Fatih Mehmet Kandemir

OBJECTIVE: The aim of this study is to investigate the protective effects of rutin against lower-extremity ischemia-reperfusion (IR)-induced skeletal muscle injury in rats, focusing on oxidative stress, inflammation, endoplasmic reticulum (ER) stress, and apoptosis, considering rutin’s well-known strong antioxidant and anti-inflammatory properties.MATERIAL AND METHODS: Twenty-eight male Wistar rats were randomly divided into four groups: control, rutin, IR, and IR+rutin. Hind limb ischemia was induced by applying a tourniquet to the upper limb for 2 hours, followed by 2 hours of reperfusion. Rutin was administered orally at a dose of 100 mg/kg prior to ischemia. Skeletal muscle tissue samples were analyzed for oxidative stress markers (MDA, SOD, CAT, GPx, GSH) using spectrophotometric biochemical assays; inflammatory mediators (NF-κB, IL-1β mRNA), endoplasmic reticulum stress markers (PERK, ATF6, IRE1α mRNA), and apoptotic markers (Bax, Bcl-2, caspase-3) were evaluated by RT-PCR. Histopathological changes were examined in sections prepared from the gastrocnemius muscle using H&E staining.RESULTS: Ischemia-reperfusion led to a significant increase in MDA levels and in the mRNA expression of NF-κB, IL-1β, PERK, ATF6, IRE1α, Bax, and caspase-3, accompanied by a reduction in antioxidant enzyme activities (SOD, CAT, GPx) and GSH content. Rutin exhibited protective activity against IR-induced muscle damage by strengthening endogenous antioxidant defenses and suppressing stress-related signaling pathways. Consistently, histopathological evaluation demonstrated that rutin mitigated muscle fiber disorganization, vascular congestion, and inflammatory cell infiltration.CONCLUSIONS: Oral rutin administration exerts strong protective effects against skeletal muscle IR injury by modulating oxidative stress, inflammatory responses, ER stress, and apoptosis. These findings highlight rutin as a promising pharmacological candidate for protecting skeletal muscle integrity in post-ischemic conditions.

Background/Objectives: This study investigated the preventive effects of apilarnil (APL) against copper nanoparticle (CuNPs)-induced liver and kidney injury in rats. Methods: Thirty-five rats were randomly allocated into five groups (n = 7): Control (physiological saline), APL (400 mg/kg), CuNPs (100 mg/kg), CuNPs + APL200 (100 mg/kg CuNPs + 200 mg/kg APL) and CuNPs + APL400 (100 mg/kg CuNPs + 400 mg/kg APL). All treatments were administered orally by gavage for 28 consecutive days. Results: CuNPs administration increased serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), blood urea nitrogen (BUN) and creatinine levels, whereas APL attenuated these biochemical alterations. CuNPs also decreased superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT) activities together with reduced glutathione (GSH) levels while increasing malondialdehyde (MDA), whereas APL attenuated these oxidative alterations. Furthermore, CuNPs markedly upregulated the mRNA expression of endoplasmic reticulum (ER) stress-related genes, including activating transcription factor 6 (ATF6), glucose-regulated protein 78 (GRP78), protein kinase RNA-like ER kinase (PERK) and C/EBP homologous protein (CHOP). In parallel, CuNPs increased the protein levels of Toll-like receptor 4 (TLR4), high-mobility group box 1 (HMGB1), nuclear factor-κB (NF-κB), monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-α (TNF-α), whereas APL attenuated these inflammatory responses. Histopathological examination showed that APL markedly attenuated CuNPs-induced hepatic and renal lesions and reduced the immunoreactivity of caspase-3 and 8-hydroxy-2′-deoxyguanosine (8-OHdG). Conclusions: Overall, APL alleviated CuNPs-induced hepatorenal toxicity and was associated with improvements in oxidative stress parameters, ER stress-related gene expression, inflammatory protein concentrations, caspase-3 immunoreactivity, and oxidative DNA damage.

The present study aimed to investigate the nephrotoxic effects of oxytetracycline (OTC) and to evaluate the protective role of vitamin E (Evit) through oxidative stress, inflammation, and autophagy pathways. A total of 28 rats were randomly assigned to four experimental groups: control, Evit, OTC, and OTC + Evit and treated for seven consecutive days. At the end of the experimental period, kidney tissues were collected for biochemical and molecular analyses. Oxidative stress parameters, including malondialdehyde (MDA), reduced glutathione (GSH), glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase (CAT), were determined using spectrophotometric methods. In addition, the gene expression levels of nuclear factor kappa B (NF-κB), interleukin-1 beta (IL-1β), tumor necrosis factor-alpha (TNF α), and the autophagy-related marker Beclin-1 were evaluated by quantitative real-time polymerase chain reaction (qRT-PCR). OTC administration significantly increased MDA levels while decreasing GSH content and the activities of antioxidant enzymes, indicating enhanced oxidative stress. Furthermore, the expression levels of NF-κB, IL-1β, TNF-α, and Beclin-1 were markedly elevated, suggesting activation of inflammatory and autophagic pathways. Evit co administration significantly reduced MDA levels, restored antioxidant enzyme activities, and suppressed the expression of inflammatory and autophagy-related markers compared with the OTC group, although these parameters did not fully return to control levels. In conclusion, Evit exerts a protective effect against OTC-induced renal injury by attenuating oxidative stress and modulating inflammation and autophagy pathways, highlighting its potential as a supportive therapeutic strategy against antibiotic-induced nephrotoxicity.

Amoxicillin-clavulanic acid (AMC) is frequently implicated in drug-induced hepatic damage during antimicrobial therapy; however, the molecular mechanisms driving this adverse event remain poorly understood. Carvacrol (CRV), a monoterpenic phenol, exhibits potent antioxidant and anti-inflammatory properties. This study aimed to investigate whether CRV exerts a hepatoprotective effect against AMC-induced liver injury. Male Wistar albino rats (n=28) were allocated into four groups: control, AMC (30 mg/kg), CRV (50 mg/kg), and AMC+CRV, administered via oral gavage daily for seven days. Hepatic damage was evaluated by assessing liver function markers, oxidative stress parameters, inflammatory pathways, autophagic markers, and histopathological alterations. AMC administration induced acute hepatic injury, significantly elevating serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels. AMC also increased hepatic malondialdehyde (MDA) content, upregulated pro-apoptotic proteins (Caspase-3 and Bax), and elevated inflammatory markers [nuclear factor kappa B (NF-κB), interleukin-17A (IL-17A), and interleukin-1β (IL-1β)], alongside autophagic markers [Beclin-1 and Light chain 3A (LC3A)]. Conversely, AMC suppressed glutathione levels, reduced superoxide dismutase, catalase, and glutathione peroxidase activities, and downregulated the anti-apoptotic protein B-cell lymphoma-2 (BCL-2). Co-administration of CRV with AMC significantly attenuated AST, ALT, MDA, NF-κB, IL-17A, IL-1β, Caspase-3, Bax, Beclin-1, and LC3A levels, while successfully restoring antioxidant defenses and BCL-2 expression. Furthermore, CRV markedly ameliorated AMC-induced histopathological tissue damage. Collectively, these findings suggest that CRV exerts a protective effect against AMC-induced hepatotoxicity, associated with the attenuation of oxidative stress, apoptosis, autophagy, and inflammation.

The present study aimed to investigate the protective effects of selenium (SE) against enrofloxacin (ENRO) induced liver damage through oxidative stress, inflammation, and autophagy pathways. Rats were divided into four groups: control (received physiological saline via oral gavage and intraperitoneal (i.p.) injection for 7 days); selenium (1 mg/kg, oral, 7 days); enrofloxacin (150 mg/kg, i.p., 7 days); and enrofloxacin (150 mg/kg, i.p., 7 days) + selenium (1 mg/kg, oral, 7 days). In liver tissues, oxidative stress markers including malondialdehyde (MDA), reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) were measured. Additionally, nuclear factor kappa B (NF-κB), interleukin-1 beta (IL-1β), tumor necrosis factor-alpha (TNF-α), and Beclin-1 expression were analyzed to evaluate inflammatory and autophagic responses ENRO administration increased NF-κB, IL-1β, TNF-α, and Beclin-1 expression together with elevated MDA levels, while decreasing GSH levels and SOD, CAT, and GPx activities. These alterations indicate increased lipid peroxidation, inflammation, and autophagy. These findings indicate that ENRO disrupts antioxidant defense systems and promotes inflammatory and autophagy-related responses in liver tissue. SE supplementation reduced MDA levels, enhanced GSH levels and antioxidant enzyme activities, and significantly ameliorated these alterations by suppressing NF-κB, IL-1β, TNF-α, and Beclin-1 expression. In conclusion, SE was found to exert hepatoprotective effects against ENRO induced liver injury by reducing lipid peroxidation, strengthening antioxidant defense systems, and regulating inflammatory and autophagic responses.

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.

This study aimed to evaluate whether polydatin (Poly) could eliminate the harmful effects of vancomycin (VCM) on the lungs of rats. Rats were administered VCM (200 mg/kg) and Poly (50 mg/kg), both separately and in combination, for a duration of 7 days. Following this, various methods were utilized to analyze proteins and pathological changes in lung tissue related to oxidative stress, inflammation, endoplasmic reticulum stress, apoptosis, and ferroptosis. It was found that Poly application significantly enhanced antioxidant enzyme activities and nonenzymatic antioxidants while decreasing VCM‐induced lipid peroxidation. The study showed that VCM elevated the expression of inflammatory cytokines as well as Janus kinase 2 (JAK‐2) and signal transducer and activator of transcription 3 (STAT‐3), whereas Poly treatment inhibited these genes. Furthermore, VCM was found to induce apoptotic markers, but Poly offered protection to lung tissue against the harmful effects of VCM by demonstrating an antiapoptotic effect. Additionally, the increased expression of prostaglandin endoperoxide synthase 2 (PTGS2) and transferrin receptor 1 (TFR1), along with the decreased expression of glutathione peroxidase 4 (GPX4) in lung tissue induced by VCM, showed improvement following Poly administration. VCM was observed to increase, while Poly decreased the expression of endoplasmic reticulum stress markers. Overall, the findings of this study suggest that Poly has therapeutic potential in combating VCM‐induced lung toxicity.

The main objective of this study was to assess the antioxidant capacity and the protective impact of carvacrol (CRV) against oxytetracycline (OXI)-mediated nephrotoxicity in albino rats. CRV, a naturally occurring phenolic compound found in various plant species, has significant antioxidant capacity, the ability to mitigate inflammatory processes, and tumor proliferation inhibiting properties. The study evaluated the efficacy of CRV in reducing oxidative stress-induced kidney damage in albino rats. Findings showed that CRV administration significantly reduced the kidney damage relative to the control group. Evaluation of the enzymatic antioxidant profile indicated a significant decrease in the activities of catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD) enzymes and GSH levels in the OXI-treated group compared to the CRV group. Furthermore, CRV treatment decreased malondialdehyde (MDA), a key biomarker of lipid peroxidation. The protective properties of CRV were confirmed by histological examination of the kidney. CRV treatment markedly suppressed pro-inflammatory molecules, specifically diminishing the expression of interleukin-1 beta (IL-1β) and mitigating nuclear factor kappa-B (NF-κB) activation. Furthermore, CRV administration attenuated OXI-induced increases in the proapoptotic proteins Bax and Caspase-3, while increasing the transcriptional activity of the antiapoptotic gene B-cell lymphoma-2 (Bcl-2). CRV diminished OXI-induced kidney tissue damage by decreasing Kidney Injury Molecule-1 (KIM-1) and increasing Aquaporin-2 (AQP-2) levels. The study results indicate that CRV administration can alleviate tissue damage in the kidney caused by OXI toxicity.

Bortezomib (BTZ) is clinically important in the nephrological field because of its increasing use in plasma cell disorders and antibody‐mediated kidney diseases, where it can both exert therapeutic benefits and, paradoxically, cause significant renal toxicity. This study investigated the protective effects of vanillic acid (VA) against BTZ‐induced acute kidney injury using biochemical and molecular approaches. BTZ administration elevated serum creatinine, blood urea nitrogen, KIM‐1 and NGAL, while co‐treatment with VA partially normalized these markers. BTZ increased apoptotic markers (BAX, PUMA and TRAIL) and inflammatory cytokines (IL‐1β, IL‐6, TNF‐α and IL‐10), which were attenuated by VA. Oxidative stress–related genes NQO1, NOX4 and XO were upregulated, and GPX4 was downregulated by BTZ; VA restored these expressions. BTZ disrupted mitochondrial dynamics and energy metabolism (MFN2, CPT1A and OxPhos decreased; FIS1 increased), with VA ameliorating these changes. Energy imbalance induced by BTZ, reflected by reduced ATP and increased LDH and TAG, was also mitigated by VA. Podocyte proteins nephrin, podocin and CD2AP were reduced, accompanied by increased LAMP1 and decreased miR‐204‐5p; VA partially restored these levels. Overall, VA protected against BTZ‐induced kidney injury via antioxidant, anti‐inflammatory, antiapoptotic and mitochondrial mechanisms, potentially involving the miR‐204‐5p–nephrin axis.