Protective Role of Linagliptin in Cisplatin‐Mediated Liver Injury: Involvement of STAT3 and AMPK/SIRT1/PGC‐1alpha Mitochondrial Energy Sensing Networks
Jan 2026· Advances in pharmacological and pharmaceutical sciences· Vol 2026· 0 citations· 59 references
Medicine
TL;DR
The results indicate that Lina protects against Cis‐induced liver damage by leveraging its antioxidant, anti‐inflammatory, and metabolic regulation properties.
Abstract
Cisplatin (Cis), a commonly used chemotherapy drug, is associated with liver toxicity, which restricts its broader clinical use. This study investigated the potential protective effects of linagliptin (Lina), a DPP‐4 inhibitor, in preventing liver damage induced by Cis in rats. There were four groups of male rats: a control group, a Cis group (8 mg/kg, IP), and cotreated groups given Lina (5 and 10 mg/kg, orally) with Cis. Lina was administered daily for 15 days, with Cis injected on Day 8. Liver function, oxidative stress markers, inflammatory mediators, energy metabolism indicators, and key signaling proteins were assessed. Cis administration resulted in significant hepatotoxicity, evidenced by elevated liver enzymes, increased oxidative stress, enhanced inflammatory response, and disrupted energy metabolism. Lina treatment, particularly at the 10‐mg/kg dose, demonstrated marked hepatoprotective effects. It significantly reduced liver enzyme levels, improved antioxidant status, attenuated inflammatory markers, and restored energy metabolism indicators. Moreover, Lina positively modulated essential signaling proteins involved in cellular stress response and metabolism, including signal transducer and activator of transcription 3 (STAT3), transforming growth factor beta 1 (TGF‐β), silent information regulator 1 (SIRT1), and peroxisome proliferator–activated receptor gamma coactivator 1‐alpha (PGC‐1α). The results indicate that Lina protects against Cis‐induced liver damage by leveraging its antioxidant, anti‐inflammatory, and metabolic regulation properties. This study offers new insights into potential strategies for mitigating Cis‐induced hepatotoxicity and enhancing its therapeutic index in cancer treatment.
Abstract Cisplatin (CP), an effective chemotherapeutic agent, is known to cause cardiotoxicity, limiting its clinical application. This study aimed to investigate the potential cardioprotective effects of linagliptin (LG) against cisplatin-induced cardiac injury and to elucidate its underlying mechanisms. There were four groups of male Wistar rats: control, cisplatin (CP, 8 mg/kg, IP), and two groups with LG treatment (5 mg/kg and 10 mg/kg, orally) and CP. CP significantly increased cardiac injury markers (CK, CK-MB, TNNC1) and oxidative stress (decreased SOD and GSH, increased MDA) compared to controls (p < 0.05). It also elevated inflammatory cytokines (TNF-α, IL-6) and disrupted mitochondrial function (altered ATP level and NADP/NADPH ratios). Furthermore, CP decreased the expression of SIRT1 and Nrf2 and the level of p-AMPK. LG treatment dose-dependently attenuated these changes, with the 10 mg/kg dose showing greater efficacy. Histopathological examination and immunohistochemistry confirmed these biochemical findings, showing improved cardiac structure and increased expression of SIRT1 and Nrf2 with LG treatment. Linagliptin demonstrates potent cardioprotective effects against cisplatin-induced toxicity, primarily through modulation of the SIRT1/AMPK/Nrf2 signaling pathway, thereby resulting in reduced oxidative stress and inflammation. These findings suggest that linagliptin may serve as a potential adjuvant therapy to mitigate cisplatin-induced cardiotoxicity.
M. Alsugoor, Naif Al Suhaymi, Bassim M S A Mohamed et al.· Drug and chemical toxicology...· 0 citations
RUPA counteracts hepatotoxicity evoked by CISP in rats via its anti‐oxidative as well as anti‐inflammatory properties via repression of hepatic HMGB1/TLR4/NF‐κB and thus restricts the activation of NLRP3/caspase‐1 signaling cascade.
Shaimaa Mohamed Abdelrahman, A. Bekhit, Olivia N. Beshay· Journal of biochemical and m...· 0 citations
N-Cur mitigates oxidative damage and inflammation, thereby preserving hepatic function during CDDP-based chemotherapy, and demonstrates significant potential as a hepatoprotective agent when administered concomitantly with CDDP chemotherapy.
Q. Alqahtani, M. Atteya, T. Almatrafi et al.· Biomedicines· 0 citations
BACKGROUND
Isotretinoin is a widely prescribed retinoid for severe acne but is limited by dose-dependent hepatotoxicity. Tranexamic acid (TXA), an antifibrinolytic agent with emerging anti-inflammatory and antioxidant effects, may offer hepatoprotective potential. Aim: This study evaluated whether TXA mitigates isotretinoin-induced liver injury in rats and explored the underlying molecular mechanisms.
METHODS
Thirty-two male Wistar rats were assigned to four groups (n = 8 each): control, TXA-only, isotretinoin (ISO, 7.5 mg/kg/day, 30 days), and TXA (100 mg/kg/day for 30 days) + ISO. Serum alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase were measured for hepatic function. Oxidative stress was assessed by hepatic malondialdehyde, myeloperoxidase (MPO), and reduced glutathione (GSH). Inflammatory cytokines tumor necrosis factor-alpha (TNF-α), interleukin1β (IL-1β), interleukin-10 (IL-10), and signaling proteins TNF receptor-associated factor 6 (TRAF6) and nuclear factor erythroid 2-related factor 2 (Nrf2) were quantified by ELISA. Vascular endothelial growth factor (VEGF) and nuclear factor kappa B (NF-κB) expressions by immunohistochemistry. Myeloid differentiation primary response 88 (MYD88) and toll-like receptor-4 (TLR4) protein expression were analyzed via Western blot. Histopathological scoring was performed to evaluate tissue injury.
RESULTS
ISO administration significantly elevated serum ALT and AST by approximately 3-fold (p < 0.001), along with a marked increase in hepatic MDA and MPO, reduced GSH, heightened TNF-α and IL-1β, and suppressed IL-10 (p < 0.05). Hepatic TRAF6, NF-κB, MYD88/TLR4, and VEGF were upregulated significantly (p < 0.05), while Nrf2 was downregulated (p < 0.05), and histology revealed severe degeneration and congestion. TXA co-treatment significantly attenuated these changes (p < 0.05), reducing liver enzyme activities and inflammatory markers while restoring antioxidant defense mechanisms.
CONCLUSION
TXA pretreatment markedly attenuated these effects, normalizing liver enzymes, restoring oxidative balance, reducing inflammation, and suppressing aberrant signaling. TXA effectively protects against isotretinoin-induced hepatotoxicity, primarily through antioxidant and anti-inflammatory mechanisms.
Abdullah Alkhammash, H. Hagar, Hatem Ali Ahmed Abdelmottaleb et al.· Immunopharmacology and immun...· 0 citations
Objective(s): Hepatic encephalopathy (HE) is a brain disorder linked to hyperammonemia from liver injury. Elevated ammonia levels are known to impair mitochondrial function, the primary energy source for cells. Therefore, this study aimed to evaluate energy-related signaling pathways enhancing mitochondrial biogenesis using thymoquinone (TQ) in an HE model. Materials and Methods: Wistar rats were randomly divided into three groups: sham, HE (200 mg/kg thioacetamide (TAA) in 2ml saline, administered intraperitoneally (IP) once every 48 hr for 14 consecutive days), and HE + TQ (20 mg/kg, IP, in 2 ml DMSO 5% administered once daily for seven consecutive days). Mitochondrial biomarkers (membrane potential [MMP], oxidative stress), gene expression (AMPK, PGC-1α), and protein expression (AMPK, P-AMPK, SIRT3, ANT1, CYPD, DRP1, VDAC, and P53) were measured in brain tissue. Additionally, electroencephalogram (EEG) recordings were obtained from the dentate gyrus (DG). Results: Our findings indicate that TQ was associated with a significant increase in MMP and a concomitant decrease in mitochondrial oxidative stress. Furthermore, TQ appeared to augment the AMPK/PGC-1α/SIRT3 signaling pathway, and was associated with the reversal of HE-induced down-regulation of ANT1 and VDAC, as well as up-regulation of CYPD, DRP1, and P53. Besides, TQ treatment was also linked to increased power recorded in the EEG from the DG region of the rat hippocampus. Conclusion: The AMPK/PGC-1α/SIRT3 signaling pathway appears to function as a key energy sensor that may help revitalize the metabolic machinery in mitochondria, potentially facilitating metabolic exchanges and energy production, particularly in response to neurodegenerative diseases such as HE.
Somayeh Hajipour, M. Dehghani, A. Sarkaki et al.· Iranian Journal of Basic Med...· 0 citations
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