Sürdürülebilir Kalkınma Amaçları
Yayınlar
- 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 Erişim2026Scopus SJRQ1A natural nephroprotective adjuvant for cancer chemotherapy: Rosmarinic acid disrupts IL-17 A-Ferroptosis coupling in Ifosfamide-induced renal injury
Süzen Celbek, Büşra; Şimşek, Hasan; Akaras, Nurhan; Kandemir, Özge; Kızıl, Hamit Emre; Mutlu, Hüseyin; Kandemir, Fatih Mehmet
Rosmarinic acid (RA) is a natural polyphenol with established pleiotropic protective effects. Ifosfamide (IFA) is a potent antineoplastic agent whose clinical utility is severely limited by dose-dependent nephrotoxicity, primarily mediated by its metabolite, chloroacetaldehyde (CAA). This study aimed to investigate whether RA protects against IFA-induced nephrotoxicity and to elucidate the underlying molecular mechanisms. Male Wistar albino rats (n = 7 per group) were allocated into four groups: Control, RA-only (50 mg/kg, p.o., 2 days), IFA-only (a single 500 mg/kg, i.p. dose), and IFA + RA. Serum biochemical markers (urea, creatinine), renal oxidative stress parameters (MDA, GSH, SOD, CAT, GPx), gene expression levels (NF-κB, TNF-α, IL-1β, IL-17 A, ACT1, TRAF6, Caspase-3, Bax, Bcl-2, PTGS2, GPX4, TfR1), and histopathological/immunohistochemical analyses (KIM-1, Nephrin, Caspase-3) were performed 24 h post-administration. IFA induced severe renal dysfunction, marked oxidative stress, and extensive histopathological damage. Mechanistically, IFA initiated a pathogenic cascade activating intrinsic apoptosis and ferroptosis, driven by a self-sustaining IL-17 A-TRAF6-NF-κB inflammatory loop. RA co-treatment (50 mg/kg) significantly reversed all functional, biochemical, and histological damage by strategically breaking this crosstalk, restoring redox homeostasis, and simultaneously restraining both cell death programs. In conclusion, RA protects against IFA nephrotoxicity by targeting the critical inflammation-ferroptosis coupling, positioning it as a highly promising adjuvant candidate for clinical use to mitigate IFA-induced renal injury.
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İncele - MakaleYalnız künye2026Scopus SJRQ2Multi-Pathway Renoprotection by Betanin Against Docetaxel Nephrotoxicity: Modulation of Inflammation, ER Stress, Apoptosis, and Ferroptosis
Süzen Celbek, Büşra; Akaras, Nurhan; Şimşek, Hasan; Mutlu, Hüseyin; Kızıl, Hamit Emre; Kandemir, Özge; Aygörmez, Serpil; Kandemir, Fatih Mehmet
Docetaxel (DTX), a cornerstone chemotherapeutic agent, has its clinical utility significantly limited by dose-dependent nephrotoxicity. This study investigated the multi-pathway renoprotective mechanisms of betanin (BTN), a natural antioxidant derived from beetroot, against DTX-induced kidney injury. Male Wistar rats received DTX (30 mg/kg, i.p., single dose) with or without BTN (100 mg/kg/day, p.o.) for 7 days. DTX induced severe renal dysfunction with elevated serum urea and creatinine, and significant oxidative stress characterized by increased MDA and decreased GSH, GPx, SOD, and CAT. Molecular analysis demonstrated widespread upregulation of pro-inflammatory (NF-κB, TNF-α, IL-1β), endoplasmic reticulum stress (PERK, ATF6), pro-apoptotic (Caspase-3, Bax, Apaf-1), and pro-ferroptotic (PTGS2, TfR1) mediators, with concurrent downregulation of protective Bcl-2 and GPx4. Histopathological examination revealed extensive tubular injury, while immunohistochemical analysis showed markedly increased kidney injury marker KIM-1 and decreased aquaporin-1 expression. Remarkably, BTN co-administration significantly attenuated all biochemical, molecular, and structural derangements, restored tissue architecture, and normalized KIM-1 and AQP-1 expression. In conclusion, betanin provides robust, multi-pathway renoprotection against docetaxel-induced nephrotoxicity by concurrently targeting oxidative stress, inflammation, ER stress, apoptosis, and ferroptosis.