Parkinson’s disease (PD) is an age-related chronic neurodegenerative disease. Although PD is known to be a result of damage to hippocampal neurons, its molecular mechanism has yet to be completely clarified. The neurodegeneration in hippocampal neurons has been suggested to include excessive production of reactive oxygen species (ROS). Mitochondrial dysfunction and disruption of intracellular Ca²⁺ homeostasis play the most important role in the increase in ROS production for the cells. Remarkably, it is stated in the literature that especially the change of Ca²⁺ homeostasis triggers neuronal degeneration. TRPM2 is a unique calcium-permeable nonselective cation channel, and densest in the numberless neuronal population. The current study aims to elucidate the effect of antioxidant resveratrol (Resv) on TRPM2-mediated oxidative stress (OS) induced by 1-methyl-4-phenylpyridinium (MPP) exposure in the primary mouse hippocampal neurons. The neurons were divided into four groups as Control, Resv , MPP, and MPP+ Resv. In the current results, the activation of TRPM2 was observed in primary hippocampal neurons with MPP incubation. TRPM2 channel expression levels in the MPP group increased in hippocampal neurons after MPP exposure. In addition, intracellular free Ca²⁺ concentration and TRPM2 channel currents were highest in MPP groups, although they were decreased by the Resv treatment. In addition, mitochondrial membrane depolarization, ROS, caspase-3, caspase-9, and apoptosis values induced by MPP decreased with resveratrol treatment. In conclusion, in our study, we observed that the dysregulation of OS-induced TRPM2 channel activation in hippocampal neurons exposed to MPP caused apoptotic cell death in neurons, while the use of resveratrol had a protective effect by reducing OS resources in the environment. Graphical abstract

Bisphenol A (BPA), an environmental toxin, exerts adverse effects by increasing mitochondrial (mROS) and intracellular (iROS) reactive oxygen species, apoptosis, and Ca²⁺ influx in neurological diseases. However, antioxidants can mitigate these detrimental effects. This study aimed to investigate the protective role of antioxidant alpha‐lipoic acid (ALA) against BPA‐induced TRPV4 channel stimulation, oxidant, and apoptotic changes in SH‐SY5Y neuronal cells. Five experimental groups were established: control, ALA, BPA, BPA + ALA, and BPA + TRPV4 antagonist (ruthenium red, RuR). BPA increased excessive Ca²⁺ influx and TRPV4 current density, while BPA‐ and TRPV4 agonist (GSK1016790A)‐induced TRPV4 stimulations were downregulated following incubation with ALA and RuR. BPA‐induced increases in oxidant markers (lipid peroxidation, mROS, iROS), apoptotic markers (caspase‐3, −8, and −9), Zn²⁺, and cell death were reduced by ALA and RuR treatment. Conversely, BPA‐induced reductions in cell viability, glutathione, and glutathione peroxidase levels were restored following treatment. In summary, ALA attenuated BPA‐induced excess Ca²⁺ influx, Zn²⁺ accumulation, apoptosis, and oxidative neurotoxicity via TRPV4 inhibition. Therefore, ALA may offer protection against BPA‐induced neuronal cell death associated with oxidative neurotoxicity.

Cisplatin (CSP) is a first-line chemotherapeutic for laryngeal squamous cell carcinoma (LSCC), but its clinical effectiveness is limited by resistance and toxicity. Hesperidin (HESP), a citrus flavonoid, may enhance chemotherapeutic efficacy through pro-apoptotic properties. This study investigated the involvement of the transient receptor potential melastatin-2 (TRPM2) channel in the HESP-mediated potentiation of CSP-induced cytotoxicity in human laryngeal carcinoma (Hep-2) cells. Hep-2 cells were treated with CSP (25 µM), HESP (25 µM), or their combination for 24 h. The findings showed that the combined application of HESP and CSP reduced cell viability by approximately 50% (p < 0.001), which was the lowest compared to CSP alone. Western blot analysis revealed that TRPM2 protein expression was higher in the CSP+HESP group compared to the control group (p < 0.001). This synergistic treatment resulted in an increase in ROS production and a decrease in MDA levels, accompanied by a reduction in cellular GSH levels (p < 0.001). Furthermore, the combination therapy increased pro-inflammatory cytokines such as IL-1β and TNF-α (p < 0.001). Functional analyses showed that HESP treatment enhanced CSP-induced Ca²⁺ influx and altered mitochondrial membrane potential (p < 0.001). The pharmacological inhibition of TRPM2 with ACA and 2-APB reversed these effects, restoring redox balance and reducing cellular damage. In conclusion, HESP amplifies CSP-induced apoptosis in Hep-2 cells through TRPM2-dependent oxidative stress, Ca²⁺ dysregulation, and mitochondrial dysfunction. These findings identify TRPM2 as a mechanistic mediator of HESP-enhanced chemosensitivity in LSCC.

Background/Objectives: Glioblastoma, the most common primary tumor of the central nervous system, is characterized by high malignancy and poor prognosis. One of the main challenges in neurological disorders is to develop an effective treatment modality that can cross the blood–brain barrier. Nanoparticles are revolutionary for neurodegenerative diseases due to their targeted delivery and ability to overcome biological barriers. Cerium oxide (Ce₂O₃) nanoparticles are suitable for use as drug delivery systems. Methods: In our study, we investigated the anticancer mechanism using SN-38, lithium, and Ce₂O₃, a powerful agent used in GBM treatment. We evaluated their anticancer activities separately and in combination with U373 cell lines. GBM cell line U373 cells were cultured. Then, all groups except the control group were treated with different doses of SN-38 and lithium combination therapy with SN-38, lithium, and Ce₂O₃ combination therapy. The results were evaluated using MTT and ELISA tests. Results: When the results were examined, anticancer activity was detected at PTEN, AKT, mTOR, and BAX/Bcl-2 levels in the SN-38 + NPs 25 µg/mL + Lithium 50 µg/mL and SN-38 + NPs 50 µg/mL + Lithium 50 µg/mL dose groups. In addition, findings that inflammation markers were correlated with the apoptosis mechanism were obtained. Conclusion: This study is the first to report that combining lithium with SN-38 and NPs increased oxidative stress more than lithium with SN-38, leading glioblastoma cells to apoptosis and its potential anticancer activity. These results provide a basis for further investigation of its clinical application in cancer treatment.