponding TBT-only groups, co-administration of Fx attenuated histopathological lesions and reduced the immunoreactivity of all three markers. The magnitude of these effects varied across the TBT dose groups, with more evident histopathological improvement at the lower exposure levels. Prolonged exposure to low experimental doses of TBT was associated with dose-dependent renal histopathological injury and increased inflammation and apoptosis-related immunoreactivity in female rats. Fx co-administration attenuated these tissue alterations, suggesting a potential protective effect against TBT-associated renal injury. However, the absence of renal functional measurements and complementary biochemical analyses limits conclusions regarding functional recovery and the underlying molecular mechanisms.
Diesel exhaust particles (DEP) are a major component of combustion-derived PM2.5 and contain complex mixtures of organic and inorganic contaminants associated with elemental carbon (black carbon). Diesel particulate matter (DPM), a reference material representative of diesel exhaust particles, can release leachable constituents into surrounding water. However, the biological effects and molecular responses associated with DPM leachates remain poorly understood. To investigate toxicological effects of DPM leachate on the marine copepod Tigriopus japonicus by integrating life-history responses with transcriptomic analyses. T. japonicus was exposed to different concentrations of DPM leachate, and developmental progression and fecundity were assessed to characterize chronic sublethal toxicity. Chemical characterization was performed to identify dissolved contaminants in the leachate. Transcriptomic responses were evaluated by identifying differentially expressed genes (DEGs) and their associated biological processes and pathway annotations in Low (25
Triptolide (TP), a bioactive diterpenoid derived from Tripterygium wilfordii Hook F., exhibits potent anti-inflammatory and immunosuppressive activities but has a narrow therapeutic window and documented toxicities in multiple organs. However, the systemic and tissue-specific metabolic responses associated with repeated TP exposure remain incompletely characterized. A gas chromatography–mass spectrometry (GC–MS)-based multi-tissue metabolomics approach was applied to characterize metabolic alterations in serum, heart, liver, kidney, lung, cortex, hippocampus, and intestine of TP-treated mice. Unsupervised principal component analysis and supervised OPLS-DA were used to assess global and group-discriminating metabolic patterns. Metabolite-level differences were evaluated using two-sided Welch’s t-tests followed by Benjamini–Hochberg false discovery rate (FDR) correction within each biological matrix. Intestinal 16S rRNA gene sequencing was additionally integrated with metabolomics to explore microbiota-associated metabolic alterations. Repeated TP exposure was associated with distinct systemic and tissue-specific metabolic remodeling. Among 134 matrix-specific candidate metabolite changes meeting VIP > 1.0 and nominal Welch’s P < 0.05, 115 remained significant after Benjamini–Hochberg correction, corresponding to 58 unique metabolites with at least one FDR-significant matrix-specific change. Pathway analysis based on these FDR-significant metabolites identified 42 nominal matrix-specific pathway associations, of which 12 remained significant after pathway-level FDR correction. The strongest pathway-level statistical support was observed in the lung, hippocampus, cortex, and intestine, particularly involving amino acid-related metabolism. Gut microbiota profiling further revealed reduced microbial richness and a moderate shift in community structure after TP exposure. Significant associations were observed between selected bacterial genera and intestinal carbohydrate- and lipid-related metabolites, although these correlations were considered exploratory. Repeated TP exposure is associated with widespread but tissue-dependent metabolic remodeling across serum and multiple organs, together with alterations in gut microbial composition. The findings highlight candidate metabolites and metabolic pathways potentially involved in TP-associated systemic responses, but do not by themselves establish organ injury, oxidative stress, or causal microbiota–metabolite relationships. Further targeted and functional validation is required.
Rubus parvifolius L. root has been used to treat chronic hepatitis in Chinese medicine practice for generations. However, the in vivo hepatoprotective mechanisms of the Rubus parvifolius L. root extract (RRE) have not been systematically investigated. We established a mouse model of chronic liver injury induced by CCl4 and evaluated the protective effect of RRE on chronic liver injury by measuring serum liver function indicators (ALT, AST), hepatic oxidative stress markers (MDA, SOD), and liver pathological changes. Oral administration of RRE can significantly alleviate liver injury in a dose-dependent manner. Molecular analyses showed that RRE up-regulated the mRNA and protein expression of HO-1, nuclear red cell 2-associated factor 2 (Nrf-2) and B-cell lymphoma-2 (Bcl-2), while down-regulating Bcl-2 associated X protein (Bax), caspase-3, NLRP3, interleukin17a (IL-17A) and transforming growth factor β1(TGF-β1). These findings suggest that RRE alleviates chronic liver injury, an effect that may be associated with up-regulation of Nrf-2 and HO-1, increased Bcl-2 with decreased Bax and Caspase-3, and reduced NLRP3, IL-17A, TGF-β1 expression. This study provides a scientific basis for the potential clinical application of RRE.
