Bahadir Suleyman

Immune checkpoint inhibitors (ICIs), including atezolizumab, enhance antitumor immune responses by interfering with inhibitory immune checkpoint signaling. Atezolizumab targets programmed death-ligand 1 (PD-L1), thereby disrupting its interaction with programmed death-1 (PD-1). Although ICIs have improved cancer treatment outcomes, their potential associations with ovarian alterations remain insufficiently understood. This study aimed to compare ovarian biochemical, hormonal, histopathological, and immunofluorescence outcomes following the co-administration of flunarizine or lutein with atezolizumab in rats. Twenty-four female Wistar rats were randomly assigned to four groups (n = 6 per group): healthy control (HG), atezolizumab (ATZ), flunarizine plus atezolizumab (FUAZ), and lutein plus atezolizumab (LTAZ). Ovarian oxidative stress markers (MDA, tGSH, SOD, and CAT), inflammatory cytokines (TNF-α and IL-1β), serum anti-Müllerian hormone (AMH) and prolactin levels, histopathological alterations, and immunofluorescence intensities of COX-1, COX-2, IL-1β, and IL-6 were evaluated. Compared with HG, the ATZ group exhibited increased MDA, TNF-α, and IL-1β levels and decreased tGSH, SOD, CAT, and serum AMH levels (p < 0.05). Histopathological examination revealed more pronounced follicular degeneration, parenchymal edema, and hyperemia in the ATZ group, whereas these alterations were milder in the FUAZ group and moderate in the LTAZ group. Immunofluorescence analysis demonstrated reduced COX-1 and increased COX-2, IL-1β, and IL-6 intensities in the ATZ group compared with HG. Both co-administration groups showed higher COX-1 and lower COX-2, IL-1β, and IL-6 intensities than the ATZ group. Several biochemical, histopathological, and immunofluorescence outcomes in the FUAZ group were closer to HG values than those in the LTAZ group. Serum prolactin levels differed significantly only between the ATZ and FUAZ groups in pairwise comparisons. Atezolizumab administration was associated with ovarian oxidative, inflammatory, and histopathological alterations. Co-administration of flunarizine or lutein was associated with differences in several evaluated parameters, with more favorable findings observed in the FUAZ group at the selected doses. However, the absence of appropriate antibody controls and adjunct-only groups limits causal attribution and precludes conclusions regarding independent protective efficacy.

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Atezolizumab, an immune checkpoint inhibitor, may induce oxidative stress, inflammation, and tissue injury in addition to its antitumor effects. This study investigated the protective effects of ivermectin against atezolizumab-associated ovarian toxicity and their dependence on treatment duration. Four experimental groups comprising six female Wistar albino rats were established: healthy (HG), atezolizumab (ATZ), ivermectin plus atezolizumab for 3 days (IVAZ-3), and ivermectin plus atezolizumab for 6 days (IVAZ-6). Ivermectin was administered orally at 2 mg/kg/day, followed one hour after the final dose by atezolizumab (10 mg/kg, intraperitoneally). Three days after atezolizumab exposure, animals were euthanized with high-dose ketamine. Serum prolactin and anti-Müllerian hormone (AMH) were measured, while ovarian tissues were analyzed for malondialdehyde (MDA), total glutathione (tGSH), superoxide dismutase (SOD), catalase (CAT), tumor necrosis factor-alpha (TNF-α), and interleukin-1 beta (IL-1β), along with histopathological and immunohistochemical changes. Compared with HG, ATZ increased MDA, TNF-α, and IL-1β and decreased tGSH, SOD, and CAT, with severe ovarian degeneration and increased caspase-3, inducible nitric oxide synthase (iNOS), IL-1β, and microtubule-associated protein-1 light chain 3-beta (LC3B) immunopositivity. IVAZ-3 significantly attenuated these alterations and preserved AMH, whereas most parameters in IVAZ-6 remained comparable to ATZ. Thus, ivermectin exhibited a treatment-duration-dependent protective effect, most pronounced with the 3-day regimen.

(1) Background: Osimertinib is an effective third-generation EGFR tyrosine kinase inhibitor, but its clinical use may be limited by cardiotoxicity. This study investigated the relationship between reduced measured cardiac ATP levels and osimertinib-associated cardiac injury and examined whether exogenous ATP administration attenuates the associated biochemical and histopathological alterations. (2) Methods: Twenty-four male Wistar rats were randomly allocated to healthy control (HG), osimertinib (OSM), ATP 5 mg/kg + osimertinib (AOSM-5), and ATP 10 mg/kg + osimertinib (AOSM-10) groups (n = 6). ATP was administered intraperitoneally once daily, followed 1 h later by osimertinib (50 mg/kg, oral gavage) for three weeks. Cardiac tissue ATP, MDA, and tGSH levels, SOD and CAT activities, and plasma TPI levels were measured, together with histopathological and immunohistochemical evaluation of COX-1, COX-2, and 8-OHdG. (3) Results: Osimertinib significantly decreased ATP and tGSH levels and SOD and CAT activities, and increased MDA and TPI levels (p < 0.001), accompanied by increased COX-2 and 8-OHdG, reduced COX-1, hemorrhage, and mononuclear cell infiltration. Exogenous ATP attenuated these alterations, with generally greater effects observed at 10 mg/kg. (4) Conclusions: These findings indicate that ATP co-administration attenuated biochemical, histopathological, and immunohistochemical alterations associated with osimertinib-induced myocardial injury in rats, with these effects being associated, at least in part, with reduced oxidative stress. However, the functional cardiac effects, underlying mechanisms, and potential influence of ATP administration on the antitumor efficacy of osimertinib require further investigation.

Ocular ischemic syndrome (OIS) is a vision-threatening disorder characterized by retinal ischemia, oxidative stress, and inflammation. In this study, the protective effects of anakinra, an interleukin-1 receptor antagonist, were investigated and compared with those of tocilizumab, an interleukin-6 receptor antagonist. Twenty-four male Wistar rats were randomly assigned to four groups (n = 6 per group): sham-operated (SG), carotid artery clamping/unclamping (CUG), anakinra-treated carotid artery clamping/unclamping (ACUG), and tocilizumab-treated carotid artery clamping/unclamping (TCUG). An experimental ocular ischemic injury model induced by transient bilateral common carotid artery occlusion was established by transient bilateral common carotid artery clamping followed by reperfusion. Retinal tissues were analyzed for malondialdehyde (MDA), total glutathione (tGSH), superoxide dismutase (SOD), catalase (CAT), tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6) levels, and histopathological examinations were performed. OIS markedly increased MDA, TNF-α, IL-1β, and IL-6 levels while significantly decreasing tGSH, SOD, and CAT activities. Both anakinra and tocilizumab attenuated oxidative stress and inflammatory responses; however, anakinra produced notably greater improvements in MDA, tGSH, SOD, and CAT levels. Histopathological evaluation demonstrated that both treatments reduced retinal injury, edema, vascular congestion, and inflammatory cell infiltration. Although retinal architecture appeared slightly better preserved in the anakinra-treated group, histopathological scores were comparable between the treatment groups. These findings suggest that anakinra may attenuate oxidative and inflammatory retinal damage in this experimental ocular ischemic injury model and may provide greater biochemical protection than tocilizumab, whereas histopathological protection was comparable between treatments. Nevertheless, further experimental and clinical studies are required to confirm these findings.

Erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), is widely used in cancer therapy; however, hepatotoxicity limits its clinical use. This study investigated the protective effects of Liv-52, a polyherbal hepatoprotective formulation, against erlotinib-induced hepatotoxicity in rats and compared its efficacy with melatonin. The animals (n = 24, Wistar albino rats) were randomly categorized into four groups: healthy (HG), erlotinib (ERG), Liv-52 + erlotinib (LEG), and melatonin + erlotinib (MEG). Liv-52 (50 mg/kg/day, orally) and melatonin (10 mg/kg/day, orally) were administered once daily for two weeks. Erlotinib (10 mg/kg, orally) was given every other day to ERG, LEG, and MEG groups for two weeks. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH) were measured. Hepatic malondialdehyde (MDA), total glutathione (tGSH), superoxide dismutase (SOD), and catalase (CAT) levels were analyzed. Additionally, double immunofluorescence staining was performed to evaluate apoptotic (poly[ADP-ribose] polymerase-1 [PARP-1], apoptosis-inducing factor [AIF]), inflammatory (cyclooxygenase-2 [COX-2]), and anti-inflammatory (interleukin-10 [IL-10]) biomarkers in liver tissues. Histopathological examination was also conducted to assess structural alterations. Erlotinib significantly increased MDA, ALT, AST, and LDH while decreasing tGSH, SOD, and CAT (p < 0.001). Strong immunoreactivity for PARP-1, AIF, IL-10, and COX-2, as well as severe hydropic degeneration and necrosis, was observed in ERG (p < 0.05). Both Liv-52 and melatonin significantly ameliorated biochemical, histopathological, apoptotic, and inflammatory alterations (p < 0.05). Notably, Liv-52 demonstrated superior hepatoprotective efficacy compared to melatonin. These findings indicate that Liv-52 effectively attenuates erlotinib-induced hepatotoxicity by modulating oxidative stress, inflammatory responses, and apoptotic pathways, thereby preserving liver function and structural integrity.

Background and Objectives: Tamoxifen, a cornerstone selective estrogen receptor modulator in breast cancer therapy, is increasingly recognized to be associated with retinal toxicity characterized by mitochondrial dysfunction, oxidative stress, lipid peroxidation, and oxidative DNA injury. By targeting mitochondrial bioenergetic dysfunction and redox disequilibrium, adenosine triphosphate (ATP) emerges as a biologically plausible candidate for retinal cytoprotection. This study aimed to evaluate the protective effect of ATP against tamoxifen-induced retinal toxicity in a rat model. Materials and Methods: Twenty-four male albino Wistar rats were randomly assigned to four groups: healthy control (HG), ATP-alone (ATPG, 4 mg/kg, intraperitoneally), tamoxifen-alone (TAMG, 5 mg/kg, orally), and tamoxifen plus ATP-treated (ATAG; ATP, 4 mg/kg, intraperitoneally; tamoxifen, 5 mg/kg, orally). Treatments were administered once daily for 30 days. Oxidative stress markers (malondialdehyde, total glutathione), antioxidant enzyme activities (superoxide dismutase, catalase), and oxidative DNA damage (8-hydroxy-2′-deoxyguanosine) were assessed in ocular tissues. Retinal histopathological evaluation included hematoxylin–eosin staining with semiquantitative assessment of edema, vascular congestion, polymorphonuclear leukocyte infiltration, and cytoplasmic vacuolization, together with quantitative measurements of retinal layer thicknesses and ganglion cell layer (GCL) cell counts. Results: Tamoxifen administration induced marked oxidative stress, antioxidant depletion, and increased oxidative DNA damage in ocular tissues, accompanied by significant thickening of retinal layers, reduced GCL cell counts, and pronounced disruption of retinal architecture. By comparison, ATP co-administration significantly suppressed lipid peroxidation and restored antioxidant defenses, thereby reducing oxidative DNA damage and preserving retinal structural integrity, as reflected by partial normalization of retinal layer thicknesses, preservation of GCL cell counts, and the presence of only mild residual edema. Conclusions: These findings indicate that ATP attenuates tamoxifen-induced retinal toxicity by supporting mitochondrial energy balance and redox homeostasis. Accordingly, ATP administration may represent a promising protective approach for reducing retinal injury associated with long-term tamoxifen therapy.

Metformin is widely used in type 2 diabetes, but its effects on oxidative and inflammatory pathways remain controversial. Beyond glycemic control, it may promote lactic acidosis by impairing mitochondrial metabolism and pyruvate flux. The potential renoprotective roles of adenosine triphosphate (ATP) and thiamine pyrophosphate (TPP) remain poorly defined. This study aimed to evaluate whether ATP and TPP mitigate metformin-induced renal injury through biochemical and histopathological assessments. Wistar rats were randomly divided into six groups: control, ATP, TPP, metformin, ATP + metformin, and TPP + metformin. Metformin (50 mg/kg, oral), ATP (4 mg/kg, intraperitoneal), or TPP (20 mg/kg, intraperitoneal) was administered daily for 10 days. Oxidative stress markers, inflammatory cytokines, renal histopathology, and serum creatinine, BUN, lactate, and LDH levels were evaluated. Metformin induced significant oxidative stress, inflammation, metabolic disturbance, and renal injury. ATP provided partial protection, whereas TPP markedly restored redox balance, reduced inflammation, and preserved renal histology. TPP confers superior protection against metformin-induced renal injury compared with ATP by modulating oxidative, inflammatory, and metabolic pathways, highlighting its therapeutic potential in preventing metformin-related nephrotoxicity.

Objective: This study investigated the effects of different doses and timing of sulforaphane (SFN) supplementation on reducing obesity induced by a high-glycemic-index diet (HGID) and on correcting poor glycemic control and dyslipidemia in C57BL/6 mice. Method: For 15 weeks, mice were administered a control diet (control), HGID, HGID + oral 5 mg/kg/day SFN (HGID + LSFN), or HGID + 20 mg/kg/day SFN (HGID + HSFN), and following 15 weeks of HGID, mice were treated with 5 mg/kg/day SFN (PO-HGID + LSFN) or 20 mg/kg/day SFN (PO-HGID + HSFN) for 5 weeks. Results: SFN reduced body weight gain and serum glucose. The lowest levels of HbA1c were observed in the control and HGID + LSFN groups. Mice in the HGID group exhibited impaired glucose clearance and were less sensitive to insulin compared to the control. A remarkable improvement in glucose and insulin tolerance was observed in both PO-HGID + SFN and HGID + SFN groups. Lipid profile parameters and serum insulin levels were found to be lower in the control and HGID + SFN groups compared to the HGID group. SFN increased serum adiponectin levels when administered concurrently with HGID. IRS1 and IRS2 levels were highest in the control and HGID + LSFN groups, and high-dose SFN supplementation suppressed IRS1 independently of timing. Exposure to HGID downregulated the expression of PGC-1α and sirtuins. SIRT1 and SIRT3 gene expressions showed a significant increase at both doses, whereas SIRT2 gene expression increased significantly only at 5 mg/kg/day SFN. FASN expression was upregulated in all HGID-fed groups with or without SFN intervention. Conclusions: SFN may reverse the adverse effects of HGID in a time- and dose-dependent manner by regulating postprandial insulin, inhibiting gluconeogenesis, and enhancing fatty acid oxidation through the activation of sirtuins and PGC-1α.

Hydroxychloroquine (HCQ), originally developed as an antimalarial agent, has been associated with hepatotoxic effects in experimental and clinical settings. Our study was designed to evaluate the effects of this agent on liver toxicity and to understand the protective roles of adenosine triphosphate (ATP), Liver-52 (Liv-52), and their combination. Male Wistar rats (250–280 g) were randomly assigned to five groups (n = 6): healthy control (C), HCQ only (H), ATP plus HCQ (AH), Liv-52 plus HCQ (LH), and ATP–Liv-52 plus HCQ (ALH). ATP (4 mg/kg) was administered intraperitoneally once daily, whereas Liv-52 (20 mg/kg) was administered orally via gavage. One hour later, all groups except C received HCQ (120 mg/kg, orally, twice daily). All treatments were continued for seven consecutive days. At the end of the experiment, serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were measured, and liver tissues were analyzed for malondialdehyde (MDA), total glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT) activities, along with histopathological evaluation. HCQ administration significantly increased oxidative stress, as evidenced by elevated MDA levels (p < 0.01) and reduced antioxidant parameters, including GSH, SOD, and CAT (p < 0.05), accompanied by prominent histopathological damage. Treatment with ATP or Liv-52 markedly ameliorated these alterations by decreasing MDA and restoring antioxidant markers. The combination treatment was observed to exhibit the most pronounced protective effect; it significantly reduced MDA levels, improved GSH, SOD, and CAT levels more effectively, and produced significant decreases in AST and ALT values (p < 0.05).