Mangiferin mitigates tacrolimus-induced nephrotoxicity in rats via modulation of oxidative stress, NLRP3 inflammasome, VEGF signaling, and PI3K/AKT/PTEN-mediated autophagy and apoptosis.
Jul 2026· Naunyn-Schmiedeberg's Archives of Pharmacology· 0 citations· 37 references
Medicine
TL;DR
Results indicate that mangiferin confers nephroprotection against TAC-induced renal injury that is highly associated with the modulation of oxidative stress, NLRP3 inflammasome, VEGF signaling, and PI3K/AKT/PTEN-mediated autophagy and apoptosis.
Thioacetamide (TAA) induces renal injury via oxidative stress and inflammation. Remogliflozin (Remo), an SGLT2 inhibitor, was evaluated for potential renoprotection. Twenty-four male Wistar rats were assigned to control, TAA (100 mg/kg IP twice weekly), TAA + Remo 25 mg/kg, or TAA + Remo 50 mg/kg (oral daily). Outcomes included renal function, oxidative stress (GSH, SOD, MDA), antioxidant biomarkers (Nrf2, HO-1), inflammatory mediators (TLR4/NF-κB, TNF-α, IL-1β), metabolic/kinase biomarkers (SIRT1, AMPK, PI3K, AKT), and histopathology/immunohistochemistry (mTOR, MYD88, Nrf2). Remogliflozin was associated with lower serum creatinine, urea, and uric acid, with endpoint-specific differences between doses. Remo was associated with higher renal Nrf2, HO-1, SIRT1, and p-AMPK, and lower MDA, TLR4, NF-κB, TNF-α, IL-1β, PI3K, and AKT. Histopathology and IHC showed associations with reduced tissue injury, lower mTOR and MYD88 immunoreactivity, and increased Nrf2 staining. While the 50 mg/kg group showed changes in more markers, this does not establish uniform dose superiority or a formal dose-response relationship; at 25 mg/kg, effects differed among AMPK-related endpoints. Direct 25-versus-50 mg/kg comparisons were included in the Tukey-Kramer analysis for each endpoint. No pharmacokinetic measurements or formal dose-response analyses were performed. In this exploratory model, remogliflozin was associated with attenuation of TAA-induced renal injury and modulation of related biomarkers. Causal mechanisms remain to be confirmed by targeted intervention studies. Findings are limited to young male Wistar rats and should not be generalized to other populations or clinical settings. Remogliflozin warrants further preclinical investigation in TAA-associated renal injury.
Marwa M. Qadri, D. Almarghalani, Abdulaziz Alarifi et al.· Toxicology Mechanisms and Me...· 0 citations
Man could be considered as a potential protective agent against HgCl2-induced liver injury through controlling oxidative stress, inflammation, and apoptosis.
Hager E Hassan, Sara H. Hazem, M. Zaghloul· Naunyn-Schmiedeberg's Archiv...· 0 citations
Objectives: The purpose of this study was to investigate the protective effects and underlying mechanisms of fucoidan on contrast-induced acute kidney injury (CI-AKI) in mice, focusing on the TLR4/NF-κB and Nrf2/GPX4 pathways. Methods: Five-week-old male ICR mice were randomly divided into normal control, contrast model, low-dose (100 mg/kg), and high-dose (300 mg/kg) fucoidan groups. Renal index, biochemical markers, histopathology, oxidative stress indicators, inflammatory cytokine levels, and the expression of TLR4/NF-κB, Nrf2/HO-1, and ferroptosis-related proteins were assessed. Untargeted metabolomics followed by KEGG pathway enrichment was also performed. Results: Our results showed that contrast successfully established the CI-AKI model, as evidenced by an increased kidney index, abnormal biochemical parameters, severe renal pathological damage, oxidative stress imbalance, inflammatory activation, ferroptosis, and metabolic disturbances. Fucoidan dose-dependently improved kidney index and biochemical markers, alleviated pathological injury, enhanced antioxidant capacity, suppressed inflammation and ferroptosis, and reversed metabolic pathway disorders (e.g., purine and glycerophospholipid metabolism), with the high dose showing more pronounced effects. Conclusions: Fucoidan could effectively ameliorate CI-AKI, and its effects are closely associated with the inhibition of the TLR4/NF-κB pathway, activation of the Nrf2/HO-1 pathway, regulation of ferroptosis-related proteins, and improvement of key metabolic disturbances, suggesting a new research direction for the prevention of CI-AKI.
Li Zhang, Qiao-Ling Zhao, Jing Tian et al.· Pharmaceuticals· 0 citations
Arsenic trioxide (ATO) is a potent therapeutic agent against acute promyelocytic leukemia; nevertheless, its clinical utility is severely restricted by dose-limiting nephrotoxicity. This study investigated the protective potential of a radiation-synthesized gallotannin hydrogel (GTH) against ATO-induced kidney injury in rats. Forty male Wistar rats were randomized into four experimental groups: Control, ATO (4 mg/kg, i.p., for 4 weeks), GTH (2 mg/kg, i.p.), and ATO + GTH. GTH treatment was initiated during the third week of ATO administration, with GTH being administrated one hour prior to ATO injection. Following the experimental period, animals were sacrificed, tissue histology was examined, and renal function was assessed by serum urea and creatinine levels. Oxidative stress was evaluated via MDA, SOD, GSH, and GPx markers. Additionally, miR-223 and TXNIP expression levels were quantified using qRT-PCR. Inflammatory mediators (NF-κB, NLRP3, Caspase-1, IL-1β, and IL-18), endoplasmic reticulum (ER) stress markers (PERK, eIF2α, and CHOP), and the apoptotic marker caspase-3 were analyzed by ELISA. Our results revealed that GTH noticeably ameliorated kidney dysfunction, as evidenced by reduced serum urea and creatinine levels. Furthermore, GTH attenuated oxidative stress by decreasing MDA levels and restoring antioxidant enzyme activities (SOD, GSH, and GPx). Histological analysis confirmed that GTH mitigated structural renal damage. Molecularly, GTH administration suppressed the ATO-induced upregulation of miR-223 and TXNIP. This downregulation correlated with a reduction in inflammatory mediators, attenuation of ER stress markers, and decreased apoptosis. These findings demonstrate that radiation-synthesized gallotannin hydrogel (GTH) exerts nephroprotective effects against ATO-induced nephrotoxicity. These benefits are driven by antioxidant, anti-inflammatory, and anti-apoptotic mechanisms mediated via modulation of the miR-223/TXNIP axis.
Omayma A. R. Abo-Zaid, Mostafa A. Farrag, Aya S. R. Shaaban et al.· Biological Trace Element Res...· 0 citations
BACKGROUND
Diabetic nephropathy (DN) is a leading cause of global end-stage renal disease, driven by oxidative stress, persistent inflammation and ferroptosis. Salvigenin, a natural flavonoid with anti-inflammatory and antioxidant activity, displays protective effects against oxidative injury. This study investigated its renoprotective actions in DN and the underlying mechanism.
METHODS
In vitro high glucose-stimulated HK-2 cell model and in vivo db/db DN mouse model were adopted. HK-2 cells were treated with gradient salvigenin for 24 h. We assessed cell viability, proliferation, inflammatory cytokines, iron and ROS levels, antioxidant status, and expression of Nrf2 pathway proteins. DN mice received intraperitoneal salvigenin every other day for 8 weeks. Renal function, histopathology, inflammation, iron deposition, ROS accumulation and Nrf2 signaling activity were comprehensively evaluated.
RESULTS
In vitro, salvigenin reversed high glucose-induced cytotoxicity and proliferative suppression. It lowered pro-inflammatory cytokine release, relieved iron overload and ROS accumulation, restored GSH, and reduced MDA and 4-HNE. Salvigenin upregulated ferroptosis mediators GPX4 and SLC7A11 and activated the Nrf2/NQO-1 pathway. In vivo, consistent with cellular data, salvigenin improved renal function, alleviated pathological lesions, suppressed inflammation and iron deposition, and enhanced Nrf2 signaling in DN mice.
CONCLUSION
This study confirms salvigenin confers potent renoprotection against DN. Mechanistically, salvigenin activates the Nrf2 cascade to strengthen antioxidant defense, alleviate oxidative and inflammatory injury, and inhibit renal tubular ferroptosis. These results uncover the molecular mechanism of salvigenin and offer experimental support for developing natural flavonoids as candidate agents for DN treatment.
Xiaoxu Ge, Juan Du, Jiajia Wang et al.· Toxicology and Applied Pharm...· 0 citations
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