Sürdürülebilir Kalkınma Amaçları
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- MakaleYalnız künye2026Scopus SJRQ1Morin counteracts KBrO3-induced hepatotoxicity by reprogramming the HOTAIR/MEG3-miR-125b-5p/miR-214-5p axis and suppressing STAT1-associated RIPK3/MLKL necroptotic signaling
Özer, Muhammed Rasit; Özdemir, Selcuk; Küçükler, Sefa; Özkaraca, Mustafa; Kizil, Hamit Emre; Akaras, Nurhan; Mutlu, Huseyin; Kandemir, Fatih Mehmet
Potassium bromate (KBrO3; PB), an oxidative contaminant in ozonated water and bakery products, induces multi-mechanistic hepatotoxicity. Its epigenetic, necroptotic, and metabolic injury dimensions remain poorly characterized. Morin (MOR), a dietary flavonoid with established antioxidant and anti-inflammatory properties, has not previously been evaluated against PB-induced subacute hepatotoxicity. To characterize MOR's hepatoprotective mechanisms against PB-induced liver injury, focusing on the HOTAIR/MEG3-miRNA epigenetic axis, STAT1-associated RIPK3/MLKL necroptotic signaling, and Glut2/HPGD-AKT/mTOR metabolic signaling. Male Sprague-Dawley rats (n = 28) were assigned to Control, MOR (100 mg/kg), PB (62 mg/kg), and PB + MOR groups for 14 days. Outcomes included hepatobiliary biochemistry, oxidative stress markers, inflammatory mediators (ELISA), lncRNA/miRNA/mRNA profiling (RT-qPCR), immunohistochemistry (RIPK3, MLKL), double immunofluorescence (Glut2/AKT1; HPGD/mTOR), histopathology, and PCA. PB produced marked redox imbalance (up arrow MDA; down arrow SOD, CAT, GPx), NF-kappa B/NLRP3-associated inflammatory mediator elevation, epigenetic disruption (up arrow HOTAIR, down arrow MEG3; up arrow miR-125b-5p/down arrow BCL2L2; down arrow miR-214-5p/up arrow SMAD4), upregulation of STAT1-associated necroptosis-related transcripts and proteins (up arrow RIPK1/RIPK3/MLKL), and metabolic dysfunction (down arrow Glut2, down arrow HPGD; up arrow AKT1/mTOR). MOR restored redox balance, suppressed inflammation, and reprogrammed the miRNA axis while normalizing MLKL (transcript and immunohistochemistry) and AKT1 and partially attenuating RIPK3, mTOR, and STAT1. MOR confers multi-targeted hepatoprotection by restoring redox and metabolic homeostasis, attenuating NF-kappa B/NLRP3-associated inflammation, reprogramming HOTAIR/MEG3-miRNA epigenetics, and attenuating STAT1-associated RIPK3/MLKL signaling, supporting its potential as a dietary hepatoprotective candidate. PB is associated with engagement of the hepatic STAT1/RIPK3/MLKL axis and disrupts the HOTAIR/MEG3-miRNA network-both previously undocumented for this toxicant. MOR partially restores miR-214-5p/miR-466 expression while suppressing their downstream effector SMAD4, consistent with attenuation of pro-fibrotic signaling. Future work should employ multi-dose designs, in vitro mechanistic dissection, sex-stratified analyses, and clinical pharmacokinetic profiling to advance MOR toward translational application.
- MakaleAçık Erişim2023Scopus SJRQ2Morin ameliorates methotrexate-induced hepatotoxicity via targeting Nrf2/HO-1 and Bax/Bcl2/Caspase-3 signaling pathways
Kızıl, Hamit Emre; Caglayan, Cuneyt; Darendelioğlu, Ekrem; Ayna, Adnan; Gür, Cihan; Kandemir, Fatih Mehmet; Küçükler, Sefa
Background: Organ toxicity limits the therapeutic efficacy of methotrexate (MTX), an anti-metabolite therapeutic that is frequently used as an anti-cancer and immunosuppressive medicine. Hepatocellular toxicity is among the most severe side effects of long-term MTX use. The present study unveils new confirmations as regards the remedial effects of morin on MTX-induced hepatocellular injury through regulation of oxidative stress, apoptosis and MAPK signaling. Methods and results: Rats were subjected to oral treatment of morin (50 and 100 mg/kg body weight) for 10 days. Hepatotoxicity was induced by single intraperitoneal injection of MTX (20 mg/kg body weight) on the 5th day. MTX related hepatic injury was associated with increased MDA while decreased GSH levels, the activities of endogen antioxidants (glutathione peroxidase, superoxide dismutase and catalase) and mRNA levels of HO-1 and Nrf2 in the hepatic tissue. MTX treatment also resulted in apoptosis in the liver tissue via increasing mRNA transcript levels of Bax, caspase-3, Apaf-1 and downregulation of Bcl-2. Conversely, treatment with morin at different doses (50 and 100 mg/kg) considerably mitigated MTX-induced oxidative stress and apoptosis in the liver tissue. Morin also mitigated MTX-induced increases of ALT, ALP and AST levels, downregulated mRNA expressions of matrix metalloproteinases (MMP-2 and MMP-9), MAPK14 and MAPK15, JNK, Akt2 and FOXO1 genes. Conclusion: According to the findings of this study, morin may be a potential way to shield the liver tissue from the oxidative damage and apoptosis.
AtıfScopus74WoS71OpenAlex82
İncele - MakaleAçık Erişim2023Scopus SJRQ2Contribution of Oxidative Stress, Apoptosis, Endoplasmic Reticulum Stress and Autophagy Pathways to the Ameliorative Effects of Hesperidin in NaF-Induced Testicular Toxicity
Emre Kızıl, Hamit; Gür, Cihan; Ayna, Adnan; Darendelioğlu, Ekrem; Küçükler, Sefa; Sağ, Sevda
The ameliorative effects of hesperidin (HES) on the toxicities created by sodium fluoride (NaF) in the testes tissue of rats were studied via oxidative stress, apoptosis and endoplasmic reticulum (ER) stress pathways. The animals were divided into five distinct groups (7 rats in each group). Group 1 was control group, group 2 received NaF-only (600 ppm), group 3 received HES-only (200 mg/kg bw); group 4 received NaF (600 ppm)+HES (100 mg/kg bw) and group 5 received NaF (600 ppm)+HES (200 mg/kg bw) for 14 days. NaF-induced testes tissue damage by reducing activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) and levels of glutathione (GSH), and increasing lipid peroxidation levels. NaF treatment significantly downregulated the mRNA levels of SOD1, CAT and GPx. NaF supplementation caused apoptosis in the testes by upregulating p53, NFkB, caspase-3, caspase-6, caspase-9, and Bax and downregulating Bcl-2. Furthermore, NaF caused ER stress via increasing mRNA transcript levels of PERK, IRE1, ATF-6 and GRP78. NaF treatment led to autophagy via upregulation of Beclin1, LC3A, LC3B and AKT2. In testes tissue, however, co-treatment with HES at doses of 100 and 200 mg/kg significantly reduced oxidative stress, apoptosis, autophagy and ER stress. Overall, the findings of this study suggest that HES may help to reduce testes damage caused by NaF toxicity.
AtıfScopus49WoS46OpenAlex47İncele