Browsing by Author "Ustundag, Hilal"

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Alleviation of LPS-Induced Acute Lung Injury by Propolis-Based Nanocomposites Through the TLR4/NFκB and P2X7/Akt Pathways: Randomized-Controlled Experimental Study
(Pergamon-Elsevier Science Ltd, 2025) Ustundag, Hilal; Kara, Adem; Tas, Necip Gokhan; Kalindemirtas, Ferdane Danisman; Kurt, Nezahat; Erbas, Elif; Kariper, Ishak Afsin
Sepsis-associated acute lung injury continues to pose a significant medical challenge with substantial morbidity and mortality rates. In this study, we investigated the therapeutic potential of propolis-based treatments and their nanocomposites in modulating inflammation and apoptosis using a lipopolysaccharide (LPS)-induced rat model of sepsis. Forty-two Sprague-Dawley rats were divided into seven groups (n = 6): control, LPS (5 mg/kg, i. p.), LPS + Propolis (100 mg/kg, i.p.), LPS + NanoPropolis (100 mg/kg, i.p.), LPS + silver nanoparticles propolis (AgNPsPro) (50 mg/kg), and a negative propolis group (100 mg/kg, i.p.). The rats were assessed for inflammatory, oxidative stress, and apoptotic markers through Western blot, histopathological analyses, and biochemical measurements. The LPS group exhibited significantly higher levels of pro-inflammatory cytokines (IL-1 beta, TNF-alpha) and the systemic infection marker presepsin (PRSN) in blood, as well as the oxidative stress marker malondialdehyde (MDA) in lung tissue. The treatment groups, particularly LPS + AgNPsPro, showed significant reductions in these markers, with decreased levels of MDA, IL-1 beta, TNF-alpha, NF-kappa B, and TLR4, and increased GSH content in lung tissue (p < 0.05). The anti-apoptotic protein BCL-2 was upregulated, while proapoptotic BAX expression was reduced, indicating enhanced cell survival. The P2X7 receptor, a key inflammation regulator, and the AKT signaling pathway, involved in cell survival, were positively modulated by the treatments. Histopathological findings corroborated these results, showing less lung tissue damage. In conclusion, propolisbased treatments, especially in combination with nanoparticles, demonstrate therapeutic potential in reducing inflammation, oxidative stress, and apoptosis in sepsis-induced lung injury.
Alleviation of LPS-Induced Acute Lung Injury by Propolis-Based Nanocomposites Through the TLR4/NFκB and P2X7/Akt Pathways: Randomized-Controlled Experimental Study (Vol 258, 108330, 2025)
(Pergamon-Elsevier Science Ltd, 2025) Ustundag, Hilal; Kara, Adem; Tas, Necip Gokhan; Kalindemirtas, Ferdane Danisman; Kurt, Nezahat; Erbas, Elif; Kariper, Ishakshak Afsin
Astaxanthin Treatment Reduces Kidney Damage and Facilitates Antioxidant Recovery in Lithium-Intoxicated Rats
(Pergamon-Elsevier Science Ltd, 2024) Erbas, Elif; Ustundag, Hilal; Ozturk, Emre; Parlak, Secil Nazife; Atcali, Tugce
Objective: This study aimed to evaluate the protective effects of astaxanthin against lithium-induced nephrotoxicity, focusing on histopathological changes, oxidative stress modulation, and alteration in the expression of key proteins related to apoptosis and inflammation. Methods: In this study, 56 male rats were utilized and divided into experimental groups subjected to lithiuminduced nephrotoxicity, with and without astaxanthin treatment, over 14 and 28 days. The parameters assessed included oxidative stress markers (MDA, GSH, SOD), protein expression levels of BCL-2, BAX, TNF- alpha, PI3K, NF-kappa B -p65, IL-1 beta, and comprehensive histopathological examinations to evaluate the integrity of renal tissue. Results: Lithium exposure led to significant renal damage, as evidenced by histological distortions in renal architecture, increased oxidative stress indicated by elevated MDA levels, and dysregulated expressions of apoptotic and inflammatory proteins. Notably, histopathological analysis revealed glomerular and tubular degeneration in lithium-treated groups. Astaxanthin treatment effectively mitigated these effects, demonstrating its efficacy in reducing lipid peroxidation, rebalancing apoptotic proteins, suppressing pro-inflammatory cytokines, and preserving renal histological structure. The concurrent use of lithium and astaxanthin showed a considerable amelioration of lithium-induced damage, suggesting astaxanthin's role in attenuating the nephrotoxic effects of lithium, both at a molecular and structural level. Conclusion: Astaxanthin demonstrates significant renoprotective effects against lithium-induced nephrotoxicity, suggesting its utility as an effective adjunctive therapy. Through its potent antioxidative, anti-inflammatory, and anti-apoptotic actions, astaxanthin effectively reduces renal damage associated with lithium treatment, underscoring its potential for enhancing renal health in patients receiving lithium therapy.
Astaxanthin-Loaded Silver Nanoparticles Mitigate 6-Ohda Parkinson's Via Er Stress and Pi3k/Akt Signaling
(Springer, 2025) Kara, Hulya; Tekiner, Deniz; Ustundag, Hilal; Bayram, Cemil; Sebin, Saime Ozbek; Ozkanlar, Seckin; Kara, Adem
Parkinson's disease (PD) is characterized by progressive dopaminergic neuronal loss, with oxidative stress and neuroinflammation as critical pathological mechanisms. The blood-brain barrier presents a significant challenge for therapeutic delivery, while current treatments provide only symptomatic relief without halting disease progression. This study investigated the neuroprotective effects of astaxanthin-loaded citrate-coated silver nanoparticles (AST-AgNPs), leveraging their potent antioxidant properties, anti-inflammatory capacity, and enhanced blood-brain barrier penetration. In vitro cytotoxicity analyses were performed using 6-hydroxydopamine (6-OHDA)-induced SH-SY5Y neuroblastoma cells, while in vivo experiments utilized a unilateral 6-OHDA-induced rat model. Following 14 days of treatment, comprehensive evaluations included behavioral assessments, biochemical analyses (MDA, GSH, SOD, TNF-alpha, IL-1 beta, IFN-gamma), histopathology, immunohistochemistry (BrdU, tyrosine hydroxylase), and molecular analyses. Western blot measured CHOP, IRE1, ATF6, p-AKT, total AKT, caspase-3, and cleaved caspase-3, while RT-PCR quantified caspase-3, Bcl-2, Bax, PI3K, mTOR, Akt, CREB, and NF-kappa B-p65 expression. AST-AgNP treatment significantly ameliorated motor dysfunction, reduced neuroinflammation (TNF-alpha, IL-1 beta), improved oxidative stress parameters (MDA, GSH, SOD), and preserved dopaminergic neurons (all p < 0.05). Western blot revealed significant downregulation of ER stress markers (CHOP, IRE1, ATF6) and cleaved caspase-3, while restoring p-AKT and total AKT levels (p < 0.05). RT-PCR demonstrated decreased pro-apoptotic gene expression (caspase-3, NF-kappa B-p65) and increased anti-apoptotic Bcl-2 expression (p < 0.05). These findings demonstrate that AST-AgNPs provide neuroprotection through simultaneous modulation of ER stress and PI3K/Akt/mTOR pathways, representing a novel dual-pathway therapeutic strategy for PD addressing multiple pathological mechanisms through enhanced nanoparticle-mediated delivery.
D-Carvone Attenuates LPS-Induced Acute Lung Injury via TLR4/NF-κB and NRF2/HO-1 Signaling Pathways in Rats
(Springer, 2025) Ulas, Nergis; Ustundag, Hilal; Ozkanlar, Seckin; Erbas, Elif; Kara, Adem; Ozkanlar, Yunusemre
Acute lung injury (ALI) is a severe respiratory disorder associated with high morbidity and mortality. Lipopolysaccharide (LPS) is widely used to induce ALI in animal models. D-carvone, a natural monoterpene, has been reported to possess anti-inflammatory and antioxidant properties. This study aimed to investigate the protective effects of D-carvone on LPS-induced ALI in rats. Thirty-six male rats were randomly divided into six groups (n = 6): control, D-carvone (10 mg/kg and 20 mg/kg p.o.), LPS (10 mg/kg E. coli lipopolysaccharide i.p.), and LPS + D-carvone (LPS with either 10 or 20 mg/kg D-carvone). D-carvone was administered orally once daily for 10 days. On day 10, sepsis was induced with LPS administration, and samples were collected after 6 h under deep anesthesia. LPS administration caused significant lung injury, as evidenced by increased histopathological scores, upregulation of pro-inflammatory markers (TLR4, IL-1 beta, TNF-alpha), and oxidative stress (increased MDA, decreased GSH and SOD). Treatment with D-carvone at both doses significantly attenuated these changes. D-carvone downregulated pro-inflammatory markers, upregulated anti-inflammatory (NRF2) and anti-apoptotic (Bcl-2) proteins, and reduced the levels of pro-inflammatory cytokines (IL-1 beta, TNF-alpha, IL-8) in lung tissues. In conclusion, D-carvone protects against LPS-induced ALI in rats, possibly through its anti-inflammatory and antioxidant properties. These findings suggest that D-carvone could be a potential therapeutic candidate for preventing and treating ALI.
The Effects of Cetuximab with Agomelatine on Gene Expression in Colon Cancer Cells
(2024) Erbaş, Elif; Kara, Adem; Ustundag, Hilal; Albayrak, Kevser; Köse, Rukiye
This study investigated the combined effects of agomelatine, a melatonergic antidepressant, and cetuximab, an EGFR inhibitor, on the colorectal cancer cell line (Caco-2). Caco-2 cells were treated with agomelatine (0.3 μg/ml and 3 μg/ml) and cetuximab (50 μg/ml), individually and in combination, for 24 and 48 hours. Cell viability was assessed using the MTT assay. Gene expression analysis of EGFR, BCL2, PIK3CA, BAX, mTOR, and AKT3 was performed using real-time PCR. All treatment groups showed significant decreases in cell viability compared to the control (p<0.05), with enhanced effects in combined treatments. EGFR expression was significantly reduced in drug-treated groups, particularly with cetuximab (p<0.05). While changes were observed in BCL2, PIK3CA, BAX, mTOR, and AKT3 expression, these were not statistically significant (p>0.05). This study demonstrates the potential synergistic cytotoxic effects of agomelatine and cetuximab on Caco-2 colorectal cancer cells. The significant reduction in EGFR expression suggests a potential mechanism of action. These findings provide insights into combining chemotherapeutic agents with drugs addressing circadian rhythm disorders in CRC treatment strategies. Further research is warranted to elucidate the clinical implications of these observations.
Molecular Mechanisms of Resveratrol and Its Silver Nanoparticle Conjugate in Addressing Sepsis-Induced Lung Injury
(Springer, 2024) Ustundag, Hilal; Kara, Adem; Doganay, Songul; Kurt, Nezahat; Erbas, Elif; Kalindemirtas, Ferdane Danisman; Kariper, Ishak Afsin
Sepsis is a life-threatening condition characterized by a systemic inflammatory response to infection. Despite extensive research on its pathophysiology, effective therapeutic approaches remain a challenge. This study investigated the potential of resveratrol (RV) and silver nanoparticle-enhanced resveratrol (AgNP-RV) as treatments for sepsis-induced lung injury using a rat model of polymicrobial sepsis induced by cecal ligation and puncture (CLP). The study focused on evaluating changes in oxidative status (TAS, TOS, and OSI) and the expression of inflammatory and apoptotic markers (IL-1 beta, TNF-alpha, P2X7R, TLR4, Caspase-3, and Bcl-2) in lung tissue. Both RV and AgNP-RV demonstrated potential in mitigating oxidative stress, inflammation, and apoptosis, with AgNP-RV exhibiting greater efficacy than RV alone (p < 0.05). These findings were corroborated by histopathological analyses, which revealed reduced tissue damage in the RV- and AgNP-RV-treated groups. Our study highlights the therapeutic potential of RV and, particularly, AgNP-RV in combating sepsis-induced oxidative stress, inflammation, and apoptosis. It also underscores the promise of nanoparticle technology in enhancing therapeutic outcomes. However, further investigations are warranted to fully understand the mechanisms of action, especially concerning the role of the P2X7 receptor in the observed effects. Nonetheless, our research suggests that RV and AgNP-RV hold promise as novel strategies for sepsis management.