Osman Ciftci

Di-n-butyl phthalate (DBP), a widely used plasticizer, induces oxidative stress and neurotoxicity through the generation of reactive oxygen species. Ellagic acid (EA), a natural polyphenolic antioxidant, may counteract these effects. This study aimed to evaluate the protective role of EA against DBP-induced oxidative brain injury. Thirty-two male rats were randomly divided into four groups: Control, DBP, EA, and DBP+EA. DBP was administered orally at a dose of 500 mg/kg/day, while EA was given by gavage at 2 mg/kg/day for four weeks. Oxidative stress parameters, including thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT) activities were analyzed in brain tissue. DBP exposure significantly increased TBARS levels while decreasing GSH and SOD activities, indicating lipid peroxidation and antioxidant depletion. In contrast, CAT activity was elevated, suggesting a compensatory enzymatic response to excess hydrogen peroxide. EA treatment markedly attenuated oxidative damage by restoring GSH and SOD levels and normalizing CAT activity. These findings indicate that DBP disrupts redox homeostasis by inducing lipid peroxidation, while EA mitigates this effect through restoration of antioxidant defenses.

This study aimed to investigate whether 18β-glycyrrhetinic acid (GA) could protect against cadmium-induced testicular damage in male rats. Twenty-four adult male Sprague Dawley rats were randomly divided into four groups (n = 6): Control, Cadmium (CAD), GA, and Cadmium + GA. Cadmium and GA were administered at doses of 1 mg/kg and 100 mg/kg, respectively, for 50 days. At the end of the experimental period, testicular and epididymal tissues were collected for biochemical, molecular, histopathological, and immunohistochemical analyses. Biochemical evaluations included oxidative stress parameters (TAS, TOS) and inflammatory cytokines (TNF-α, IL-6). Apoptotic gene expression (Bcl-2, Bax, Caspase-3) was assessed by RT-PCR. Histopathological and immunohistochemical analyses were performed to evaluate Bcl-2, Bax, iNOS, and NF-κB expression. Cadmium exposure significantly increased oxidative stress and inflammatory cytokine levels and induced marked histological damage, including Leydig cell necrosis and severe tubular degeneration. Immunohistochemical analysis revealed increased Bax, iNOS, and NF-κB expression in testicular and epididymal tissues. Cadmium also upregulated Bax and Caspase-3 while downregulating Bcl-2 gene expression. Conversely, GA treatment significantly attenuated cadmium-induced oxidative stress, inflammation, apoptosis, and histological damage. These findings suggest that GA exerts protective effects against cadmium-induced testicular toxicity and may represent a promising therapeutic agent for preventing cadmium-related male infertility.

Letrozole, a widely used aromatase inhibitor for hormone receptor–positive breast cancer, has been suggested to be associated with potential neurotoxic effects; however, the underlying mechanisms remain unclear. This study aimed to investigate the neurotoxic effects of letrozole and evaluate the neuroprotective potential of hesperidin, a natural flavonoid with antioxidant and anti‐inflammatory properties. Adult female rats received letrozole alone or in combination with hesperidin for 4 weeks. Biochemical analyses showed that letrozole significantly increased total oxidant status (TOS) and decreased total antioxidant status (TAS), indicating oxidative stress. Gene expression results revealed upregulation of pro‐apoptotic Bax and downregulation of anti‐apoptotic Bcl 2 in letrozole‐treated rats, reflecting apoptotic activation. Additionally, inflammatory cytokine measurements demonstrated elevated pro‐inflammatory markers (IL‐1, IL‐6, TNF‐α) and reduced anti‐inflammatory IL‐10 following letrozole administration. Histopathological examination revealed cortical microhemorrhages, edema, and hyperemia. Importantly, co‐treatment with hesperidin attenuated oxidative imbalance, normalized apoptotic gene expression, modulated inflammatory cytokine levels towards an anti‐inflammatory profile, and ameliorated histological damage. These findings indicate that hesperidin confers neuroprotection by restoring redox balance, regulating apoptosis, and suppressing inflammation in letrozole‐induced neurotoxicity. Further studies are warranted to elucidate the precise molecular mechanisms and potential therapeutic applications of hesperidin in letrozole‐induced neurotoxicity.

Lung cancer is among the most common cancers in the world, and current treatments are inadequate due to the development of resistance and serious side effects. This situation brings new therapeutic strategies for cancer treatment. Among these, silver-based N-heterocyclic carbenes (Ag-NHCs) have emerged as promising candidates due to their unique chemical properties, such as strong metal-ligand bonding and modulation of biological reactivity. This study investigates the cytotoxic and antitumoral effects of newly synthesized Ag-NHC complexes on lung cancer (A549) cells. Ag-NHC complexes (X, Y, and Z) were synthesized using benzimidazolium salts and characterized by NMR spectroscopy. Cytotoxicity was evaluated on A549 and normal fibroblast (L929) cells using MTS assays. Apoptotic cell death and mitochondrial membrane potential were evaluated in A549 cells. Gene expression analysis for apoptosis-related markers was performed using RT-PCR. Ag-NHC complexes showed dose- and time-dependent antiproliferative effects in the A549 cell line. Annexin V/PI analysis revealed significant apoptotic induction by complexes X, Y and Z; the highest apoptotic rates were observed in A549 cells treated with Y and Z. Complexes Y and Z significantly decreased mitochondrial membrane potential, indicating increased apoptosis via intrinsic pathways. RT-PCR revealed increased pro-apoptotic gene expression (Bax, BAD, caspase-3, -8, -9) and decreased anti-apoptotic Bcl-2 expression in treated A549 cells. Complexes Y and Z also upregulated extrinsic apoptotic markers (DR4 and DR5). The newly synthesized Ag-NHC complexes (X, Y, Z) exhibited significant antiproliferative and pro-apoptotic effects in A549 lung cancer cells, indicating their potential as new therapeutic agents with reduced toxicity compared to conventional chemotherapy.

Nivolumab is an effective immunotherapy drug, but its long-term side effects remain unknown. This study was designed as a preventive experimental model to investigate the potential preventive and protective effects of hesperidin against testicular toxicity that may be caused by nivolumab. Thirty-two male Wistar Albino rats were used in the study (n = 8 per group). The groups were as follows: control, nivolumab (3 mg/kg), hesperidin (50 mg/kg), and nivolumab (3 mg/kg) + hesperidin (50 mg/kg). After the completion of drug administration, blood and testicular tissues were collected under anesthesia. ELISA, real-time PCR, and histopathological analyses were performed to assess the biochemical, molecular, and histopathological changes in the testicular tissue. Histopathological analysis revealed that nivolumab caused notable damage to the testicular tissue. Severe cytoplasmic expression of 8-hydroxyguanosine (8-OHdG) and Caspase-3 was observed in spermatocytes, indicating oxidative stress and apoptosis. Hesperidin administration attenuated these histopathological changes. Biochemical analysis showed that nivolumab disrupted the balance of total oxidants and antioxidants, leading to oxidative stress, whereas hesperidin enhanced antioxidant activity and reduced oxidative damage. Additionally, nivolumab significantly reduced serum testosterone levels, while hesperidin increased testosterone levels. In terms of molecular pathways, nivolumab downregulated PI3K, AKT, and MTOR expressions, disrupting this signaling cascade, while hesperidin restored these expressions to levels closer to the control group. Nivolumab also reduced PD-1 expression, but hesperidin did not alter PD-1 expression levels. This preventive experimental design demonstrated that nivolumab caused oxidative damage and histopathological changes in rat testicular tissue, whereas hesperidin provided preventive protection against these adverse effects through its antioxidant and anti-apoptotic properties.

Bleomycin (BLM), a chemotherapeutic agent commonly used in cancer treatment, is associated with oxidative stress and testicular toxicity, leading to impaired reproductive health. Hesperidin (HES), a citrus‐derived flavonoid with strong antioxidant properties, has the potential to counteract these adverse effects. This study aimed to evaluate the protective effects of HES against the reproductive toxicity induced by BLM, focusing on oxidative stress, sperm characteristics and histological changes in the male reproductive system. Thirty‐two rats were divided into four groups: Control, BLM, HES and BLM + HES. BLM was administered intraperitoneally at 10 mg/kg twice a week, while HES was given orally at 50 mg/kg/day for 30 days. The findings revealed that BLM induced significant oxidative stress by promoting lipid peroxidation and impairing antioxidant defence mechanisms in the testis. Additionally, BLM treatment caused a marked decline in sperm motility, an increase in abnormal sperm rates and severe histopathological damage in testicular tissue. However, co‐administration of HES significantly mitigated these adverse effects by improving oxidative balance, restoring sperm quality and reducing histopathological injuries. In conclusion, HES demonstrated potential in alleviating BLM‐induced reproductive toxicity, suggesting its therapeutic role in protecting against chemotherapy‐induced male infertility.

Purpose: This study aimed to investigate the protective effects of insulin-like growth factor-1 (IGF-1) against doxorubicin (DOX)-induced liver and kidney damage in rats using biochemical, immunohistochemical, and histopathological methods. Materials and Methods: A total of 32 Wistar albino rats were randomly assigned into four groups: Control, DOX (4 mg/kg/week), IGF-1 (1 µg/kg daily), and DOX + IGF-1 (DOX 4 mg/kg/week + IGF-1 1 µg/kg daily). After the four-week experimental protocol, blood, liver, and kidney tissues were collected under anesthesia. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), urea, and creatinine were analyzed biochemically. Total antioxidant status (TAS) and total oxidant status (TOS) in liver and kidney tissues were measured using ELISA. Gene expression levels of HIF-1α and iNOS were evaluated by real-time PCR. Histopathological and immunohistochemical (Caspase-3, TNF-α, and FGF-2) evaluations were conducted on liver and kidney tissues. Results: DOX significantly increased serum ALT, AST, BUN, urea, and creatinine levels and elevated TOS while reducing TAS in tissues). HIF-1α expression was markedly upregulated (+5.50-fold), indicating oxidative damage. IGF-1 administration reduced serum ALT, AST, BUN, urea, and creatinine levels, increased TAS, and decreased TOS. Expression levels of HIF-1α and iNOS approached those of the control group. DOX caused significant histopathological damage and increased Caspase-3 and TNF-α expressions in the liver and Caspase-3 and FGF-2 expressions in the kidney. These alterations were ameliorated by IGF-1 treatment. Conclusion: The findings suggest that IGF-1 exerts protective effects against DOX-induced hepatorenal toxicity, possibly through its antioxidant, anti-inflammatory, and anti-apoptotic properties.

Objectives: Letrozole (LTZ), an aromatase inhibitor, is associated with significant side effects such as uterine toxicity. This study investigated the potential of hesperidin (HSP) and taurine (TAU), both natural antioxidant molecules, to mitigate LTZ-induced uterine toxicity. Methods: A total of 48 female rats were divided into six groups and treated orally for 30 days as follows: Control (sham), LTZ (1 mg/kg), HSP (100 mg/kg), TAU (100 mg/kg), LTZ+HSP, and LTZ+TAU. Histopathological, gene expression, and biochemical analyses were conducted on uterine tissues and serum samples. Results: LTZ caused a significant decrease in serum IL-1β, IL-6, estradiol, and FSH levels (p0.05). However, HSP significantly reduced oxidative stress (p<0.05), decreased the expression of genes related to apoptosis and inflammation (p0.05). Although TAU exhibited effects similar to HSP in certain parameters, its protective efficacy was comparatively less pronounced. Conclusions: The results suggest that HSP is a promising agent for mitigating LTZ-induced uterine toxicity. However, further studies with different doses and application protocols are required to more definitively elucidate the potential effects of TAU.

Paclitaxel (PAC), derived from Taxus brevifolia, is used to treat solid tumours but causes reproductive toxicity due to oxidative stress, affecting sperm quality and testicular tissue. Nerolidol (NRL), an antioxidant sesquiterpene alcohol, has not been studied for its potential to reduce PAC‐induced reproductive damage. This study investigates NRL's ability to mitigate PAC‐induced reproductive toxicity in rats. Forty healthy adult male Spraque Dawley rats were randomly divided into four equal groups (Control, PAC, NRL, PAC + NRL). PAC was given intraperitoneally at a dose of 2 mg/kg once a week for 4 weeks. NRL was given orally at a dose of 100 mg/kg/day for 4 weeks. Control group received PAC and NRL vehicles. After 4 weeks, testis tissue samples were collected, and parameters, including oxidants, antioxidants, sperm motility, density, abnormal spermatozoon ratios and cytokines, were measured. PAC administration increased oxidant levels and decreased antioxidant enzyme activities. Nerolidol mitigated these alterations significantly. Similarly, PAC elevated IL‐1, IL‐6, TNF‐α levels and lowered IL‐10 levels, these effects attenuated by nerolidol in the PAC + NRL group. In conclusion, it was determined that PAC induces reproductive toxicity through oxidative stress, and NRL demonstrates potential in ameliorating these effects through its antioxidant activity.

Peripheral neuropathy (PN) is a common side effect of docetaxel (DTX). In this study, we aimed to evaluate the effects of montelukast (MNT), a leukotriene receptor antagonist drug, against DTX-induced PN in rats. Thirty-two male rats were divided into four groups and treated for four weeks: control (sham), DTX (5 mg/kg per week, ip), MNT (10 mg/kg per day, po), and DTX+MNT (5 mg/kg per week, ip + 10 mg/kg per day, po). Behavioral tests (hot plate, tail flick, and rotarod) were conducted. Histopathological, molecular (RT-PCR), and biochemical (ELISA) analyses were performed on sciatic nerve, liver, and serum samples. MNT reduced the malondialdehyde (MDA) levels and increased the superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH) parameters in sciatic nerve tissues. Unlike DTX, MNT resulted in increased Bcl-2 gene expression and decreased caspase-3 (Cas-3) and Bax expressions. DTX caused sensory and motor neuropathy, as revealed by the hot plate, tail flick, and rotarod tests. The co-administration of MNT significantly mitigated the sensory and motor neuropathy induced by DTX. MNT improved the levels of NCAM, p38α MAPK, and nuclear factor kappa B (NF-κB), which were impaired in the sciatic nerve tissues due to DTX administration. Additionally, it reduced the levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), which had increased due to DTX. Histopathological examination revealed that DTX-related sciatic nerve damage was mitigated by MNT administration. The results indicated that MNT may have a protective effect against DTX-induced PN in rats.