Sürdürülebilir Kalkınma Amaçları

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• MakaleAçık Erişim2026Scopus SJRQ1/r/munzur/1500
  Effects of Melatonin Formulations on Caffeine-Evoked Cortical Activity and Pentobarbital-Induced Sleep in Mice

  Sahin, Nurhan; Yabas, Mehmet; Er, Besir; Erten, Fusun; Kursun, Oznur Ece Durmaz; Cikim, Ismail Gurkan; Kaplan, Berkan; Erek, Gozde; Ozmen, Busra; Orhan, Cemal

  Melatonin has chronobiotic, antioxidant, anti-inflammatory, and neuromodulatory properties, and its oral effects may vary according to formulation. This study compared conventional melatonin with a lipid-multiparticulate (LMP) formulation in two acute pharmacological mouse paradigms. Eighty-four male BALB/c mice were assigned to caffeine-evoked cortical activity or pentobarbital-induced sedative-hypnotic experiments. Mice received caffeine (7.5 mg/kg, i.p.) alone or with standard or LMP-melatonin (10 or 20 mg/kg, oral). ECoG recorded cortical electrical activity under urethane anaesthesia. In a separate cohort, latency to and duration of pentobarbital-induced loss of the righting reflex were measured. Circulating neurochemical and redox markers, as well as neurotransmitter- and inflammation-related gene and protein expression, were evaluated. Caffeine increased spike frequency and altered ECoG amplitude, together with unfavorable changes in circulating neurochemical and redox markers and in neurotransmitter receptor- and inflammation-related outcomes. Both melatonin formulations attenuated several of these changes in a dose-dependent manner, with the strongest effects generally observed in the high-dose LMP-melatonin group. Compared with conventional melatonin, LMP-melatonin produced greater modulation of ECoG activity, circulating biochemical markers, neurotransmitter-receptor expression, and IL-6 and TNF-α-related outcomes. LMP-melatonin also produced a greater reduction in the latency to and a greater prolongation of the duration of pentobarbital-induced loss of the righting reflex. LMP-melatonin produced greater formulation-dependent effects than conventional melatonin on caffeine-evoked cortical electrical activity, pentobarbital-induced sedative-hypnotic responses, and selected biochemical and molecular outcomes. However, pharmacokinetic exposure, physiological sleep stages, sleep architecture, sleep quality, and direct measures of neuronal injury were not assessed. Therefore, the findings do not directly establish enhanced bioavailability, physiological sleep promotion, or neuroprotection.

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• MakaleAçık Erişim2026Scopus SJRQ2/r/munzur/1495
  Synergistic Effects of Caffeine and Paclitaxel in Breast Cancer Cells: Mechanistic Insights Into NF-κB and Nrf2 Signaling

  Gencoglu, Hasan; Delioglu, Saime; Nergiz, Mehmet Akif; Metin, Rumeysa; Erten, Fusun; Tokmak, Muhammed; Orhan, Cemal; Sahin, Kazim

  Breast cancer remains one of the most prevalent malignancies among women. Recent studies have explored the potential of phytochemicals such as caffeine as chemosensitizing agents in enhancing the efficacy of standard chemotherapeutics like paclitaxel. This study aimed to investigate the cytotoxic, apoptotic, inflammatory, and oxidative stress-related effects of caffeine alone and in combination with paclitaxel in MCF-7 cells. Cells were treated with various concentrations of caffeine (1–100 mM), paclitaxel (0–350 µg/mL), and their combinations for 24, 48, and 72 h. Cell viability was assessed using the MTS assay, and IC₅₀ values were calculated. The expression levels of Bax, Bcl-2, NF-κB, and Nrf2 proteins were analyzed by Western blotting. Both caffeine and paclitaxel induced time- and dose-dependent reductions in MCF-7 cell viability. The combination treatment showed synergistic cytotoxicity, with significantly lower IC₅₀ values compared to single-agent treatments. Western blot analysis showed that both treatments boosted pro-apoptotic Bax and decreased anti-apoptotic Bcl-2, with slightly less effect in the combination group. NF-κB levels increased considerably in caffeine and paclitaxel groups, but were lower in the combination group compared to paclitaxel alone, suggesting a possible reduction in inflammatory signaling. Nrf2 expression increased significantly with caffeine, suggesting oxidative stress responses. In MCF-7 cells, caffeine enhanced paclitaxel's pro-apoptotic and cytotoxic actions and modified inflammation and oxidative stress pathways in a complicated, dose-dependent manner. Cytotoxicity was synergistic; however, apoptotic and stress indicators may be antagonistic. In clinical circumstances, caffeine may be an adjuvant in breast cancer treatment, however mechanistic and in vivo investigations are needed.

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• MakaleAçık Erişim2026Scopus SJRQ1/r/munzur/1310
  Modulation of SIRT1/PPARγ pathways and tight junction proteins by nicotinamide riboside under chronic variable stress

  Celik, Abdullah; Sahin, Nurhan; Orhan, Cemal; Er, Besir; Erten, Fusun; Ozmen, Busra; Tuzcu, Mehmet; Ozercan, Ibrahim Hanifi; Sahin, Kazim

  Abstract: Chronic stress disrupts homeostasis, leading to major health problems such as liver damage, intestinal barrier dysfunction, and impaired glucose metabolism. Although current treatments, including anxiolytics, sedatives, antidepressants, and beta blockers, are effective, their adverse effects emphasize the need for safer alternatives. Nicotinamide riboside (NR), a precursor of nicotinamide adenine dinucleotide (NAD+), plays a central role in energy metabolism and oxidative stress regulation; elevated NAD + levels have been associated with reduced risk of chronic diseases such as obesity and type 2 diabetes. However, the effects of NR on liver metabolism, intestinal barrier integrity, and related protein pathways remain unclear. This study investigated the effects of NR supplementation in rats exposed to chronic variable stress (CVS). Fifty-six male Sprague Dawley rats were divided into normal and CVS groups and treated in a 2 × 4 factorial design with 0, 150, 300, or 600 mg/kg NR. Under CVS conditions, serum glucose, corticosterone, ACTH, and insulin levels increased, whereas NAD+, NADPH, nicotinamide (NAM), and nicotinic acid (NA) decreased significantly (p < 0.001). NR supplementation effectively corrected these biochemical imbalances and upregulated hepatic markers, including PPARγ, SIRT1, GLUT2, IRS1, and FASN (p < 0.001). Furthermore, the increased expression of key transport proteins such as PepT1, LAT2, EAAT3, FABP2, and FATP4 contributed to maintaining intestinal barrier integrity and improving gut health. NR also promoted the recovery of tight and adherens junction proteins. Notably, high-dose NR (600 mg/kg) markedly alleviated liver fibrosis, improved glucose metabolism, and strengthened intestinal barrier function, demonstrating its therapeutic potential as an alternative strategy against stress-induced metabolic disorders. Key points: • NR mitigated chronic stress-induced liver, intestinal, and glucose dysregulation. • NR improved glycemia and NAD⁺-related biomarkers under stress. • NR reduced hepatic fibrosis markers. • NR strengthened TJ/AJ proteins, supporting intestinal barrier integrity. • Findings support NR’s therapeutic potential in stress-related metabolism.

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• MakaleAçık Erişim2026Scopus SJRQ1/r/munzur/1287
  Comparative effects of topical Maresin-1 and cyclosporine A in a capsaicin-induced rat model of neurotrophic keratopathy

  Canan Sezis, Selen; Güngör Kobat, Sabiha; Kuloğlu, Tuncay; İlhan, Nevin; Erten, Füsun

  Purpose: To evaluate and compare the effects of topical Maresin-1 (MaR1) and cyclosporine A (CsA) in a capsaicin-induced rat model of neurotrophic keratopathy (NK). Methods: A total of 40 Sprague-Dawley rats were allocated to five groups (n = 8 per group): Control, NK, NK + Vehicle, NK + CsA (0.05%), and NK + MaR1. Except for the Control group, all animals received a single subcutaneous injection of capsaicin (50 mg/kg) on postnatal day 2. Topical treatments were applied twice daily for 14 days. Corneal TrkA, TNF-α, and Caspase-3 expression were assessed by immunohistochemistry and Western blot. Results: Both treatment groups significantly restored TrkA expression and reduced TNF-α and Caspase-3 relative to NK + Vehicle (p < 0.05 for all). CsA produced greater suppression of TNF-α than MaR1 (p < 0.001), whereas MaR1 demonstrated greater reduction in Caspase-3 than CsA (p = 0.013), with no significant difference between groups for TrkA (p = 0.054). Conclusion: Both MaR1 and CsA significantly attenuated the neurotrophic, inflammatory, and apoptotic changes associated with experimental NK. The distinct efficacy profiles of the two agents suggest complementary mechanisms of action and warrant further investigation of MaR1 in neurotrophic keratopathy.

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• MakaleAçık Erişim2026Scopus SJRQ2/r/munzur/1258
  Effects of fenugreek and shatavari on vasomotor and hormonal balance in ovariectomized rats

  Erten, Füsun; Er, Beşir; Orhan, Cemal; Morde, Abhijeet A.; Padigaru, Muralidhara; Şahin, Kazim

  Trigonella foenum-graecum L. (fenugreek, TFG) and Asparagus racemosus Willd. (shatavari, AR) have been extensively used in Ayurvedic, Unani, and traditional folk medicine to support women’s health. TFG seeds are traditionally employed as galactagogues and hormonal modulators, while AR roots are valued as rejuvenating tonics with phytoestrogenic activity, prescribed for menopausal complaints and reproductive well-being. Both plants also exhibit antioxidant and hepatoprotective effects, suggesting their potential as safe, nonhormonal alternatives to conventional hormone replacement therapy. This study investigated the dose-dependent effects of TFG and AR, administered individually or in combination, on vasomotor symptoms, hormonal balance, oxidative stress, and neuroendocrine markers in an ovariectomized (OVX) rat model of menopause. Adult female rats underwent bilateral ovariectomy and were randomized into eight groups: Control, OVX, OVX+TFG (30 and 60 mg/kg), OVX+AR (30 and 60 mg/kg), and OVX+TFG/AR combinations. Treatments were administered orally for 8 days. Tail, core, and skin temperatures were recorded to assess thermoregulation, while blood and tissue samples were analyzed for hormone levels, oxidative stress, and molecular markers. OVX rats showed classical menopausal alterations, including increased follicle-stimulating hormone, luteinizing hormone, cortisol, and malondialdehyde, and decreased 17β-estradiol, progesterone, dopamine, and antioxidant enzymes, along with dysregulated neuroendocrine markers. All treatments partially reversed these changes, while the high-dose combination (TFG/AR 60 mg/kg each) demonstrated the most pronounced effects, normalizing hormone levels, reducing hot-flash-like temperature fluctuations, restoring antioxidant activity, downregulating neuroendocrine markers (c-FOS, GnRH, Kisspeptin, NKB, and TRPV1) expression, and elevating brain-derived neurotrophic factor levels (p < 0.05). High-dose combined supplementation of TFG and AR effectively alleviates vasomotor disturbances, restores hormonal and oxidative balance, and modulates neuroendocrine pathways in OVX rats. These findings validate their traditional use and highlight their potential as safe phytoestrogen-based, nonhormonal alternatives for the management of menopausal symptoms, warranting further clinical evaluation.

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• MakaleAçık Erişim2026Scopus SJRQ2/r/munzur/1254
  Water extracts of Fucus vesiculosus and Laminaria digitata enhance male reproductive parameters via antioxidant and NO/cGMP mechanisms in rats

  Gencoglu, Hasan; Erten, Fusun; Er, Besir; Orhan, Cemal; Acisu, Tutku Can; Sahin, Kazim

  Male sexual dysfunction is increasingly prevalent, driving interest in marine algal bioactives as potential natural modulators of reproductive physiology. Brown seaweeds such as Fucus vesiculosus and Laminaria digitata contain phlorotannins, fucoidans, and antioxidant compounds of applied relevance in phycology and biotechnology. This study assessed the effects of standardized water extracts of these two species on reproductive behavior, hormonal status, sperm quality, oxidative balance, and nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) signaling in male Sprague–Dawley rats. Animals received the seaweed extracts orally by gavage (300 mg kg⁻1 day⁻1) for 52 days. Both extracts improved male reproductive behavior by reducing the time required to initiate mounting, intromission, and ejaculation (mount latency, intromission latency, and ejaculation latency), while increasing the number of these sexual behaviors during the test period (p < 0.05). Serum follicle-stimulating hormone and testosterone concentrations increased, alongside higher testicular superoxide dismutase, catalase, and glutathione peroxidase activities and lower malondialdehyde levels. Sperm count and motility improved, particularly with L. digitata extract. Western blot analyses revealed phosphorylated phosphodiesterase-5, endothelial NO synthase, and cGMP levels, with reduced endothelin-1 in testicular and epididymal tissues (p < 0.05–0.001). These findings indicate that extracts of F. vesiculosus and L. digitata, chosen for their well-documented antioxidant and phlorotannin-rich profiles, confer protective and prosexual effects associated with enhanced antioxidant defense and upregulation of NO/cGMP-related pathways, with the L. digitata extract exhibiting comparatively stronger activity.

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• MakaleYayıncıda açık erişim2026Scopus SJRQ1/r/munzur/1220
  tVNS Mitigates Neuroinflammation and Nociception in a Rodent LPS Endotoxemia Model

  Atalar, Kerem; Alim, Ece; Calikusu, Aysen; Abbasoglu Topa, Elif Gulcicek; Gok Dagidir, Hale; Bahcelioglu, Meltem; Bukan, Neslihan; Erten, Fusun; Sahin, Kazım; Akarca Dizakar, Saadet Özen

  The vagus nerve plays a modulatory role in the gut-brain axis. Intestinal barrier dysfunction and lipopolysaccharide (LPS) leakage into the systemic circulation are associated with several conditions, such as irritable bowel syndrome (IBS) and migraine headache. This study investigates the impact of non-invasive transauricular vagus nerve stimulation (tVNS) on the neuroinflammatory markers and pain behavior following an acute LPS challenge. Sprague–Dawley rats (n = 28) were given LPS or vehicle and subjected to tVNS or sham intervention in an acute LPS animal model that mimics the systemic consequences of barrier dysfunction. Behaviors were evaluated at the baseline and 6 h later, complemented by testing the levels of serum and brain neuroinflammatory markers. Behavioral analyses revealed that LPS exposure reduced the time spent in the open arm, grooming duration, and periorbital mechanical pain thresholds, and increased freezing duration. The tVNS intervention reversed these behavioral changes induced by LPS. LPS administration triggered elevated serum levels of IL-6, CGRP, haptoglobin, and VE-cadherin. LPS also increased IL-1β, PAR-2, haptoglobin, CGRP, and HMGB1 levels in the brain tissue. The tVNS intervention reversed the effects observed in the brain, but it did not change the elevated levels of inflammatory molecules in the systemic circulation. tVNS has the potential to modulate neuroimmune interactions, with an early impact on the brain during LPS surge. tVNS may have potential therapeutic benefits in managing pain-related disorders associated with LPS endotoxemia.

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• Derleme MakaleAçık Erişim2026Scopus SJRQ1/r/munzur/1156
  Nutraceuticals in Uro-Oncology: A Structured Expert Review and Precision-Oriented Framework

  Erten, Fusun; Kalemoglu, Ecem; Kucuk, Omer; Sahin, Kazim

  Urologic malignancies (UMs), including prostate cancer (PCa), bladder cancer (BCa), renal cell carcinoma (RCC), and testicular germ cell tumors (TGCT), are governed by interconnected molecular pathways that regulate proliferation, angiogenesis, metabolism, invasion, immune escape, and treatment resistance. Key pathways include PI3K/AKT/mTOR, VEGF/VEGFR, EGFR, FGFR, c-MET, androgen receptor signaling, DNA damage response, inflammatory transcriptional programs, and regulation of the tumor microenvironment. This structured expert review evaluates mechanistic, translational, epidemiological, and clinical evidence on food- and botanical-derived nutraceuticals that may influence cancer-related signaling, redox balance, inflammation, metabolic adaptation, and host–tumor interactions. Nutraceuticals are considered investigational adjunctive exposures rather than anticancer treatments or alternatives to standard care. Relevant literature was identified through a structured, non-systematic search of PubMed/MEDLINE, Scopus, Web of Science Core Collection, and Embase from database inception to 17 June 2026, supplemented by backward and forward citation searches. Eligible evidence comprised preclinical, observational, interventional, pharmacokinetic, formulation, safety, and drug–nutraceutical interaction studies. Evidence was evaluated by cancer type, compound class, molecular context, formulation, exposure, translational maturity, and safety, and was classified into five stages: prevention signal, mechanistic plausibility, bioavailability and exposure feasibility, exposure-linked biomarker activity, and clinical benefit. An exposure–species–compartment framework was used to assess whether parent compounds and relevant metabolites reached systemic, urinary, or target-tissue concentrations compatible with the proposed effects. Findings based solely on supraphysiological concentrations of unconjugated parent compounds were considered hypothesis-generating unless supported by human exposure or tissue-distribution data. Curcumin, green tea catechins, isoflavones, carotenoids, flavonols, stilbenes, and triterpenoids affect several cancer-related pathways, primarily in experimental models. Translation to clinical practice is constrained by inconsistent formulations, limited bioavailability, inadequate target-tissue exposure data, few biomarker-linked studies, and possible interactions with anticancer therapies. PCa and BCa provide the most suitable settings for exposure-verified mechanistic studies. In RCC, safety and treatment interactions should be prioritized, whereas in TGCTs, non-interference with curative cisplatin-based therapy must be demonstrated. Future studies should use chemically defined formulations, verify clinically relevant exposure, incorporate mechanism-matched biological-response endpoints, and confirm compatibility with established treatment. Current evidence does not support nutraceuticals as treatments for urologic malignancies.

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• MakaleYalnız künye2026Scopus SJRQ1/r/munzur/1022
  Boron source–dependent regulation of bone mineralization and osteogenic molecular pathways in broilers with tibial dyschondroplasia

  Orhan, Cemal; Sahin, Emre; Erten, Fusun; Er, Besir; Sahin, Nurhan; Ozercan, Ibrahim Hanifi; Kom, Mustafa; Akdemir, Fatih; Balci, Tansel Ansal; Denli, Muzaffer

  Rapid genetic selection for growth rate and slaughter weight in broilers has been associated with a higher incidence of skeletal disorders, particularly tibial dyschondroplasia (TD), which causes considerable economic losses in poultry production. We investigated the effects of boric acid (BA) and sodium pentaborate pentahydrate (SPP) on growth performance, bone mineralization, tibial histopathology, and osteogenic protein expression in broilers with manganese (Mn) deficiency-induced TD. A total of 360 Ross 308 broiler chicks were used in a 2 × 2 × 3 factorial design with TD status (normal or Mn deficiency–induced TD), boron source (BA or SPP), and supplemental boron level (0, 4.37, and 8.74 mg elemental B/kg diet). Birds were randomly allocated to 12 groups with six replicates of five birds each. Clinical and histopathological findings confirmed TD induction. TD decreased body weight, feed intake, and carcass weight, while increasing feed conversion ratio (p < 0.05). Boron supplementation improved tibial mineral density and content in a dose-dependent manner (p < 0.05). In TD broilers, serum osteocalcin (OCN) concentrations were higher with high-level SPP supplementation than with BA supplementation (p = 0.012). Boron source and level significantly affected serum and bone boron concentrations, bone calcium concentrations (p < 0.05). In TD broilers, tibial osteoprotegerin levels were markedly elevated in the high-level SPP group (p < 0.001), whereas SRY-box transcription factor 9, hypoxia-inducible factor-1α, and tumor necrosis factor-α were reduced (p < 0.05). These findings indicate that SPP exerts regulatory effects on bone metabolism and osteogenic signaling pathways in TD-affected broilers.

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• MakaleAçık Erişim2025Scopus SJRQ3/r/munzur/1788
  EFFECTS OF LACTOBACILLUS PLANTARUM ON THE AKT/ENOS CARDIAC PATHWAY IN RATS WITH FRUCTOSE-INDUCED METABOLIC SYNDROME

  Kursun, Oznur Ece Durmaz; Yalim, Goknur; Demirel, Murside Ayse; Erten, Fusun; Sahin, Kazim; Akar, Fatma

  Background. This study investigated the effects of Lactobacillus plantarum supplementation on the Akt/eNOS pathway in the cardiac tissue of rats subjected to a fructose-rich diet, which induced metabolic syndrome. Materials and methods. Twenty-two male Wistar albino rats were randomly assigned to three groups: (1) control, (2) fructose, and (3) fructose ± L. plantarum. Rats in the fructose group were administered a 20% fructose solution in their drinking water for 15 weeks. In the L. plantarum-treated group, the probiotic was administered via gastric gavage at a daily dose of 1×109 CFU/mL/100 g during the final six weeks of the study. Results. The administration of Lactobacillus plantarum resulted in a significant increase in the levels of Akt (p < 0.0001), IRS-1 (p = 0.0113), mTOR (p < 0.0001), eNOS (p < 0.0001), and SIRT1 (p = 0.0031) in the cardiac tissue of rats compared to the fructose group. Moreover, a marked reduction in iNOS, NF-κB, and TNF-α levels (p < 0.0001) was observed, highlighting the potential of L. plantarum to counteract the adverse effects of fructose consumption. Conclusion. The findings of this study suggest that L. plantarum has the potential to reduce inflammation in the heart, enhance insulin sensitivity via the Akt/eNOS pathway, and protect against cardiovascular diseases associated with metabolic syndrome.

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