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- ArticleYalnız künye2026The role of adenosine triphosphate in the treatment of linezolid-induced ovarian damage and reproductive dysfunction in rats: An investigation into the pathogenesis
Delibasi, Ilhan Bahri; Yavuzer, Bulent; Suleyman, Bahadir; Gumusburun, Neset; Coban, Taha Abdulkadir; Mendil, Ali Sefa; Uyar, Elif Esra; Yucel, Nurinisa; Suleyman, Halis
Linezolid is an oxazolidinone-derived antibacterial agent that inhibits bacterial protein synthesis by binding to the peptidyl transferase center of the 50S ribosomal subunit. This study investigated whether exogenously administered adenosine triphosphate (ATP) mitigates ovarian damage and reproductive dysfunction induced by linezolid in rats. Forty-eight female albino Wistar rats were randomly assigned to four groups (n = 12 each): healthy control (HG), ATP-only (ATPG), linezolid-only (LZDG), and ATP plus linezolid (ATLDG). ATPG and ATLDG received intraperitoneal ATP (4 mg/kg), whereas HG and LZDG received saline (0.9 % NaCl). One hour later, linezolid (125 mg/kg) was administered orally to LZDG and ATLDG, and the regimen was repeated twice daily for 28 consecutive days. At study end, six rats per group were euthanized for ovarian biochemical, histopathological, and immunohistochemical evaluations; prior to euthanasia (i.p. thiopental sodium, 50 mg/kg), blood was collected for serum prolactin and anti-Müllerian hormone (AMH) analysis. For fertility assessment, the remaining six females per group were co-housed with two proven fertile males for seven days and then monitored for pregnancy for one month. Linezolid exposure increased oxidative stress, caused ovarian tissue injury, decreased AMH, elevated prolactin, and resulted in a 66.7 % infertility rate. ATP co-treatment attenuated these alterations and reduced infertility to 33.3 %. These findings suggest that ATP may provide a protective therapeutic approach against linezolid-induced ovarian toxicity and reproductive dysfunction.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2026Comparative Study on the Protective Effect of Thiamine and Thiamine Pyrophosphate Against Hydroxychloroquine-Induced Cardiomyopathy in Rats
Emir, Izzet; Yavuzer, Bulent; Suleyman, Bahadir; Sarigul, Cengiz; Mendil, Ali Sefa; Sezgin, Esra Tuba; Altuner, Durdu; Gursul, Cebrail; Suleyman, Halis
Background: Hydroxychloroquine (HCQ), widely used in autoimmune and inflammatory diseases, has been associated with cardiotoxicity driven by oxidative, mitochondrial, and metabolic disturbances. However, no comparative evidence exists regarding whether thiamine, thiamine pyrophosphate (TPP), or their combination (TTPC) can mitigate HCQ-induced myocardial injury. Objective: This study examined the biochemical and histopathological effects of thiamine, TPP, and their combination in a rat model of HCQ-induced cardiomyopathy. Methods: Thirty male Wistar rats were assigned to five groups: healthy control, HCQ, thiamine + HCQ, TPP + HCQ, and TTPC + HCQ. Thiamine (20 mg/kg, intraperitoneal), TPP (20 mg/kg, intraperitoneal), or TTPC (20 mg/kg each, intraperitoneal) was administered once daily, followed by HCQ (120 mg/kg, oral, twice daily). After seven days, cardiac tissue was analyzed for MDA, tGSH, SOD, and CAT, while serum TnI, lactate, and LDH were measured from tail-vein blood samples. Cardiac samples underwent histopathological examination. Results: HCQ exposure markedly increased MDA, TnI, LDH, and lactate levels while reducing tGSH, SOD, and CAT, indicating severe oxidative and metabolic insult. Thiamine co-treatment failed to ameliorate these disturbances. Conversely, TPP restored redox balance, attenuated biomarker elevations, and improved cardiac biochemical profiles. TTPC produced comparable improvements but did not exceed those of TPP alone. Histopathologically, HCQ caused pronounced myocyte degeneration and mononuclear infiltration, whereas TPP and TTPC groups showed only mild inflammatory changes with preserved myocardial architecture. Conclusions: HCQ induces a marked redox imbalance accompanied by well-defined histopathological myocardial degeneration. TPP afforded robust cardio-protection, whereas thiamine offered no meaningful benefit. Collectively, these findings position TPP as a biologically plausible, clinically relevant candidate for mitigating HCQ-induced cardiomyopathy.
RDL Kalıcı Kaydıİncele - ArticleYalnız künye2026Identification of the chemical constituents of Juglans regia ethanol extract by L-MS/MS and its effects on 5-FU-induced autophagy, oxidative stress, and apoptosis
Uslu, Hamit; Atila Uslu, Gözde; Çoban, Taha Abdulkadir; Özkaraca, Mustafa; Mendil, Ali Sefa; Can, Hasan
5-fluorouracil (5-FU) is an important chemotherapeutic agent that has been used alone or in combination with other chemotherapeutics for years in the treatment of various malignancies. However, as with other chemotherapeutic agents, the disadvantage of 5-FU is that it damages healthy cells as well as cancer cells. Natural compounds are the first option that comes to mind to reduce and/or prevent undesirable side effects of chemotherapeutics. In this study, we aimed to determine the effects of Juglans regia extract (JR), whose antioxidant, anti-inflammatory, anti-diabetic, and antimicrobial effects were previously determined, on 5-FU-induced autophagy, oxidative stress, and apoptosis after its constituents were determined by LC-MS/MS. Experimental groups were formed as Control (C), JR, 5-FU, and JR + 5-FU. Rats were pretreated with JR at a dose of 200 mg/kg for seven days, and on the eighth day, a single dose of 100 mg/kg 5-FU was administered intraperitoneally to the JR + 5-FU and 5-FU groups. 5-FU disturbed the oxidant-antioxidant balance by increasing Keap1, TOS, and 8-OHdG levels and decreasing TAS levels and triggered cellular autophagy and apoptosis by increasing LC3B, Bax, and Caspase-3 levels and decreasing Bcl-2. JR pretreatment was shown to have modulating effects on the Keap1/Nrf2 pathway in the reorganization of the oxidant-antioxidant balance, to show anti-apoptotic activity, and to partially alleviate autophagy. JR’s bioactive components were shown to alleviate oxidative stress and associated DNA damage via Keap1/Nrf2 and also attenuate fluorouracil-induced kidney damage by reducing autophagy and apoptosis, two important forms of programmed cell death, and have a promising potential against nephrotoxicity.
RDL Kalıcı Kaydıİncele - CorrectionAçık Erişim2026Correction: Nobiletin reduces 5-FU-induced lung injury with antioxidative, anti-inflammatory and anti-apoptotic activities (Naunyn-Schmiedeberg's Archives of Pharmacology, (2025), 398, 7, (8543-8554), 10.1007/s00210-024-03773-6)
Atila Uslu, Gözde; Uslu, Hamit; Çoban, Taha Abdulkadir; Özkaraca, Mustafa; Mendil, Ali Sefa; Aygörmez, Serpil
In the originally published version of this article, inaccuracies were identified in Figure 9. Specifically, the images in Figures 9C and 9D were incorrectly presented due to the misplacement of the representative image for Figure 9D. This error has now been corrected, and Figure 9D has been revised accordingly. Additionally, errors were found in the annotation of Figure 9. Figure 9B was mistakenly labeled as the Nobiletin group; however, it actually represents the negative control group (NFκB). Conversely, Figure 9C was incorrectly labeled as the negative control group, whereas it should be identified as the Nobiletin group (IL-1β). The legend of Figure 9 has been corrected to accurately reflect these revisions. These corrections do not affect the results or conclusions of the study. The corrected figure and legend are provided below. (Figure presented.) Fig. 9 A Negative control group IL-1β, B Negative control group NFκB, C Nobiletin group IL-1β, D Nobiletin group NFκB. (IL-1β and NFκB immune negativities.) IHC
RDL Kalıcı Kaydıİncele - ArticleYalnız künye2026Effects of apigenin, hesperidin and their combinations on different physiopathological pathways in 5-fluorouracil-induced pulmonary damage
Uslu, Hamit; Atila Uslu, Gözde; Çoban, Taha Abdulkadir; Özkaraca, Mustafa; Kurt, Nezahat; Mendil, Ali Sefa
Background: Chemotherapeutics target cancerous cells, but they also have unavoidable toxicities in healthy tissues. Aim: In this study, the effects of the commonly used chemotherapeutic 5-fluorouracil (5FU) on lung tissue were investigated, along with the possible protective benefits of apigenin (API), hesperidin (HES), and their combination. Methodology: The study consisted of control, 5FU, API + 5FU, HES + 5FU, and API+HES + 5FU groups. API 50 mg/kg and HES 200 mg/kg were administered for 7 days. On the 8th day, 5FU was administered a dose of 100 mg/kg. Results: Analyses showed that API and HES were effective in preventing oxidative stress induced by 5FU in lung tissue, attenuating inflammation and apoptosis by suppressing MAPK/NFκB and Caspase-3/Bax/Bcl-2 pathways, suppressing autophagy by decreasing LC3B expression, and regulating Sigmar1 expression. Conclusion: These results suggest that the two flavonoids, when administered separately or in combination, may be useful in reducing side effects that often occur during the use of chemotherapeutics.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2026Pretreatment of trans-ferulic acid improved neurotoxicity in a thioacetamide-induced hepatic encephalopathy rat model; participation of the MAPK/NF-κb signaling pathway
Kilic, Adil Furkan; Suleyman, Bahadir; Mammadov, Renad; Bulut, Seval; Mendil, Ali Sefa; Suleyman, Halis
Aim – Trans-ferulic acid (TFA), a naturally occurring phenolic compound, has attracted significant attention due to its strong hepatoprotective and neuroprotective properties. Despite extensive research on its overall biological activities, the specific mechanisms by which TFA influences hepatic encephalopathy (HE) remain unclear. This study aims to explore the therapeutic potential of TFA by examining its effects on inflammatory signaling, glial activation, and apoptotic pathways in a thioacetamide (TAA)-induced rat model of HE. Methods – Rats were separated into four groups: a normal control group, the TAA group (which received TAA at 300 mg/kg/day for 3 days), and groups pre-treated with TFA (at doses of 25/50 mg/kg, administered orally) for 10 days, with TAA administered from the eighth to the 10th day. Results – TFA pre-treatment effectively reduced TAA-induced biochemical disturbances, as shown by lower serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and ammonia. This biochemical improvement was complemented by a significant reduction in TAA-related hepatic histopathological damage. TFA also alleviated systemic inflammation by suppressing TAA-induced increases in pro-inflammatory mediators, including tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), while also elevating the anti-inflammatory cytokine IL-10. Consistent with these results, TFA further suppressed the activation of MAPK/NF-κB inflammatory signaling pathways in both liver and brain tissues and decreased glial fibrillary acidic protein (GFAP) expression in the brains of TAA-treated rats, indicating reduced neuroinflammation and astrocyte activation. Additionally, immunochemical analysis showed that TFA pre-treatment effectively prevented the TAA-induced increase in pro-apoptotic markers Caspase-3 and Bax in both liver and brain tissues. This study underscores the strong protective effects of TFA against TAA-induced HE, mainly through inhibition of MAPK/NF-κB signaling, suppression of astrocyte activation, and reduction of apoptosis. Conclusion – These outcomes imply that TFA could be an effective treatment for HE.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2025Sıçanlarda Etanol ile İndüklenen Gastrik Ülser Modelinde Idebenon ve Krisinin Koruyucu Etkileri
Gezer, Arzu; Mendil, Ali Sefa; Ustundag, Hilal; Bedir, Gürsel
Bu çalışmada, sıçanlarda etanol ile indüklenen gastrik ülsere karşı idebenon ve krisinin koruyucu etkileri araştırılmıştır. Yirmi sekiz Sprague-Dawley erkek sıçan dört gruba ayrılmıştır: 1 ml serum fizyolojik alan kontrol grubu, gastrik ülser indüklemek için etanol (ET) (5 ml/kg) alan ET grubu ve iki tedavi grubu; biri ET'yi takiben idebenon (200 mg/kg), diğeri ET'yi takiben krisin (100 mg/kg) alan gruplar. Tedaviler oral gavaj yoluyla uygulanmıştır. Gastrik mukozal hasarı ve tedavilerin koruyucu mekanizmasını değerlendirmek için, somatostatin ve aquaporin-1 düzeylerine odaklanan histopatolojik incelemeler ve immünohistokimyasal analizler gerçekleştirilmiştir. Histopatolojik incelemelerde, ET ile muamele edilen grupta şiddetli dejeneratif ve nekrotik değişiklikler gözlenmiştir. Sonuçlar, tedavi gruplarında gastrik mukozal hasarın ET grubuna kıyasla önemli ölçüde azaldığını ve nekrotik lezyonların şiddetinde anlamlı bir azalma olduğunu göstermiştir. Kantitatif analiz, tedavi gruplarında somatostatin ve aquaporin-1 ekspresyonunda anlamlı bir artış olduğunu ortaya koymuştur (P < 0,05), bu da artmış gastrik mukozal savunmayı göstermektedir. İdebenon ve krisinin, ET ile indüklenen gastrik ülserlerde histopatolojik hasarı önemli ölçüde azalttığı ve somatostatin ile aquaporin-1 ekspresyonunu artırdığı bulunmuştur. Nekrotik lezyonlardaki azalma ve gastrik mukozal savunma mekanizmalarının güçlenmesi, idebenon ve krisinin gastrik ülserlerin önlenmesi ve tedavisi için terapötik potansiyel sunabileceğini düşündürmektedir.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2025Biochemical and Histopathologic Investigation of the Effect of Rilmenidine on Ovarian Ischemia-Reperfusion Injury in Rats
Yilmaz, Betul Kalkan; Bulut, Seval; Yilmaz, Nesrin; Yucel, Nurinisa; Cicek, Betul; Kadioglu, Berrin Goktug; Bakan, Nuri; Mendil, Ali Sefa; Suleyman, Halis
Background and Objective: Rilmenidine is an antihypertensive drug with sympatholytic properties as well as antioxidative and anti-inflammatory properties. To investigate the biochemical and histopathological effects of Rilmenidine on Ovarian IschemiaReperfusion (I/R) injury in a rat model, this study aims to determine its potential protective role against oxidative stress and tissue damage associated with ovarian IR injury. Materials and Methods: The 24 albino Wistar female rats were divided into four groups: Healthy (HG), sham-operation (SOG),ovarian ischemia-reperfusion (OIRG) and Rilmenidine+ovarian ischemia-reperfusion (ROIRG). Ovaries in SOG, OIRG and ROIRG groups were exposed to ischemia for three hrs, followed by reperfusion for 6 days. The ROIRG rats were treated with Rilmenidine (0.2 mg/kg) daily for 6 days before ischemia. The ovaries were analyzed for oxidant, antioxidant and proinflammatory cytokines and examined histopathologically. Statistical analysis was performed using one-way ANOVA and Kruskal-Wallis tests (p<0.05). Results: The IR procedure increased tissue malondialdehyde, tumor necrosis factor-a, interleukin-6 and interleukin-1$ levels and decreased total glutathione, superoxide dismutase and catalase levels (p<0.001). Severe histopathologic damage and 8-hydroxy-20deoxyguanosine immunopositivity were also observed in ovarian tissues ofOIRG (p<0.001). Rilmenidine inhibited IR-related biochemical, histopathological and immunohistochemical abnormalities (p<0.05). Conclusion: Rilmenidine may be an efficient therapeutic strategy for the protection from ovarian IR injury.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2025Myricetin protects against doxorubicin-induced acute kidney injury in rats by mitigating oxidative damage and apoptotic response
Karadogan, Muhammed Talha; Cicek, Betul; Cinisli, Kagan Tolga; Mendil, Ali Sefa; Ozkaraca, Mustafa; Yilmaz, Furkan; Suleyman, Halis
Introduction: Doxorubicin (DOX) is a potent anti-neoplastic agent widely preferred in treating various tumors. However, DOX’s off-target toxicity in healthy tissues, such as nephrotoxicity, limits its clinical utilization. DOX generates oxidative stress and apoptosis in the kidneys, which stimulates cytotoxic cellular signaling. Myricetin (MYC), an important natural flavonoid, exhibits antioxidant and antiapoptotic features. In this regard, the current report was designed to explore the renoprotective potential of MYC on DOX-induced nephrotoxicity. Methods: Animals were divided into four groups with six rats in each group: control, MYC, DOX, MYC + DOX. MYC was given orally to rats at 100 mg/kg for 10 days and DOX was injected intraperitoneally as a single dose of 20 mg/kg on the eighth day. Serum samples were evaluated for creatinine and blood urea nitrogen (BUN), and histopathological analysis of the kidneys was conducted. The levels of malondialdehyde (MDA), myeloperoxidase (MPO), total oxidant status (TOS), glutathione (GSH), glutathione peroxidase (GPx), and total antioxidant capacity (TAC) were measured in the renal tissues. Additionally, biochemical assessments of Bax and Bcl-2 proteins, along with immunohistochemical evaluations of the expression levels of caspase-3 and apoptosis-inducing factor (AIF), were conducted to evaluate apoptosis. Results: Pre-treatment of MYC decreased DOX-elicited elevation in creatinine and BUN levels (p < 0.05). Histopathological findings demonstrated the nephroprotective role of MYC on renal damage (p < 0.05), which was in harmony with the biochemical findings. Furthermore, MYC demonstrated antioxidant properties by reversing the increase in MDA, TOS, and MPO levels and the decrease in GSH, GPx, and TAS levels caused by DOX (p < 0.05). MYC pre-treatment also markedly prohibited DOX-induced elevation of Bax level, and rise of expression of caspase-3 and AIF, and reduction of Bcl-2 levels (p < 0.05). Conclusion: It could be supposed that the nephroprotective role of MYC towards DOX-induced kidney damage might be mediated by its antioxidant and antiapoptotic features.
RDL Kalıcı Kaydıİncele - ArticleYalnız künye2025The effect of methylphenidate on the reproductive function of female rats
Cim, Numan; Cim, Bunyamin; Akyuz Cim, Emine Fusun; Bulut, Seval; Mammadov, Renad; Suleyman, Bahadır; Yucel, Nurinisa; Mendil, Ali Sefa; Coban, Taha Abdulkadir; Suleyman, Halis
Aim: Research on the effects of methylphenidate on female fertility is limited. This study evaluated the effects of methylphenidate on reproductive function, oxidants, antioxidants, proinflammatory cytokines, prolactin, and cortisol in female rats. Methods: Forty-eight albino Wistar female rats were divided into four groups consisting of 12 rats, which were given pure water orally once daily for 7 days (HG-1), 10 mg/kg methylphenidate orally once daily for 7 days (MP-1), pure water orally once daily for 30 days (HG-2), and 10 mg/kg methylphenidate orally once daily for 30 days (MP-2). At the end of the treatment periods, tail vein blood was collected from six rats per group for prolactin and cortisol determination. Subsequently, euthanasia was performed and the ovaries were removed. Ovaries were analyzed for malondialdehyde (MDA), total glutathione (tGSH), superoxide dismutase (SOD), catalase (CAT), interleukin-1 beta (IL-1β), and tumor necrosis factor-alpha (TNF-α), and immunohistochemically. For breeding, the remaining six rats were mated with male rats for 1 month. Rats that failed to give birth were classed as infertile. Results: A comparison of MP-1 and MP-2 groups to healthy controls revealed an elevation in MDA and corticosterone levels, and a decline in tGSH, SOD, and CAT levels (p < 0.001). Methylphenidate did not affect prolactin, IL-1β, and TNF-α levels (p > 0.05). MP-1 and MP-2 exhibited immunopositivity for 8-hydroxy-2'-deoxyguanosine (8-OHDG). MP-2 rats developed 66.7% infertility while MP-1, HG-1, and HG-2 rats did not. Conclusion: In ovaries, methylphenidate caused oxidative stress, but did not induce inflammation. Long-term use of methylphenidate caused increased cortisol levels and infertility.
RDL Kalıcı Kaydıİncele - ArticleYalnız künye2025Hormonal mechanism and pathogenetic therapy of citalopram-induced infertility in female rats
Delibasi, Ilhan Bahri; Gumusburun, Neset; Bulut, Seval; Mammadov, Renad; Yilmaz, Betul Kalkan; Suleyman, Bahadir; Bakan, Nuri; Mendil, Ali Sefa; Suleyman, Halis; Altuner, Durdu
Citalopram is a selective serotonin reuptake inhibitor (SSRI) and has been associated with reproductive dysfunction in women. In this study, the effects of citalopram on reproductive health in female rats were investigated. Albino Wistar rats was divided into six groups (each group/n = 12): healthy (HG), citalopram (CTP), cabergoline (CBR), metyrapone (MTP), cabergoline+citalopram (CBR+CTP), and metyrapone+citalopram (MTP+CTP). Initially, cabergoline 0.1 mg/kg and metyrapone 50 mg/kg were administered orally. A dose of 10 mg/kg of citalopram was given orally one hour later. For 30 days, the treatment protocol was applied once a day. Then, blood samples were taken from the tail veins of six rats from each group for prolactin and corticosterone analyses and ovaries were removed after euthanasia. The ovaries were examined for oxidants and antioxidants and histopathologically. During two months, the remaining animals were kept with male rats. The rats that did not deliver during this period were considered infertile. In terms of oxidants and antioxidants, there was no significant difference between the groups (p > 0.05). In half of the female rats, citalopram caused infertility, increased levels of prolactin and corticosterone, and damaged the ovaries histopathologically (p < 0.05). Cabergoline suppressed the elevation of prolactin by citalopram (p < 0.001) but did not prevent infertility. In contrast, metyrapone significantly prevented the citalopram-induced increase in corticosterone, infertility, and tissue damage induced by citalopram (p < 0.05). According to the results of our study, the preventive effect of drugs that suppress excessive corticosterone on citalopram-induced infertility in rats may be encouraging for further clinical studies.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2025Association of Tramadol-Induced Ovarian Damage and Reproductive Dysfunction with Adenosine Triphosphate and the Protective Role of Exogenous ATP Treatment
Gumusburun, Neset; Delibasi, Ilhan Bahri; Bulut, Seval; Suleyman, Halis; Kalkan Yilmaz, Betul; Coban, Taha Abdulkadir; Mendil, Ali Sefa; Suleyman, Zeynep
Background: Tramadol, a weak opioid analgesic agent, is known to induce ovarian damage. Previous studies have held oxidative stress responsible for the adverse effects of tramadol on female reproduction. This study examined the protective effects of ATP against tramadol-induced ovarian damage and reproductive dysfunction in rats. Methods: Rats were divided into four groups (n = 12); healthy (HG), only ATP (ATPG), only tramadol (TMDG), and ATP + tramadol (ATMG). ATP was injected intraperitoneally at 25 mg/kg. Tramadol at 50 mg/kg was initiated one hour after ATP. The treatment was administered once a day for 14 days. Six rats from each group were euthanized. For two months, the remaining rats were paired with male rats. Rats that failed to give birth during this period were considered infertile. A maternity period was calculated for the rats that were delivered. Results: Tramadol caused an increase in malondialdehyde and interleukin-6, and decreased total glutathione, superoxide dismutase, and catalase levels in the ovarian tissue. Furthermore, tramadol disrupted the histological structure of the ovaries, and immunohistochemical staining revealed severe immunopositivity. Tramadol again caused infertility and delayed pregnancy in fertile women. By suppressing biochemical changes, ATP significantly reduced tramadol-induced ovarian damage. Both histopathologically and immunohistochemically, ATP treatment regressed ovarian damage. Additionally, ATP significantly reduced tramadol-induced infertility and maternal delay. Conclusions: The results indicate that tramadol-induced oxidative and inflammatory ovarian injury, infertility, and caspase 3 were suppressed by ATP, as demonstrated by our experimental findings.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2025Effects of adenosine triphosphate, thiamine pyrophosphate, melatonin, and liv-52 on subacute pyrazinamide proliferation hepatotoxicity in rats
Ciftel, Sedat; Ciftel, Serpil; Altuner, Durdu; Huseynova, Gulbaniz; Yucel, Nurinisa; Mendil, Ali Sefa; Sarigul, Cengiz; Suleyman, Halis; Bulut, Seval
Background: Hepatotoxicity of pyrazinamide, an antituberculosis drug, limits its therapeutic use and oxidative stress has been implicated in this toxicity. This study investigated the protective effects of adenosine triphosphate (ATP), thiamine pyrophosphate (TPP), melatonin, and Liv-52, which have previously been shown antioxidant activities, on pyrazinamide-induced hepatotoxicity. Methods: 36 albino Wistar male rats were divided into randomized six groups; healthy (HG), pyrazinamide (PZG), ATP + pyrazinamide (APZG), TPP + pyrazinamide (TPZG), melatonin + pyrazinamide (MPZG) and Liv-52 + pyrazinamide (LPZG) groups. ATP 4 mg/kg and TPP 25 mg/kg were administered intraperitoneally (IP). Melatonin 10 mg/kg and Liv-52 20 mg/kg were given orally. One hour after administration of ATP, TPP, melatonin, and Liv-52, 250 mg/kg pyrazinamide was applied orally to all rats except HG group. The treatment was repeated (1 × 1) for 4 weeks. Then, blood samples were taken for determination of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities. Immediately after, the rats were euthanized with thiopental sodium (50 mg/kg, IP), and the livers were removed. The tissues were analyzed for malondialdehyde (MDA), total glutathione (tGSH), superoxide dismutase (SOD), and catalase (CAT) also hydropic degeneration, necrosis, and apoptosis (caspase 3) were examined.One-Way ANOVA was used in biochemical analyses and Tukey test was used as post-hoc. For histopathological and immunohistochemical analysis, the Kruskal-Wallis test was used and Dunn’s test as a post-hoc. Results: Pyrazinamide increased MDA land decreased tGSH, SOD, and CAT levels in liver tissues (p < 0.001). It also increased serum ALT and AST activities and caused severe hydropic degeneration and necrosis in liver tissue (p < 0.001). ATP, TPP, melatonin, and Liv-52 significantly prevented the biochemical and histopathological changes induced by pyrazinamide (p < 0.05). On the other hand, Liv-52 was more successful than other potential protectors in protecting liver tissue from pyrazinamide damage (p < 0.05). Conclusions: ATP, TPP, melatonin, and Liv-52 can be used to protect liver tissue from pyrazinamide-induced hepatotoxicity in rats.
RDL Kalıcı Kaydıİncele - ArticleYalnız künye2025Biochemical and histopathological changes in ovary, uterus and testicular tissues after acrylamide exposure
Uslu, Hamit; Atila Uslu, Gözde; Çoban, Taha Abdulkadir; Mendil, Ali Sefa; Toraman, Emine; Şahin, Mahmut; Özkaraca, Mustafa
Acrylamide (ACR) is a popular substance to which our exposure increases with the changes in our lifestyle and brings with it various health problems. In order to determine appropriate therapeutics against ACR damage, it is important to investigate the multiple mechanisms that may be effective in its pathophysiology. This study investigated the effects of ACR exposure on ovarian, uterine, and testicular tissues by considering different pathophysiological pathways. Male-control (MC), male-acrylamide (MACR), female-control (FC), and female-acrylamide (FACR) groups were formed. ACR was administered at a dose of 60 mg/kg for 5 days. ACR exposure decreased CAT and TrxR-specific activities, GSH levels, and Bcl-2 expression, while significantly increasing MDA, IL-6, and NFĸB p65 levels, caspase 3, and Bax expression in ovarian, uterine, and testicular tissues. Based on these results, it was determined that acrylamide induced damage in ovarian, uterine and testicular tissues through various pathways such as oxidative stress, inflammation, and apoptosis. Consequently, when selecting a therapeutic target, the substance whose efficacy is being investigated should be effective in these pathways. Furthermore, this study is the first to demonstrate the occurrence of bladder retention in both sexes following acrylamide exposure and will be an important step for future research.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2025Hepatoprotective Activity of Prunus laurocerasus Fruit Extract Against 5-FU-Induced Liver Injury and LC-MS/MS Profiling
Atila Uslu, Gözde; Uslu, Hamit; Çoban, Taha Abdulkadir; Özkaraca, Mustafa; Mendil, Ali Sefa; Can, Hasan
5-Fluorouracil (5-FU), one of the most widely used chemotherapy drugs, is known to cause widespread toxicity and irreparable tissue damage. The purpose of this work was to analyze the phytochemical components of Prunus laurocerasus (PL) fruit extract using liquid chromatography with tandem mass spectrometry (LC-MS/MS) and to look into the effectiveness of PL pretreatment on 5-FU-induced liver damage. The study consisted of control (C), PL, 5-FU, PL+5-FU groups, and PL groups received 500 mg/kg PL as pretreatment for seven days. On the eighth day, 100 mg/kg 5-FU was administered intraperitoneally as a single dose to the PL+5-FU and 5-FU groups. In the LC-MS/MS results, it was determined that the phenolic compounds found in the foreground in PL were quinic acid and chlorogenic acid. PL pretreatment increased total antioxidant status levels and B-cell lymphoma 2 (Bcl-2) expression and also decreased Keap1, total oxidant status, oxidative stress index levels, and Bcl-2-associated X protein, Caspase-3, and light chain-3B expressions. 8-hydroxy-2'-deoxyguanosine levels were higher in the 5-FU group compared to the C and PL groups. Moreover, in the PL+5-FU group, the levels were similar to the C, PL, and 5-FU groups. In conclusion, PL pretreatment demonstrated hepatoprotective action via regulating the Kelch-like ECH-associated protein 1/nuclear factor-erythroid 2-related factor 2 pathway in 5-FU-induced liver damage, lowering oxidative stress, and decreasing apoptosis and autophagy from programmed cell death.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2025The Protective Effect of Thiamine and Thiamine Pyrophosphate Against Linezolid-Induced Oxidative Liver Damage and Lactic Acidosis in Rats
Isik, Bahar; Ates, Irem; Yucel, Nurinisa; Suleyman, Bahadir; Mendil, Ali Sefa; Sezgin, Esra Tuba; Suleyman, Halis
Linezolid, an antimicrobial agent, has been linked to lactic acidosis, oxidative stress, and liver damage. Oxidative stress is considered to play a key role in this damage. Thiamine pyrophosphate (TPP), the active form of thiamine, may prevent lactate accumulation and enhance aerobic capacity. Therefore, this study aimed to evaluate the protective effect of TPP against possible linezolid-induced liver damage and lactic acidosis in rats. Twenty-four male Wistar albino rats were randomly assigned to four groups (n = 6): healthy control (HG), linezolid (LZD), thiamine plus linezolid (TLZD), and TPP plus linezolid (TPLZD). Thiamine and TPP (20 mg/kg, intraperitoneal (i.p.)) were administered once daily, while linezolid (125 mg/kg, per os (p.o.)) was given twice daily (250 mg/kg/day) for 28 days. Animals were euthanized under high-dose anesthesia (with 50 mg/kg, i.p. thiopental sodium). Liver tissues were analyzed for MDA, tGSH, SOD, and CAT, and examined histopathologically. Blood samples were collected prior to euthanasia to assess lactate, LDH, ALT, AST, and TPP levels. In the LZD group, MDA, lactate, ALT, AST, and LDH levels significantly increased, while tGSH, SOD, CAT, and TPP decreased (p < 0.001). Histopathology showed hydropic degeneration, necrosis, and mononuclear cell infiltration (p < 0.05). Thiamine did not prevent these alterations (p > 0.05), whereas TPP significantly prevented both biochemical and histopathological changes (p < 0.05), indicating its protective efficacy. TPP may offer significant protection against linezolid-induced hepatotoxicity and lactic acidosis.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2025Nobiletin reduces 5-FU-induced lung injury with antioxidative, anti-inflammatory and anti-apoptotic activities
Atila Uslu, Gözde; Uslu, Hamit; Çoban, Taha Abdulkadir; Özkaraca, Mustafa; Mendil, Ali Sefa; Aygörmez, Serpil
Like other chemotherapeutic agents, 5-fluorouracil (5-FU) targets cancerous cells, but it also causes many unwanted side effects on healthy tissues and cells. Based on the undesirable effects of 5-FU, the aim of this study was to determine how 5-FU affects lung tissue and whether nobiletin has any protective effect. The study consisted of negative control, Nobiletin, 5-FU and Nobiletin + 5-FU groups. Nobiletin and Nobiletin + 5-FU groups received 10 mg/kg Nobiletin i.g. for 7 days. On day 8, 100 mg/kg 5-FU was administered i.p. to 5-FU and Nobiletin + 5-FU groups. Biochemical and immunohistochemical analyses were performed on the lung tissues dissected at the end of the study. 5-FU caused growth retardation, disturbed the oxidant-antioxidant balance by increasing MDA levels and decreasing GSH levels, triggered cellular apoptosis by increasing Bax and caspase-3 levels and decreasing Bcl-2, also increased lung tissue inflammation and damage by increasing NFκB and IL-1β levels. However, it was determined that Nobiletin prevented the disruption of the oxidant-antioxidant balance, showed significant anti-apoptotic effects, especially by reducing Bax levels and partially modulating caspase-3 and Bcl-2 levels, and also exhibited anti-inflammatory effects by reducing NFκB and IL-1β levels and supported the normal development of animals. Our results showed that nobiletin pretreatment showed anti-inflammatory activity by inhibiting the NFκB pathway in 5-FU-induced lung injury, suppressed oxidative stress with its antioxidant activity and was effective in modulating cellular apoptosis with its anti-apoptotic activity. In conclusion, Nobiletin has been shown to have an important potential in reducing fluorouracil-induced tissue damage by acting through multiple pathways.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2025Comparative Investigation of the Effects of Adenosine Triphosphate, Melatonin, and Thiamine Pyrophosphate on Amiodarone-Induced Neuropathy and Neuropathic Pain in Male Rats
Kahramanlar, Agah Abdullah; Ozgodek, Habip Burak; Ince, Ramazan; Yavuzer, Bulent; Admis, Ozlem; Mendil, Ali Sefa; Ekinci, Bilge; Suleyman, Halis
Background: Amiodarone is a widely used class III antiarrhythmic agent, but its use can lead to peripheral neuropathy mediated by mitochondrial dysfunction, oxidative stress, and neuroinflammatory injury, while effective preventive options remain limited. Agents that support mitochondrial energy metabolism, sustain redox balance, and modulate inflammation, including adenosine triphosphate (ATP), melatonin, and thiamine pyrophosphate (TPP), may counteract these mechanisms; however, their relative neuroprotective potential in amiodarone-induced neuropathy remains unclear. This study aimed to comparatively evaluate the effects of ATP, melatonin, and TPP on amiodarone-induced peripheral neuropathy and neuropathic pain in rats. Methods: Thirty male albino Wistar rats were assigned to five groups: healthy; amiodarone (50 mg/kg/orally); amiodarone + ATP (5 mg/kg/intraperitoneally); amiodarone + melatonin (10 mg/kg/orally); or amiodarone + TPP (20 mg/kg/intraperitoneally). Treatments were given once daily for 14 days. Oxidative stress indices (malondialdehyde (MDA), total glutathione (tGSH), superoxide dismutase (SOD), catalase (CAT)) and proinflammatory cytokines (tumor necrosis factor-alpha (TNF-α), interleukin-1 Beta (IL-1β), interleukin-6 (IL-6)) were quantified in sciatic nerve by Enzyme-Linked Immunosorbent Assay (ELISA). Paw withdrawal thresholds were measured with the Randall-Selitto test before and after treatment. Histopathology was performed using Hematoxylin-eosin staining. Results: Amiodarone exposure resulted in pronounced elevations in MDA and proinflammatory cytokine levels, accompanied by significant reductions in tGSH, SOD, CAT activities, and paw withdrawal thresholds. ATP, melatonin and TPP ameliorated these alterations to varying degrees. Among them, TPP provided the most robust antioxidant and anti-inflammatory effects, followed by ATP and melatonin. Histopathological examination confirmed most severe axonal degeneration, interstitial edema and Schwann cell proliferation in the amiodarone group, with substantial amelioration in the TPP-treated rats. Conclusions: Amiodarone induces neuropathic pain through oxidative and inflammatory injury to peripheral nerves. TPP exhibited superior neuroprotective efficacy compared with ATP and melatonin, highlighting its potential as a candidate therapeutic agent for amiodarone-related neuropathy. Further clinical research is warranted to support translational application of these findings.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2025The molecular mechanism of the protective effect of tianeptine against ovarian ischemia-reperfusion injury
Kalkan, Betul; Yavuzer, Bulent; Aliyev, Aydin; Cakir, Osman Kagan; Gozen, Fusun; Mendil, Ali Sefa; Coban, Taha Abdulkadir; Suleyman, Halis
Torsion of the ovary is a gynecologic emergency that occurs when the ovary and fallopian tube rotate around the infundibulopelvic ligament, causing ischemic changes in the adnexa. Tianeptine is an atypical antidepressant that has been shown to be effective in treatment-resistant depression and has fewer side effects than other antidepressants. In this study, the protective effect of tianeptine on ovarian ischemia-reperfusion (I/R) injury in female rats was evaluated. Four groups were created from twenty-four female albino Wistar rats before surgery (n = 6/each group): TPG (5 mg/kg/orally tianeptine-only), SG (sham operation), OIR (ovarian I/R), and TOIR (5 mg/kg/orally tianeptine + I/R). One hour before surgery procedures, the TPG and TOIR applied tianeptine. Tianeptine administration procedure was repeated once daily for six days. Under 60 mg/kg intraperitoneal (IP) ketamine and sevoflurane (inhaler) anesthesia, the right ovaries, fallopian tubes, and vessels in the OIR and TOIR groups were clamped by torsion. After 3 h of ischemia, a 6-day reperfusion period was started. Tianeptine administration procedure was repeated once daily for six days. In the SG group, the abdominal cavity was opened and closed with sutures without any intervention on the ovaries. On the seventh day, rats were sacrificed (120 mg/kg ketamine, IP), and ovaries were extracted. Levels of oxidants (malondialdehyde), antioxidants (total glutathione, superoxide dismutase, and catalase), and pro-inflammatory cytokines (tumor necrosis factor-alpha, interleukin-1β, interleukin-6) were measured in excised ovarian tissue. Ovarian tissues also examined histopathologically and immunohistochemically. I/R increased the levels of oxidants and pro-inflammatory cytokines and decreased the levels of antioxidants in rat ovaries. In parallel, histopathologic and immunohistochemical examination of the ovarian tissue revealed the presence of severe (grade 3) oxidative damage. Tianeptine significantly suppressed oxidative stress and pro-inflammatory cytokine increases related with I/R in the ovarian tissue, while also alleviating histopathological damage and oxidative DNA damage. Our experimental results suggest that tianeptine treatment may be effective against I/R-induced ovarian injury.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2024Role of Oxidant and Proinflammatory Cytokines and the Effect of Leflunomide in the Pathogenesis of Ovarian IschemiaReperfusion Injury
Isaoglu, Unal; Uyar, Elif Esra; Sahin, Nurullah; Bulut, Seval; Mammadov, Renad; Yilmaz, Betul Kalkan; Gunay, Murat; Mendil, Ali Sefa; Suleyman, Halis
Background and Objective: Ischemia-reperfusion (IR) causes tissue damage by inducing oxidative stress and inflammation. In this study, the protective ability of leflunomide, which is reputed to have antioxidant and anti-inflammatory effects, against IR-induced ovarian damage in rats was researched. Materials and Methods: Twenty-four albino Wistar female rats were divided into 4 groups of six each: Healthy (HG), sham-operated (SOG),ovarian IR (OIR) and leflunomide+ovarian IR (LOIR).One hour beforethe IR procedure, the LOIRgroup received 10 mg/kg leflunomide orally. Ovaries of rats in OIR and LOIR groups were subjected to 3 hrs ischaemia and 6 hrs reperfusion. For six days, leflunomide were implemented once a day. On day seven, the animals were euthanized and their ovaries were collected. The tissues were examined biochemically and histopathologically. Results: Leflunomide treatment significantly suppressed IR-induced rise in malondialdehyde (MDA),Tumor Necrosis Factor-Alpha (TNF-) and Interleukin 6 (IL-6) and the decline in Total Glutathione (tGSH), superoxide dismutase (SOD) and catalase (CAT) (p<0.001). Severe stromal hemorrhage, edema and follicular hemorrhage were noted in the ovaries of the IR group. Leflunomide treatment significantly prevented IR-induced ovarian tissue damage (p<0.05). Conclusion: Leflunomide could protect the ovaries with antioxidant and anti-inflammatory activity in ovarian IR injury.
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