Betül Yazğan

Environmental contaminants like bisphenol A (BPA) and nonylphenol (NP) are recognized neurotoxicants; however, the molecular mechanisms underlying their impact on sensory ganglia, specifically the trigeminal ganglion (TG), remain critically underexplored. This study explored the potential of BPA and NP to drive neuronal injury and ferroptosis linked to oxidative stress, acting through the transient receptor potential melastatin 2 (TRPM2)–poly (ADP‐ribose) polymerase‐1 (PARP1) signaling axis. Forty‐two adult male Wistar rats were allocated into seven groups (control, low‐dose [25 mg/kg]/high‐dose [100 mg/kg] BPA, low‐dose [25 mg/kg]/high‐dose [100 mg/kg] NP, and low‐dose [25 mg/kg]/high‐dose [100 mg/kg] BPA + NP) and treated orally for 21 days. We employed a combinatorial approach of biochemical assays and immunohistochemistry to evaluate oxidative stress markers, ferroptosis hallmarks (glutathione peroxidase 4 [GPX4], solute carrier family 7 member 11 [SLC7A11], and transferrin receptor [TfRC]), apoptotic mediators (Caspase‐3 and Caspase‐9), and inflammatory cytokines, as well as the expression of TRPM2 and PARP‐1. Results demonstrated that BPA and NP exposure triggered a robust, dose‐dependent accumulation of reactive oxygen species (ROS) and lipid peroxidation, concomitant with downregulation of anti‐ferroptotic proteins (GPX4 and SLC7A11) and upregulation of TfRC. This toxic insult simultaneously activated apoptotic and inflammatory cascades. Crucially, TRPM2 and PARP‐1 were significantly upregulated, implying a potential role for the TRPM2–PARP‐1 axis as an upstream modulator of oxidative stress‐induced ferroptosis and neuroinflammation. Collectively, these findings provide novel mechanistic insights into phenol‐induced neurotoxicity, highlighting the inhibition of the TRPM2–PARP‐1 axis as a promising therapeutic strategy to mitigate environmental neurodegeneration in sensory neurons.

Electromagnetic field (EMF) exposure, unavoidable in modern life, is linked to oxidative stress and ferroptosis, processes linked to neurodevelopmental disorders. This study investigated the effects of EMF exposure during different pregnancy trimesters on rat offspring trigeminal ganglia (TGs), focusing on transient receptor potential melastatin 2 (TRPM2) ion channels, and assessed the neuroprotective potential of ferrostatin‐1 (Fer), a ferroptosis inhibitor, against EMF‐induced damage. Pregnant rats were exposed to 900 MHz EMF for 2 h/day during early (1–7 days, EMF 1), mid (8–14 days, EMF 2), or late (15–21 days, EMF 3) gestation. Fer (2.5 µmol/kg, i.p.) was administered immediately after daily EMF exposure in Fer treatment groups. Offspring TG tissues were analyzed on postnatal Day 28 using histopathological, immunohistochemical, and biochemical approaches. EMF exposure significantly reduced antioxidant capacity and elevated lipid peroxidation, reactive oxygen species (ROS), pro‐inflammatory cytokines, apoptotic markers, and TRPM2 activation, with the most pronounced alterations in mid‐gestation exposure. Fer administration largely normalized these parameters and reduced structural damage in TG. In conclusion, these findings suggest that prenatal EMF triggers ferroptotic/apoptotic neurodegeneration via TRPM2, and that Fer holds promise as a neuroprotective agent.

Objective: Cisplatin (CIS) is a powerful chemotherapeutic agent that has long been used alone or in combination in the treatment of various cancers. However, the toxicity of CIS in various tissues limits its use. Gallic acid (GAL) has anti-microbial, anti-inflammatory, and anti-tumor properties. Since GAL has broad biological properties and exhibits antioxidant activity, this study aimed to investigate the effect of GAL on CIS-induced cardiotoxicity in H9c2 cardiomyocyte cell lines. Materials and Methods: H9c2 cardiomyocyte cells as control (CON), CIS, and GAL25, GAL50 in combination along with CIS were used. In the analyses made, glutathione (GSH) and glutathione peroxidase (GSH-Px) enzyme activity, lipid peroxidation levels, inflammation markers IL1β, IL 6, and TNF α, Total Oxidant/ Antioxidant (TOS and TAS) status, reactive oxygen species (ROS) and caspase (Casp 3-9) activity in the cells were determined. Results: CIS treatment caused cardiomyocyte cell toxicity and increased Casp 3-9, ROS, IL 1β, TNF α, IL 6, TOS, and MDA levels while decreasing GSH-Px, GSH, and TAS levels. Increased inflammation and impaired oxidant/antioxidant balance in cardiomyocyte cells after CIS treatment were regulated by GAL treatment. Conclusions: GAL treatment was found to have a protective effect on CIS-induced cardiotoxicity in cardiomyocyte cells.

Aims: Cisplatin (CPL) is a potent chemotherapeutic agent widely used to treat various cancers. However, CPL causes toxicity in various tissues, including the heart. Lipoic acid (LPA) is a thiol compound with antioxidant, anti-inflammatory, and antiapoptotic properties. Although LPA has been reported to have protective effects in various cardiac diseases, the mechanisms underlying its cardio-protective effects have not been elucidated. This study aimed to establish a CPL-induced cardiotoxicity model in the H9c2 cardiomyocyte cell line, to understand the mechanisms underlying this cardiotoxicity, and to investigate the effect of LPA on cardiotoxicity. Methods: H9c2 cardiomyocyte cells as control (CNT), CPL (40 µm), and LPA-1 (300 µm LPA, and 40 µm CPL), LPA-2 (500 µm LPA, and 40 µm CPL) in combination along with CIS were used. In the analyses made, glutathione (GSH) and glutathione peroxidase (GSHPx) enzyme activity, lipid peroxidation [malondialdehyde, (MDA)] levels, inflammation markers interleukin (IL) -1ß, IL-6, and tumor necrosis factor (TNF) -? levels, total oxidant/antioxidant (TOS and TAS) status levels, reactive oxygen species (ROS) and caspase activity (Casp 3 and 9) in the cells were determined. Results: CIS treatment caused cardiomyocyte cell toxicity and increased Casp 3, Casp 9, ROS, IL-1ß, IL-6, TNF-?, TOS, and MDA levels while decreasing GSHPx, GSH, and TAS levels. Increased inflammation and impaired oxidant/antioxidant balance in cardiomyocyte cells after CPL treatment were regulated by LPA treatment. Conclusion: LPA treatment was found to have a protective effect against CPL-induced cardiotoxicity in cardiomyocyte cells.

Pain is an unpleasant and uncomfortable sensation that informs us that something is wrong and overrides other neuronal signals. Nociceptive pain is an unconscious response of sensory receptors to noxious stimuli. Transient Receptor Potential (TRP) channels are a family of non-selective cation channels located at nociceptive sensory nerve endings that respond to thermal, mechanical, or chemical stimuli with threatening/irritating potential. Depending on the type and intensity of the stimulus, different TRP proteins alter calcium ion permeability and modulate cellular response patterns. TRP Vanilloid Receptor-1 (TRPV1), which has the most crucial role in the activation of pain transmission pathways in this family, is sensitive to vanilloid-like chemicals, temperature (>430C), and low pH. Recent studies indicate that gonadal hormones are actively involved not only in reproductive behavior and sex determination but also in all physiological systems. Current literature shows that gonadal hormones play active roles not only in reproductive behavior and sex determination but also in all physiological systems. Estrogen, the most potent of these hormones, has been the subject of numerous studies due to its vital effects on the nervous system, such as neuronal viability, excitability, and perception of somatosensory stimuli. Although the literature shows that estrogen has essential roles in the modulation of pain, there is insufficient evidence regarding the molecular pathways of its effect. This review aims to investigate the importance of calcium signaling in the molecular pathways of pain and the effects of estrogen on TRPV1 cation channels that alter the calcium ion permeability of nociceptors. FULL TEXT PDF

Pain is an unpleasant and uncomfortable sensation that informs us that something is wrong and overrides other neuronal signals. Nociceptive pain is an unconscious response of sensory receptors to noxious stimuli. Transient Receptor Potential (TRP) channels are a family of non-selective cation channels located at nociceptive sensory nerve endings that respond to thermal, mechanical, or chemical stimuli with threatening/irritating potential. Depending on the type and intensity of the stimulus, different TRP proteins alter calcium ion permeability and modulate cellular response patterns. TRP Vanilloid Receptor-1 (TRPV1), which has the most crucial role in the activation of pain transmission pathways in this family, is sensitive to vanilloid-like chemicals, temperature (>430C), and low pH. Recent studies indicate that gonadal hormones are actively involved not only in reproductive behavior and sex determination but also in all physiological systems. Current literature shows that gonadal hormones play active roles not only in reproductive behavior and sex determination but also in all physiological systems. Estrogen, the most potent of these hormones, has been the subject of numerous studies due to its vital effects on the nervous system, such as neuronal viability, excitability, and perception of somatosensory stimuli. Although the literature shows that estrogen has essential roles in the modulation of pain, there is insufficient evidence regarding the molecular pathways of its effect. This review aims to investigate the importance of calcium signaling in the molecular pathways of pain and the effects of estrogen on TRPV1 cation channels that alter the calcium ion permeability of nociceptors. FULL TEXT PDF

Aim: Doxorubicin (DOX), an anthracycline, is widely used in chemotherapy due to its effectiveness in fighting many cancers. Experimental and clinical studies prove that this drug damages non-targeted tissues (including cardiomyocytes) and reduces patients' quality of life during and after DOX treatment. The discovery of potent compounds as a protective tool to slow cardiomyocyte damage during the use of anti-cancer drugs such as DOX is crucial for both more effective cancer treatment and to improve patient's quality of life. Gossypin (GOS) is a flavonoid with several important properties, such as anti-cancer, analgesic, antioxidant, and anti-inflammatory. GOS shows supportive effects against oxidative stress and inflammation by activating antioxidant defense enzymes. Material and Method: For the study, four groups were formed from H9c2 embryonic cardiomyocyte cells as Control, DOX (1 μM, 48 h), GOS25 (25 µg/ml, 48 h), and GOS50 (50 µg/ml, 48 h). In the study, Total antioxidant and oxidant status (TAS and TOS), levels of the inflammatory cytokines IL 1 beta and 6, and TNF α, lipid peroxidation levels as malondialdehyde (MDA), glutathione peroxidase (GSHPx), and glutathione (GSH) levels in the H9c2 embryonic cardiomyocyte cells were determined. Results: The results showed that DOX treatment caused cell toxicity in the embryonic cardiomyocyte cells and increased TOS, IL 1 beta and 6, TNF α, and MDA levels while decreasing TAS, GSH, and GSHPx levels. This situation improved with GOS treatment. Conclusion: As a result, it was determined that GOS treatment showed a protective effect in the DOX-induced cell toxicity model in H9c2 embryonic cardiomyocyte cell lines.

Migraine is a complex neurological problem whose primary symptom is headache and is common in the human population. It is well known that neuroinflammation plays a vital role in the pathogenesis of migraine, with adverse effects on the nervous system, including headache disorders such as migraine. The infusion of the nitric oxide donor glyceryl trinitrate (GTN) is often used in experimental models of migraine because it is the best-known model of migraine provocation. N-(p-amyl cinnamoyl) anthranilic acid (ACA) has been shown to inhibit both TRPM2 and phospholipase A2 (PLA2). Recent research has explored potential interventions to mitigate GTN-induced neurotoxicity. One such candidate is ACA, a compound with anti-inflammatory and antioxidant properties. Thirty-six C57BL/6j black mice were divided into the control groups of ACA, GTN, and ACA+GTN. Mice in the ACA were treated intraperitoneally with ACA (25 mg/kg) for three days. Mice in the GTN were treated intraperitoneally with a single dose of GTN (10 mg/kg) for migraine induction. After the experimental stages were completed, the mice in all groups were sacrificed, and brain tissue and erythrocyte samples were taken from the mice. The levels of inflammatory cytokines (TNF α, IL 1β, and IL 6), apoptosis, intracellular ROS, lipid peroxidation, caspase 3-9, and mitochondrial membrane potential increased in the GTN group. However, their levels were decreased in the ACA+GTN group by the injection of ACA. The treatment of ACA regulated the GTN treatment-induced decreases of glutathione levels, glutathione peroxidase activation, and cell viability in the brain and erythrocytes. In conclusion, GTN plays a role in neurotoxicity caused by increased apoptosis and ROS. We observed that ACA modulated the brain and erythrocyte oxidant, antioxidant parameters, and apoptotic processes. The neuro-protective role of ACA treatment may be explained by its modulating activity against increased apoptosis and oxidative stress.

Klasik bir antifolat olan metotreksat (MTX), çeşitli kanserlerin tedavisinde yaygın olarak kullanılan ve yan etkilerinden dolayı üzerinde çalışılan antikanser ajanlardan biridir. Ne yazık ki, MTX'in hücre üzerine toksik etkisi, sadece tümör hücreleri ile sınırlı olmayıp diğer hayati organları da etkilemektedir. Bu durum MTX’in antikanser etkinliğini azaltmadan, hücresel toksik etkilerini azaltabilecek başka ajanlarla birlikte kullanımını zorunlu kılmaktadır. Antikanser ilaçların istenmeyen yan etkilerini azaltabilecek doğal antioksidanların kullanımıyla ilgili kapsamlı araştırmalar yapılmaktadır. Yapılan çalışmalarda, kurkuminin (KUR) çeşitli dokularda meydana gelen hücresel toksisite üzerindeki koruyucu etkileri, onun antioksidan, antienflamatuar ve antikanser etkilerinin olmasına atfedilebilir. Bu çalışma, MTX’in neden olduğu hücresel toksisitenin, KUR ile azaltılabileceği varsayılarak yapıldı. MTX’e maruz bırakılan insan embriyo böbrek (HEK-293) hücre serisinde, antioksidan bir ajan olan KUR’un düzenleyici rolü araştırıldı. HEK-293 hücreleri, Kontrol, KUR, MTX ve MTX+KUR olarak dört gruba ayrıldı. Kontrol grubundaki hücrelere herhangi bir uygulama yapılmadan, kültür ortamında 48 saat boyunca tutuldu. Diğer gruplardaki hücreler kültür ortamında 24 saat tutulduktan sonra, KUR grubundaki hücrelere 10 μM KUR, MTX grubundaki hücrelere 5 μM MTX ve MTX+KUR grubundaki hücrelere ise 5 μM MTX ve 10 μM KUR uygulandı. Uygulamaları takiben hücreler 24 saat boyunca kültür ortamında tutuldu. HEK-293 hücrelerindeki MTX kaynaklı lipit peroksidasyon (Lip-Px) aktivitesi Placer ve arkadaşlarının yöntemine göre, glutatyon (GSH) seviyeleri Sedlak ve Lindsay yöntemine göre ve glutatyon peroksidaz (GSH-Px) seviyeleri Lawrence ve Burk yöntemine göre spektrofotometrik (UV-1800) olarak ölçüldü. MTX ile inkübe edilen hücrelerde Lip-Px aktivitesinin arttığı, GSH ve GSH-Px aktivitelerinin ise önemli ölçüde azaldığı belirlenmiştir. KUR uygulamasının ise Lip-Px aktivitesini önemli ölçüde azaltırken, GSH ve GSH-Px aktivitelerini önemli ölçüde artmıştır. Bu sonuçlar, KUR uygulamasının MTX kaynaklı hücresel stres ve toksisiteyi, antioksidan mekanizmalarla düzenleyerek, MTX kemoterapisine etkili bir yardımcı ajan olabileceğini göstermektedir.

It is well known that 17β-estradiol (E2) has an antioxidant role on neurological systems in the brain. Raloxifene (RLX) and tamoxifen (TMX) are selective estrogen receptor modulators. An E2 deficiency stimulates mitochondrial functions for promoting apoptosis and increasing reactive oxygen species (ROS) production. However, RLX and TMX may reduce the mitochondrial ROS production via their antioxidant properties in the brain and erythrocytes of ovariectomized (OVX) rats. We aimed to investigate the effects of E2, RLX, and TMX on oxidative stress, apoptosis, and cytokine production in the brain and erythrocytes of OVX rats. Forty female rats were divided into five groups. The first group was used as a control group. The second group was the OVX group. The third, fourth, and fifth groups were OVX + E2, OVX + TMX, and OVX + RLX groups, respectively. E2, TMX, and RLX were given subcutaneously to the OVX + E2 and OVX + TMX, OVX + RLX groups for 14 days after the ovariectomy respectively. While brain and erythrocyte lipid peroxidation levels were high in the OVX group, they were low in the OVX + E2, OVX + RLX, and OVX + TMX groups. OVX + E2, OVX + RLX, and OVX + TMX treatments increased the lowered glutathione peroxidase activity in erythrocytes and the brain and reduced glutathione and vitamin E concentrations in the brain. β-carotene and vitamin A concentrations in the brain and TNF-α and interleukin (IL)-1β levels in the plasma of the five groups were not significantly changed by the treatments. However, increased plasma IL-4 levels and Western blot results for brain poly (ADP-ribose) polymerase (PARP) in the OVX groups were decreased by E2, TMX, and RLX treatments, although proapoptotic procaspase 3 and 9 activities were increased by the treatments. In conclusion, we observed that E2, RLX, and TMX administrations were beneficial on oxidative stress, inflammation, and PARP levels in the serum and brain of OVX rats by modulating antioxidant systems, DNA damage, and cytokine production.