Yener 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.

Current treatments for glioblastoma (GBM), defined as the brain and spinal cord tumour with the worst prognosis in adults, do not sufficiently improve the prognosis. Therefore, there is a clear need to investigate the possible molecular pathways of tumour proliferation and metastasis and new strategic approaches for its treatment. In this study, we aimed to elucidate the synergistic chemotherapeutic activity of gallic acid (GA) with doxorubicin (DOX) in human glioblastoma tumour cells (DBTRG) and the molecular mechanisms of these effects. For this purpose, we investigated the stimulatory role of GA on DOX-induced human glioblastoma tumour cell (DBTRG) death via TRPM2 channel activation. For the study, five groups were formed from DBTRG cells as Control, GA (4O μM), DOX (1 μM), GA + DOX, and ACA + DOX (ACA, 25 μM). In the analyses made, Total Antioxidant/Oxidant/ (TAS and TOS) status, cell viability, lipid peroxidation levels, glutathione peroxidase (GSH-Px) and glutathione (GSH) enzyme activity, caspase activity, reactive oxygen species (ROS), inflammation markers, Poly ADP Ribose Polymerase-1, (PARP-1), and Transient Receptor Potential Melastatin 2 (TRPM2) levels in the cells were determined. DOX treatment reduced TAS, GSH, GSH-Px, and cell viability levels while increasing inflammatory indicators, TOS, ROS, MDA, caspase, PARP-1, and TRPM2 levels and causing DBTRG cell cytotoxicity. The treatment was even more successful when GA and DOX were used together. In conclusion, the increase in cell death and ROS levels mediated by TRPM2 activation in DOX DBTRG cells was further enhanced by GA treatment.

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.

Aims: Chrysin is a flavonoid with economic value and medicinal effects commonly found in propolis, honey, and blue passion flowers. It has many pharmacological properties such as anticancer, antitumor, antioxidant, neurotrophic, and antidepressant. Glutamate plays an important role in brain functions; however, its high concentration in the central nervous system causes neurotoxic effects. This study aimed to investigate the effect of Chrysin on glutamate-induced cytotoxicity in SH-SY5Y neuroblastoma cells. Methods: This study was conducted in 4 groups; control, Chrysin (50 µM), glutamate (10 mM), and glutamate+Chrysin. cell viability, total oxidant status (TOS), total antioxidant status (TAS), tumor necrosis factor alpha (TNF-alpha), and interleukin 1 ß (IL-1ß) levels in the cells were determined by ELISA kit. Results: It is shown that glutamate application caused cytotoxicity in SH-SY5Y neuroblastoma cells and increased TOS, TNF-alpha, and IL-1ß levels. However, in SH-SY5Y cells treated with Chrysin before glutamate incubation, TOS, TNF-alpha, and IL-1ß levels decreased compared to the glutamate group, while TAS and cell viability levels increased. Conclusion: Chrysin’s antioxidant properties played a protective role in SH-SY5Y cells against glutamate-induced increased oxidative stress and inflammation.

Cadmium (CAD) is a prevalent environmental contaminant that poses serious cardiotoxic risks. The heart, kidney, liver, and brain are just a few of the essential organs that can sustain serious harm from CAD, a very poisonous heavy metal. The cardiotoxic mechanism of CAD is linked to oxidative damage and inflammation. A trace element with anti-inflammatory, anti-apoptotic, and antioxidant qualities, selenium (SEL) can be taken as a dietary supplement. The biotoxicity of heavy metal CAD is significantly inhibited by SEL, a mineral that is vital to human and animal nutrition. Through ROS-induced PARP-1/ADPR/TRPM2 pathways, this study seeks to assess the preventive benefits of selenium against cardiovascular damage caused by CAD. The SEL showed encouraging results in reducing inflammatory and oxidative reactions. Rats were given 0.5 mg/kg SEL and 3 mg/kg 2-Aminoethyl diphenylborinate (2-APB) intraperitoneally for five days, in addition to 25 mg/kg CAD given via gavage. Histopathological examination findings revealed that the morphologic changes in the hearts of the CAD group rats were characterised by marked necrosis and the degeneration of myocytes and congestion of vessels. Compared to the rats in the CAD group, the hearts of the SEL, 2-APB and SEL+2-APB groups showed fewer morphological alterations. Moreover, in rats given CAD, there was an increase in cardiac malondialdehyde (MDA), total oxidant (TOS), reactive oxygen species (ROS), caspase (Casp-3-9), and TNF-α, whereas glutathione (GSH), glutathione peroxidase (GSH-Px), superoxide dismutase (SOD) and total antioxidant (TAS) decreased. SEL improved antioxidants, avoided tissue damage, and reduced cardiac MDA, TOS, and ROS. In rats given CAD, SEL decreased cardiac PARP-1, TRPM2, TNF-α, and caspase. In summary, by reducing oxidative stress and cardiac damage and modifying the ROS/PARP-1/TRPM2 pathway, SEL protected against CAD cardiotoxicity.

The prognosis for glioblastoma multiforme (GBM), the adult brain and spinal cord tumour with the poorest prognosis, has not improved enough with current therapies. Investigating potential molecular routes of tumour growth and metastasis and novel therapeutic methods are, therefore, obviously necessary. Although some natural substances have been shown to increase intracellular Ca²⁺ concentration and ROS generation by activating TRPM2 channel and potentiate the anticancer effects of doxorubicin (DOX), and chrysin (CHR) has been shown to enhance the anticancer effect of DOX, its anticancer effect through TRPM2-mediated Ca²⁺ homeostasis and ROS generation in glioblastoma tumour cells (DBTRG) has not been investigated. This work aimed to clarify the molecular processes behind the synergistic chemotherapeutic action of DOX and CHR in DBTRG cells. For this purpose, we investigated the stimulatory role of CHR on DOX-induced cell death via TRPM2 channel activation in DBTRG cells. DOX treatment caused cell cytotoxicity, increased apoptosis (caspase 3 and 9), ROS, lipid peroxidation levels, and decreased cell viability and antioxidant levels. The combination of CHR and DOX made the treatment even more effective. The effects in cells were reduced with treatments with 2APB, a TRPM2 antagonist. In conclusion, the increase in ROS and cell death levels mediated by TRPM2 activation in DOX-induced DBTRG cells was further enhanced by CHR treatment. The combination of CHR and DOX can be used as a successful agent in the treatment of glioblastoma tumours.

Blastocystis, a common intestinal protozoan in humans, is associated with gastrointestinal disorders, irritable bowel syndrome, urticaria, and colorectal cancer. Its genetic diversity and potential for treatment resistance make it a focus of ongoing research. This study evaluated the in vitro antiprotozoal activity of a postbiotic derived from Pediococcus acidilactici as a natural alternative treatment. P. acidilactici cultures were grown in MRS broth under anaerobic conditions, and the postbiotic was collected and characterized for pH, yield, organic acid composition, and phenolic compound content. Human isolates of Blastocystis subtypes ST1 and ST3 were cultured in Jones’ medium and exposed to varying postbiotic concentrations for 72 h. Viability was assessed microscopically. The cytotoxic effect of the postbiotic-derived P. acidilactici was evaluated by investigating its impact on the viability of HT-29 cells using the Cell Counting Kit 8. The postbiotic showed a 7% yield and a pH of 4.52 ± 0.11. It contained seven different organic acids, predominantly lactic acid, and eleven phenolic compounds, with naringin as the most abundant. At 4.38 mg/mL, the postbiotic achieved over 94% inhibition and 100% inhibition at 8.75 mg/mL and above. A pH analysis confirmed that the inhibition was independent of the culture medium acidity. Cell viability was not affected at the postbiotic concentration showing 100% antiprotozoal activity (8.75 mg/mL). These findings suggest that the P. acidilactici postbiotic is effective on a mixed culture of ST1 and ST3 subtypes and holds promise as a safe, natural antiprotozoal agent. Further in vivo studies are needed to confirm this.

Cisplatin (CIS) is widely used in the treatment of laryngeal cancer, one of the most common and lethal cancers. However, it is not a satisfactory chemotherapeutic agent. Therefore, there is a need to identify new agents, such as gallic acid (GAL), that can exert a synergistic effect to elucidate the pathophysiological mechanisms of the chemotherapeutic effects of CIS and to increase the effectiveness of treatment by preventing drug resistance. For this purpose, we investigated the stimulatory role of GAL on CIS-induced human laryngeal cancer (Hep-2) cell death via TRPM2 channel activation. For the study, four groups were formed from human laryngeal cancer (Hep-2) cells as Control, GAL (1OO μM), CIS (25 μM), and GAL + CIS. In the analyses made, cell viability, glutathione (GSH) and glutathione peroxidase (GSH-Px) enzyme activity, lipid peroxidation (LPx) levels, inflammation markers I-1β, IL-6, and TNF-α, Total Oxidant/Antioxidant (TOS and TAS) status, reactive oxygen species (ROS), caspase (Cas-3-9) activity, Transient Receptor Potential Melastatin 2 (TRPM2), and Poly Adp Ribose Polymerase-1, (PARP-1) levels in the cells were determined. CIS treatment caused laryngeal cancer cell cytotoxic and increased Cas-3-9, ROS, IL-1β, TNF-α, IL-6, TOS, LPx, TRPM2, and PARP-1 levels while decreasing cell viability, GSH-Px, GSH, and TAS levels. The combination of GAL and CIS treatment made the treatment even more effective. In conclusion, the increase in ROS and cell death levels mediated by TRPM2 activation in CIS Hep-2 cells was further enhanced by GAL treatment. Thus, CIS chemotherapy in Hep-2 cells may be enhanced by the synergistic effect of the GAL combination, and drug resistance may be reduced.

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.