Search

WOS: 000530579900004 PubMed: 32356430 AIM: Transient receptor potential (TRP) channels expression is enhanced significantly in colon cancer cells and Low Lever Laser Treatment (LLLT), is known to have effects and is used clinically in the treatment ofmany diseases, including colon cancer. We aimed to reveal the effects of (LLLT) on apoptosis of colon cancer and on the efficacy of cyclophosphamide via Transient receptor potential melastatin 2 (TRPM2) channels. METHOD: Human colon cancer cells (Caco-2) were cultured and cells were divided into seven main groups. Cells were incubated with cyclophosphamide, TRPM2 channel inhibitor, stimulator and low level laser exposure separately and together. The effects of cyclophosphamide and low level laser were investigated on apoptosis. RESULTS: It was found that the levels of apoptosis in cyclophosphamide group were significantly increased in cancer cells compared to the control group. TRPM2 channel stimulator administration resulted in significantly increased apoptosis levels compared to the control group, in cyclophosphamide + low level laser group the apoptosis level was significantly increased compared to the cyclophosphamide-only group. CONCLUSIONS: It has been shown that apoptotic effects of cyclophosphamide on colon cancer cells were directly related to TRPM2 channels, low level laser increased apoptosis in colon cancer cells through TRPM2 channels and induced apoptotic effect of cyclophosphamide (Fig. 5, Ref. 26).

WOS: 000558485900001 PubMed: 32781866 Memantine (MEM) has been used to treat patients with Alzheimer' disease though inhibition of reactive oxygen species (ROS), Ca(2+)entry and glutamate receptor. The Ca(2+)permeable TRPA1, TRPM2 and TRPV1 channels are activated in the hippocampus by ROS, and antioxidant MEM as a potent TRPA1, TRPM2 and TRPV1 channel antagonist may reduce A beta-induced oxidative stress and apoptosis in the neurons. In the current study, we investigated the neuroprotective properties of MEM in A beta-induced hippocampal neuron cultures. Freshly isolated hippocampal neurons of mice were divided into eight groups as control, A beta, Hcy, MEM, A beta + Hcy, A beta + Hcy + MEM, A beta + MEM and Hcy + MEM. The neurons were exposed to incubated with A beta (20 mu M for 24 h), Hcy (250 mu M for 30 min) and MEM (10 mu M for 24 h). TRPA1, TRPM2 and TRPV1 of the eight groups were further stimulated by cinnamaldehyde, cumene hydyroperoxide and capsaicin, respectively although they were further inhibited by AP-18, N-(p-Amylcinnamoyl) anthranilic acid (ACA) and capsazepine (CPZ). The [Ca2+] concentration, apoptosis, caspase 3, caspase 9 activations, mitochondrial membrane depolarization and intracellular ROS production values in the neurons were higher in A beta and Hcy groups than in control although they were lower in the MEM group than in A beta and Hcy groups. The values were further decreased by MEM + AP-18, MEM + CPZ and MEM + ACA treatments as compared to MEM only. A beta and Hcy-induced decrease of cell viability level was increased by MEM treatment although A beta and Hcy-induced increase of caspase 3, caspase 9, PARP1, TRPA1, TRPM2 and TRPV1 expression levels were decreased by MEM treatments. In conclusion, TRPA1, TRPM2 and TRPV1 channels are involved in A beta and Hcy-induced neuronal death, and modulation of the activity of these channels by MEM treatment may account for their neuroprotective activity against apoptosis, excessive ROS production, and Ca(2+)entry. Scientific Research Project Unit of Suleyman Demirel UniversitySuleyman Demirel University [BAP-4420-D2-15] The study was partially supported by Scientific Research Project Unit of Suleyman Demirel University (BAP-4420-D2-15).

Memantine (MEM) has been used to treat patients with Alzheimer' disease though inhibition of reactive oxygen species (ROS), Ca

Aim: Paclitaxel is widely used in adjuvant treatment of early breast cancer and second-line treatment of metastatic breast cancer. It has been reported that transient receptor potential melastatin-2 (TRPM2) channels are expressed intensively in breast cancer and has significant effects on oxidative stress. Selenium is an essential element and has effects on reproduction, toxicity, antiaging and DNA reproduction. In this study, we aimed to reveal the role of selenium and TRPM2 channels on apoptotic effects of paclitaxel in breast cancer cells. Material and Methods: Breast cancer cells (MCF-7) were cultured and cells were divided into seven main groups. Cells were incubated with paclitaxel and selenium separately and together administrated on breast cancer cell cultures. Cell cultures incubated with TRPM2 channel antagonist anthranilic acid and stimulator cumene-hydroperoxyde. The effects of paclitaxel and selenium were invastigated on molecular pathways of apoptosis. Results: It was found that the levels of apoptosis in paclitaxel group were significantly increased in cancer cells compared to control group (p

WOS: 000522713300001 PubMed: 32146544 Purpose Neuroblastoma is a malignant solid tumor that originates from the sympathetic nervous system in early childhood. Temozolomide is used for treatment in high-risk groups with low treatment response of neuroblastomas. TRPA1 channels in neuroblastoma cells are calcium permeable channels that can be activated by reactive oxygen species (ROT). In this study, we aimed to evaluate the level of activity of temozolomide and selenium in neuroblastoma cells via TRPA1 channels. Method Seven main groups were formed using SH-SY5Y neuroblastoma cells. The control was divided into temozolomide (TMZ) (100 mu M, 24 h), TMZ+SEL+AP18, SEL (sodium selenite, 100 mu M, 24 h), and SEL+AP18 groups. Intergroup calcium signaling, intracellular reactive oxygen species, caspase-3 and caspase-9, and mitochondrial depolarization analyses were performed by channel activation with TRPA1 agonist cinnamaldehyde in all groups. Results Cytosolic calcium concentration, apoptosis, caspase-3 and caspase-9 activation, mitochondrial membrane depolarization, and ROT levels were higher in TMZ (p < 0.001), TMZ+SEL (p < 0.001), and SEL (p < 0.05) groups than the control group. TRPA1 was lower in TTMZ+AP18, TMZ+SEL+AP18, and SEL+AP18 groups with channel blockers than respectively TMZ, TMZ+SEL, and SEL groups without channel blockers (p < 0.05). Conclusion The use of selenium with temozolomide increased the apoptotic efficacy of temozolomide via TRPA1 channels on tumor cells.

Objectives This study was conducted to explore whether Hypericum perforatum L. (HPL) as a potent antioxidant protects against oxidative stress, cytokine production and caspase expression in muscle (soleus), brain and blood of sciatic nerve injury (SNI)-induced rats. Methods Thirty-five rats were equally divided into five groups. The first and second were used as untreated control and sham control groups, respectively. The third, fourth and fifth were sham + HPL, SNI and SNI + HPL groups, respectively. The third and fifth groups received 30 mg/kg HPL via gastric gavage for 28 days. Key findings High levels of muscle, brain and red blood cell (RBC) lipid peroxidation, plasma cytokine (TNF-α, IL-1β and IL-2), muscle PARP, caspase 3 and 9 expression levels were decreased by HPL treatments. Plasma glutathione peroxidase (GPx) activity, α-tocopherol and melatonin, muscle, brain and RBC reduced glutathione (GSH) concentrations were decreased by SNI induction, whereas their values were increased by HPL treatments. β-carotene and retinol concentrations did not change in the five groups. Conclusion HPL may play a role in preventing SNI-induced inflammatory, oxidative and apoptotic blood, muscle and brain damages through upregulation of the GSH and GPx values but downregulation of PARP, caspase level and cytokine production in SNI-induced rats.

Amaç: Imatinib mesilat bir tirozin kinaz inhibitörüdür ve kronik miyeloid löseminin standart bir birinci basamak tedavisi olarak onaylanmıştır. Kemoterapiye bağlı kardiyotoksisitede oksidatif stresin yanı sıra hücre içi kalsiyum aşırı yüklenmesi ve mitokondriyal disfonksiyon önemli rol oynar. İmatinib ile indüklenen kardiyotoksisitenin neden olduğu altta yatan patofizyolojik mekanizma tam olarak anlaşılamamıştır. Bu çalışmada, geçici reseptör potansiyel melastatin 2 (TRPM2) kanalları üzerinden kalsiyum akışı, oksidatif stres ve apoptozdaki değişimleri araştırdık. Ayrıca, imatinib mesilat kaynaklı kardiyotoksisite sırasında astaksantinin kardiyomiyositlerde modülatör rolü olup olmadığını araştırdık.Gereç ve yöntemler: Hücreler, kontrol, imatinib, imatinib + antranilik asit, imatinib + astaksantin, imatinib + antranilik asit + astaksantin, astaksantin ve astaksantin + antranilik asit grupları olmak üzere yedi ana gruba ayrıldı. Gruplardaki hücreler, ilgili deneylerde TRPM2 kanallarının aktivasyonu ve inaktivasyonu için sırasıyla kümen hidroperoksit ile uyarıldı ve antranilik asit ile inhibe edildi. Sitosolik kalsiyum, hücre içi reaktif oksijen, mitokondriyal depolarizasyon, kaspaz 3 ve kaspaz 9 seviyeleri ölçüldü.Bulgular: Apoptoz değerleri astaksantin ve imatinib + astaksantin grubunda, imatinib grubundaki kardiyomiyositlerden anlamlı olarak daha düşüktü (p, Aim: Imatinib mesylate is a tyrosine kinase inhibitor and is approved as a standard first-line therapy of chronic myeloid leukemia. Oxidative stress, as well as intracellular calcium overload and mitochondrial dysfunction, play an important role in chemotherapy-induced cardiotoxicity. The underlying pathophysiological mechanism associated with imatinib-induced cardiotoxicity is not well understood. In the present study, we investigated alterations in calcium influx, oxidative stress and apoptosis through transient receptor potential melastatin 2 (TRPM2) channels. Also, we aimed to investigate if there is a modulator role of astaxanthin in cardiomyocytes during imatinib mesylate-induced cardiotoxicity. Materials and methods: The cells were divided into seven main control groups: imatinib, imatinib+antranilic acid, imatinib+astaxanthin, imatinib+antranilic acid+astaxanthin, astaxanthin and astaxanthin+antranilic acid groups. Cells in the groups were stimulated with cumene hydroperoxide and inhibited with antranilic acid in related experiments for activation and inactivation of TRPM2 channels, respectively. We measured cytosolic calcium, intracellular reactive oxygene, mitochondrial depolarization, caspase 3 and caspase 9 levels.Results: The apoptosis values were significantly lower in the astaxanthin and the imatinib+astaxanthin group than in the imatinib group of cardiomyocytes (p< 0.001). The cell viability values were significantly higher in the imatinib+astaxanthin+antranilic acid (p

A potent antioxidant, selenium might modulate dementia-induced progression of brain and blood oxidative and apoptotic injuries. The present study explores whether selenium protects against experimental dementia (scopolamine, SCOP)-induced brain, and blood oxidative stress, apoptosis levels, and cytokine production in rats. Thirty-two rats were equally divided into four groups. The first group was used as an untreated control. The second group was treated with SCOP to induce dementia. The third and fourth groups received 1.5 mg/kg selenium (sodium selenite) and SCOP + selenium, respectively. Dementia was induced in the second and forth groups by intraperitoneal SCOP (1 mg/kg) administration. Brain, plasma, and erythrocyte lipid peroxidation levels as well as plasma TNF-α, interleukin (IL)-1β, and IL-4 levels were high in the SCOP group though they were low in selenium treatments. Selenium and selenium + SCOP treatments increased the lowered glutathione peroxidase activity, reduced glutathione, vitamins A and E concentrations in the brain, erythrocytes and plasma of the SCOP group. Apoptotic value expressions as active caspase-3, procaspase-9, and PARP were also increased by SCOP, while they were decreased by selenium and selenium + SCOP treatments. In conclusion, selenium induced protective effects against experimental dementia-induced brain, and blood oxidative injuries and apoptosis through regulation of cytokine production, vitamin E, glutathione concentrations, and glutathione peroxidase activity.

Overload of Ca2+ entry and excessive oxidative stress in neurons are the two main causes of depression. Activation of transient receptor potential (TRP) vanilloid type 1 (TRPV1) and TRP melastatin 2 (TRPM2) during oxidative stress has been linked to neuronal survival. Duloxetine (DULOX) in neurons reduced the effects of Ca2+ entry and reactive oxygen species (ROS) through glutamate receptors, and this reduction of effects may also occur through TRPM2 and TRPV1 channels. In order to better characterize the actions of DULOX in peripheral pain and hippocampal oxidative injury through modulation of TRPM2 and TRPV1, we tested the effects of DULOX on apoptosis and oxidative stress in the hippocampal and dorsal root ganglion (DRG) neurons of rats. Freshly isolated hippocampal and DRG neurons were incubated for 24 h with DULOX. In whole-cell patch-clamp and intracellular-free calcium ([Ca2+]) concentration (Fura-2) experiments, cumene hydroperoxide and ADP-ribose-induced TRPM2 currents in the neurons were inhibited by N-(p-amylcinnamoyl) anthranilic acid (ACA) and capsaicin-induced TRPV1 currents were inhibited by capsazepine (CPZ) incubations. TRPM2 and TRPV1 channel current densities, [Ca2+] concentration, apoptosis, caspase 3, caspase 9, mitochondrial depolarization, and intracellular ROS production values in the neurons were lower in the DULOX group than in controls. In addition, the above values were further decreased by DULOX + CPZ and DULOX + ACA treatments. In conclusion, TRPM2 and TRPV1 channels are involved in Ca2+ entry-induced neuronal death and modulation of the activity of these channels by DULOX treatment may account for their neuroprotective activity against apoptosis, excessive ROS production, and Ca2+ entry.

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.

In breast cancers, calcium signaling is a main cause of proliferation and apoptosis of breast cancer cells. Although previous studies have implicated the transient receptor potential vanilloid 1 (TRPV1) cation channel, the synergistic inhibition effects of selenium (Se) and cisplatin in cancer and the suppression of ongoing apoptosis have not yet been investigated in MCF-7 breast cancer cells. This study investigates the anticancer properties of Se through TRPV1 channel activity in MCF-7 breast cancer cell line cultures when given alone or in combination with cisplatin.The MCF-7 cells were divided into four groups: the control group, the Se-treated group (200 nM), the cisplatin-treated group (40 μM) and the Se + cisplatin-treated group.The intracellular free calcium ion concentration and current densities increased with TRPV1 channel activator capsaicin (0.01 mM), but they decreased with the TRPV1 blocker capsazepine (0.1 mM), Se, cisplatin, and Se + cisplatin incubations. However, mitochondrial membrane depolarization, apoptosis, and the caspase 3, and caspase 9 values increased in the Se-treated group and the cisplatin-treated group, although Western blot (procaspase 3 and 9) results and the cell viability levels decreased with the Se and Se + cisplatin treatments. Apoptosis and caspase-3 were further increased with the Se + cisplatin treatment. Intracellular reactive oxygen species production increased with the cisplatin treatment, but not with the Se treatment.This study's results report, for the first time, that at a cellular level, Se and cisplatin interact on the same intracellular toxic cascade, and the combination of these two drugs can result in a remarkable anticancer effect through modulation of the TRPV1.

Neuropathic pain and hippocampal injury can arise from the overload of diabetes-induced calcium ion (Ca2+) entry and oxidative stress. The transient receptor potential (TRP) melastatin 2 (TRPM2) and TRP vanilloid type 1 (TRPV1) are expressed in sensory neurons and hippocampus. Moreover, activations of TRPM2 and TRPV1 during oxidative stress have been linked to neuronal death. Melatonin (MEL) and selenium (Se) have been considered potent antioxidants that detoxify a variety of reactive oxygen species (ROS) in neurological diseases. In order to better characterize the actions of MEL and Se in diabetes-induced peripheral pain and hippocampal injury through modulation of TRPM2 and TRPV1, we tested the effects of MEL and Se on apoptosis and oxidative stress in the hippocampal and dorsal root ganglion (DRG) neurons of streptozotocin (STZ)-induced diabetic rats. Fifty-eight rats were divided into six groups. The first group was used as control. The second group was used as the diabetic group. The third and fourth groups received Se and MEL, respectively. Intraperitoneal Se and MEL were given to diabetic rats in the fifth and sixth groups. On the 14th day, hippocampal and DRG neuron samples were freshly taken from all animals. The neurons were stimulated with a TRPV1 channel agonist (capsaicin) and a TRPM2 channel agonist (cumene hydroperoxide). We observed a modulator role of MEL and Se on intracellular free Ca2+ concentrations, current densities of TRPM2 and TRPV1 channels, apoptosis, caspase 3, caspase 9, mitochondrial depolarization, reduced glutathione, glutathione peroxidase, lipid peroxidation, and intracellular ROS production values in the neurons. In addition, procaspase 3 and 9 activities in western blot analyses of the brain cortex were also decreased by MEL and Se treatments. In conclusion, in our diabetes experimental model, TRPM2 and TRPV1 channels are involved in the Ca2+ entry-induced neuronal death and modulation of this channel activity by MEL and Se treatment may account for their neuroprotective activity against apoptosis and Ca2+ entry. Graphical Abstract Possible molecular pathways of involvement of melatonin and selenium in diabetes-induced apoptosis, oxidative stress, and calcium accumulation through TRPM2 and TRPV1 channels in the hippocampus and DRG neurons of rats. The TRPM2 channel is activated by ADP-ribose and oxidative stress although it is inhibited by ACA. The TRPV1 channel is activated by oxidative stress and capsaicin and it is blocked by capsazepine (CPZ). Diabetes can result in augmented ROS release in hippocampal and DRG neurons through polyol reactions, leading to Ca2+ uptake through TRPM2 and TRPV1 channels. Mitochondria were reported to accumulate Ca2+ provided intracellular Ca2+ rises, thereby leading to the depolarization of mitochondrial membranes and release of apoptosis-inducing factors such as caspase 3 and caspase 9. Melatonin and selenium reduce TRPM2 and TRPV1 channel activation through the modulation of polyol oxidative reactions and selenium-dependent glutathione peroxidase (GSH-Px) antioxidant pathways.

Calcium ions (Ca2+) are important second messengers in neurons. Ketamine (KETAM) is an anesthetic and analgesic, with psychotomimetic effects and abuse potential. KETAM modulates the entry of Ca2+ in neurons through glutamate receptors, but its effect on transient receptor potential melastatin 2 (TRPM2) and transient receptor potential vanilloid 1 (TRPV1) channels has not been clarified. This study investigated the short-term effects of KETAM on oxidative stress and TRPM2 and TRPV1 channel gating in hippocampal and dorsal root ganglion (DRG) neurons of rats. Freshly isolated hippocampal and DRG neurons were incubated for 24 h with KETAM (0.3 mM). The TRPM2 channel antagonist, N-(p-amylcinnamoyl)anthranilic acid (ACA), inhibited cumene hydroperoxide and ADP-ribose-induced TRPM2 currents in the neurons, and capsazepine (CPZ) inhibited capsaicin-induced TRPV1 currents. The TRPM2 and TRPV1 channel current densities and intracellular free calcium ion concentration of the neurons were lower in the neurons exposed to ACA and CPZ compared to the control neurons, respectively. However, the values were not further decreased by the KETAM + CPZ and KETAM + ACA treatments. KETAM decreased lipid peroxidation levels in the neurons but increased glutathione peroxidase activity. In conclusion, short-term KETAM treatment decreased oxidative stress levels but did not seem to influence TRPM2- and TRPV1-mediated Ca2+ entry.

The original version of this article unfortunately contained few errors. The dose of sodium selenite was incorrectly indicated as 100 μM in the published version of “Selenium enhances TRPA1 channel-mediated activity of temozolomide in SH-SY5Y neuroblastoma cells”. The correct indication of sodium selenite is 5 µM. Additionally the authors accidenttally referred to reference 11 instead of reference 10 in Group 6.

Aim : 5-fluorouracil has been widely used in breast cancer treatment. Low level laser therapy (LLLT) has been shown to modulate biological processes and used in cancer treatment. It has been reported that apoptosis is induced by stimulation of transient receptor potential protein channels in numerous cancer cells, including breast cancer. We aimed to reveal the effects of 5-fluorouracil / Leucovorin (5-FU/LV) and . low level laser on apoptosis via transient receptor protein ancyrin 1 (TRPA1) channels. Material and Methods: Breast cancer cells (MCF-7) were cultured and cells were divided into seven main groups. Cells were incubated with 5-FU/LV and LLLT exposure separately and together performed on MCF-7 cell cultures. Cell cultures incubated with TRPV1 channel antagonist capsazepin and stimulator capsaicin. The effects of 5-FU and LLLT were investigated on all molecular pathways of apoptosis. Results: It was found that the levels of apoptosis in 5-FU/LV group were significantly increased in cancer cells compared to control group .TRPA1 channel stimulator administration resulted in significantly increased apoptosis levels compared to the control group, in 5-FU/LV + low level laser group the apoptosis level significantly reduced compared to 5-FU/LV-only group. (p

Scientific Reports 6; Article number: 37196; published online: 22 November 2016; updated: 04 July 2018 In this Article, the legend of Figure 2 contains errors. The two instances of ‘TRPM2’ should read ‘TRPV1’. Figure 3 contains errors. Figure 3c was inadvertently duplicated from Figure 4c. Figure 3eis incorrect.

OZ, Ahmi/0000-0003-1881-8460 WOS: 000437757500009 PubMed: 29081061 Increased intracellular free calcium ion (Ca2+) concentration induces excessive oxidative stress and apoptosis. Medical procedures such as zoledronic acid (Zol), bevacizumab (Bev), and dexamethasone (Dex) are usually used in the treatment of bone diseases (osteoporosis, Paget's disease, etc.) and to prevent metastasis in the bone although the procedures induce osteonecrosis of the jaw through excessive production of reactive oxygen species (ROS). Recently, we observed regulator roles of selenium (Se) on apoptosis and Ca2+ entry through transient receptor potential vanilloid 1 (TRPV1) channels in the cancer cell lines. Therefore, Se may modulate Zol, Bev, and Dex-induced oxidative stress and apoptosis through regulation of TRPV1 channel. In the current study, we investigated the protective effects of Se on apoptosis and oxidative stress through TRPV1 in Zol, Bev, and Dex-induced osteoblast-like cell line. We used human osteoblast-like cell line (Saos-2), and the cells were divided into 12 groups as control, Zol, Bev, Dex, Se, Zol+Se, Bev+Se, Dex+Se, Zol+Dex, Zol+Dex+Se, Zol+Bev, and Zol+Bev+Se which were incubated with drugs (Zol, Bev, Dex, and Se) for 24 h. The cytosolic free Ca2+ concentration was increased by Zol, Bev, Dex, Zol+Bev, and Zol+Dex, although it was reduced by Se treatment. However, Zol, Bev, and Dex-induced increase in apoptosis, caspase 3, caspase 9, poly (ADP-ribose) polymerase 1 expression levels, and intracellular ROS production values in the cells were decreased by Se treatments. In conclusion, we observed that Zol, Bev, and Dex-induced apoptosis, mitochondrial oxidative stress, and calcium signaling are decreased in human osteoblast-like cell line by the Se treatment. Our findings may be relevant to the etiology and treatment of Zol, Bev, and Dex-induced osteonecrosis by Se. Scientific Project Unit of SDUSuleyman Demirel University [4475-OYP-D2-15, OYP05259-DR-12] The abstract of the study as poster presentation was published in the ACBID 10th International Congress, held 11 and 15 May 2016 in Antalya, Turkey (www.acbid.org). The study was supported by Scientific Project Unit of SDU (Protocol No: 4475-OYP-D2-15 and Protocol No: OYP05259-DR-12). All authors approved the final manuscript.

Transient receptor transient receptor potential vanilloid 1 (TRPV1) is a Ca(2+)-permeable channel gated by oxidative stress and capsaicin (CAP) and modulated by melatonin (MEL) and capsazepine (CPZ). A combination of doxorubicin (DOX) and MEL may offer a potential therapy for breast cancer by exerting antitumor and anti-apoptotic effects and modulating Ca(2+) influx and TRPV1 activity. We aimed to investigate the effects of MEL and DOX on the oxidative toxicity of MCF-7 human breast cancer cells, in addition to the activity of the TRPV1 channel and apoptosis. The MCF-7 cells were divided into the following six treatment groups: control, incubated with MEL (0.3 mM), incubated with 0.5 μM DOX, incubated with 1 μM DOX, incubated with MEL + 0.5 μM DOX, or incubated with MEL + 1 μM DOX. The intracellular free Ca(2+) concentration was higher in the DOX groups than in the control, and the concentration was decreased by MEL. The intracellular free Ca(2+) concentration was further increased by treatment with the TRPV1 channel activator CAP (0.01 mM), and it was decreased by the CPZ (0.1 mM). The intracellular production of reactive oxygen species, mitochondrial membrane depolarization, apoptosis level, procaspase 9 and PARP activities, and caspase 3 and caspase 9 activities were higher in the DOX and MEL groups than in the control. Apoptosis and the activity of caspase 9 were further increased in the DOX plus MEL groups. Taken together, the findings indicate that MEL supported the effects of DOX by activation of TRPV1 and apoptosis, as well as by inducing MCF-7 cell death. As the apoptosis and caspase activity of cancer cells increase because of their elevated metabolism, MEL may be useful in supporting their apoptotic capacity.

Transient Receptor Potential (TRP) channels superfamily has mostly calcium ion (Ca2+) permeable non-selective cation channels. Transient receptor potential melastatin subfamily 2 (TRPM2) is widely expressed in central nervous system. Intracellular Ca2+ concentration ([Ca2+]i) may change depend on TRPM2 and TRPM8 activations from extracellular liquid to cytosol. Curcumin as natural antioxidant shows phenolic structure, synthesized by Curcuma longa L. (Indian saffron, turmeric), has powerful non-enzymatically antioxidant effects. Low dose curcumin treatment can decrease calcium signaling via TRPM2 channel inhibition and prevent elevation of [Ca2+]i levels. Hence, we investigated effects of four different concentrations (5, 10, 25 and 50 µM) of curcumin on apoptosis and cell viability (MTT), reactive oxygen species (ROS) production, mitochondrial membrane potential levels, caspase 3 and caspase 9 values in DBRG glioblastoma cells. We found that curcumin reduces cell viability by concentration dependent manner. It was also observed that curcumin induces apoptosis via caspase 3 and 9 related pathways. However, it was not found any direct relationship between the effect of increased concentrations of curcumin and inhibition or activation of TRPM2 mediated Ca2+ signaling in the DBTRG cells. The [Ca2+]i concentration was lower in 5 µM group as compare to control group. Curcumin acted important role on decrease of mitochondrial membrane potential and intracellular ROS production in the cells. Moreover, curcumin treatment markedly supported GSH concentration levels in the cells. In conclusion, it was firstly assessed the effects of different doses of curcumin on TRPM2 mediated calcium signaling and interaction with various apoptosis parameters in DBTRG glioblastoma cells.

Hypericum perfortarum (HP, St John's wort) is a modulator of Ca(2+) entry in neutrophils and it may modulate intracellular free Ca(2+) ([Ca(2+)]i) entry in leukocytes of patients with multiple sclerosis (MS). We investigated effects of HP on oxidative stress, apoptosis, and [Ca(2+)]i concentrations in serum and leukocytes of patients with MS.Neutrophils of nine newly diagnosed MS patients and nine healthy subjects within four subgroups were used in the study. The first group was a control; the second group was patients with MS. The neutrophils from patient group were incubated non-specific TRPM2 channel blocker (2-APB), voltage-gated calcium channel blockers, verapamil and diltiazem (V + D) with HP before N-formyl-L-methionyl-L-leucyl-L-phenylalanine stimulation, respectively.Neutrophil and serum lipid peroxidation, neutrophil apoptosis and [Ca(2+)]i levels in patients with MS were higher than in control although their levels were decreased by HP, 2-APB, and V + D incubations. The modulator role of V + D in MS and MS + HP groups was higher than in the 2-APB group. Neutrophilic glutathione peroxidase (GSH-Px) and serum vitamin A and E concentrations were lower in the MS group than in control. However, the neutrophil GSH-Px activity was increased by HP incubation. The neutrophil reduced glutathione, serum vitamin C and β-carotene concentrations did not change in control and patients.We observed that HP-induced protective effects on oxidative stress and [Ca(2+)]i concentrations by modulating transient receptor potential and voltage gated calcium channel in the patients with MS. Thus, it may provide useful treatment of neutrophil activity in the patients.

Dexmedetomidine (DEX) may act as an antioxidant through regulation of TRPM2 and TRPV1 channel activations in the neurons by reducing cerebral ischemia-induced oxidative stress and apoptosis. The neuroprotective roles of DEX were tested on cerebral ischemia (ISC) in the cultures of rat primary hippocampal and DRG neurons. Fifty-six rats were divided into five groups. A placebo was given to control, sham control, and ISC groups, respectively. In the third group, ISC was induced. The DEX and ISC+DEX groups received intraperitoneal DEX (40 μg/kg) 3, 24, and 48 hours after ISC induction. DEX effectively reversed capsaicin and cumene hydroperoxide/ADP-ribose-induced TRPV1 and TRPM2 densities and cytosolic calcium ion accumulation in the neurons, respectively. In addition, DEX completely reduced ISC-induced oxidative toxicity and apoptosis through intracellular reactive oxygen species production and depolarization of mitochondrial membrane. The DEX and ISC+DEX treatments also decreased the expression levels of caspase 3, caspase 9, and poly (ADP-ribose) polymerase in the hippocampus and DRG. In conclusion, the current results are the first to demonstrate the molecular level effects of DEX on TRPM2 and TRPV1 activation. Therefore, DEX can have remarkable neuroprotective impairment effects in the hippocampus and DRG of ISC-induced rats.

Overload of Ca

Inhibition of Ca2+ entry into the hippocampus and dorsal root ganglion (DRG) through inhibition of N-methyl-D-aspartate (NMDA) receptor antagonist drugs is the current standard of care in neuronal diseases such as Alzheimer's disease, dementia, and peripheral pain. Oxidative stress activates Ca2+-permeable TRPM2 and TRPV1, and recent studies indicate that selenium (Se) is a potent TRPM2 and TRPV1 channel antagonist in the hippocampus and DRG. In this study, we investigated the neuroprotective properties of Se in primary hippocampal and DRG neuron cultures of aged rats when given alone or in combination with scopolamine (SCOP). Thirty-two aged (18-24 months old) rats were divided into four groups. The first and second groups received a placebo and SCOP (1 mg/kg/day), respectively. The third and fourth groups received intraperitoneal Se (1.5 mg/kg/ over day) and SCOP + Se, respectively. The hippocampal and DRG neurons also were stimulated in vitro with a TRPV1 channel agonist (capsaicin) and a TRPM2 channel agonist (cumene hydroperoxide). We found that Se was fully effective in reversing SCOP-induced TRPM2 and TRPV1 current densities as well as errors in working memory and reference memory. In addition, Se completely reduced SCOP-induced oxidative toxicity by modulating lipid peroxidation, reducing glutathione and glutathione peroxidase. The Se and SCOP + Se treatments also decreased poly (ADP-ribose) polymerase activity, intracellular free Ca2+ concentrations, apoptosis, and caspase 3, caspase 9, and mitochondrial membrane depolarization values in the hippocampus. In conclusion, the current study reports on the cellular level for SCOP and Se on the different endocytotoxic cascades for the first time. Notably, the research indicates that Se can result in remarkable neuroprotective and memory impairment effects in the hippocampal neurons of rats. Graphical abstract Possible molecular pathways of involvement of selenium (Se) in scopolamine (SCOP) induced apoptosis, oxidative stress, and calcium accumulation through TRPM2 and TRPV1 channels in the hippocampus neurons of aged rats. The TRPM2 channel is activated by ADP-ribose and oxidative stress, although it is inhibited by ACA. The TRPV1 channel is activated by oxidative stress and capsaicin, and it is blocked by capsazepine (CPZ). The beta-amyloid plaque induces oxidative stress in hippocampus. SCOP can result in augmented ROS release in hippocampal neurons, leading to Ca2+ uptake through TRPM2 and TRPV1 channels. Mitochondria were reported to accumulate Ca2+ provided that intracellular Ca2+ rises, thereby leading to the depolarization of mitochondrial membranes and release of apoptosis-inducing factors such as caspase 3 and caspase 9. Se reduced TRPM2 and TRPV1 channel activation through the modulation of aging oxidative reactions and Se-dependent glutathione peroxidase (GSH-Px) antioxidant pathways.

Non-ionic contrast media (CM) can induce tissue kidney injury via activation of phagocytosis and oxidative stress, although the mechanisms of injury via neutrophils are not clear. We investigated the effects of CM on oxidative stress and Ca2+ concentrations in serum and neutrophils of humans. Ten migraine patients were used in the study. Serum and neutrophil samples from patients’ peripheral blood were obtained before (control) and 30 min after non-ionic (iopromide) CM injection. The neutrophils were incubated with non specific transient receptor potential 2 (TRPM2) channel blocker, 2-aminoethoxydiphenyl borate (2-APB), and voltage gated Ca2+ channel blockers, verapamil plus diltiazem. Serum and neutrophil lipid peroxidation, apoptosis and intracellular Ca2+ concentrations levels were higher in the CM group than in controls. The neutrophilic reduced glutathione (GSH) and glutathione peroxidase (GSH-Px) levels as well as serum vitamin E and β-carotene concentrations were lower in the CM group than in controls. Neutrophil lipid peroxidation levels were lower in the CM+2-APB and CM+verapamil-diltiazem groups than in the CM group, although GSH, GSH-Px and intracellular Ca2+ values increased in the CM+2-APB and CM+verapamil-diltiazem groups. However, caspase-3, caspase-9, vitamin A and vitamin C values were unaltered by CM treatment. In conclusion, we observed that CM induced oxidative stress and Ca2+ influx by decreasing vitamin E, β-carotene and Ca2+ release levels in human serum and neutrophils. However, we observed protective effects of Ca2+ channel blockers on Ca2+ influx in neutrophils.

The aim of this study was to investigate the levels of the oxidant and antioxidant changes in orthodontic tooth movement and the effects of vitamin E on these parameters. For this purpose, 50 orthodontic patients (aged 13-18 years) required non-extracted treatment were divided randomly into the following groups: Control and Vitamin E. Same pre-adjusted appliances were applied to all patients, and vitamin E (300 mg day(-1)) was given during 1 month in vitamin E group. Gingival crevicular fluid was collected and periodontal indexes were recorded at the baseline and after 1 month. Lipid peroxidation (LP) levels as malonyldialdehyde, reduced glutathione (GSH) and glutathione peroxidase (GSH-Px), vitamin C and E levels were measured in the anterior and posterior regions of the dentition. After 1 month, orthodontic treatment LP levels increased in control group in both anterior and posterior regions in vitamin E group. LP levels also increased in vitamin E group in only posterior region. The level of GSH and vitamin C did not change statistically in control and vitamin E groups. Periodontal indexes did not show any differences in comparison with the groups. In conclusion, we observed protective role of vitamin E on LP levels in anterior region of patients with orthodontic tooth movement.

Behcet disease (BD) is a chronic, inflammatory, and multisystemic condition with an uncertain pathogenesis. One of the major immunologic findings in BD pathogenesis is increase in activity of neutrophil. An increase in the cytosolic free Ca²⁺[Ca²⁺](i) concentration that induces Ca²⁺ signaling is an important step that participates in the neutrophil activation and reactive oxygen species production that leads to tissue damage in body cells. We aimed to investigate the effects of colchicine on oxidative stress and Ca²⁺ release in serum and neutrophil of BD patients with active and inactive periods. Twelve Behcet patients (6 active and 6 inactive) and 6 control subject were included in the study. Disease activity was considered by clinical findings. Serum and neutrophil samples were obtained from the patients and control subjects. Neutrophils from patients with active BD were divided into three subgroups and were incubated with colchicine, verapamil + diltiazem, and colchicine + verapamil + diltiazem, respectively. Erythrocyte sedimentation rate, leucocytes counts, serum C-reactive protein, neutrophil, and serum lipid peroxidation and intracellular Ca²⁺ release levels were higher in active and inactive groups than in the control group, although their levels were lower in active group than in inactive group. However, neutrophil Ca²⁺ release levels were decreased in colchicine, verapamil + diltiazem, and colchicine + verapamil + diltiazem groups group compared to active group. Serum glutathione, vitamin A, vitamin E, and β-carotene concentrations were lower in active and inactive groups than in the control group, although serum vitamin E and β-carotene concentrations were higher in the inactive group than in the active group. Neutrophil and serum glutathione peroxidase activity within the three groups did not change. In conclusion, we observed the importance of Ca²⁺ influx into the neutrophils and oxidative stress in the pathogenesis and activation of the patients with BD. Colchicine induced protective effects on oxidative stress by modulating Ca²⁺ influx in BD patients.

We investigated the effects of acamprosate on alcohol-induced oxidative toxicity, microsomal membrane Ca(2+)-ATPase (MMCA) activity and N-methyl-D: -aspartate receptor (NMDAR) subunits in rat brain. Forty male rats were equally divided into four groups. The first group was used as control, and the second group received ethanol. Acamprosate and acamprosate plus ethanol each day were administered to rats constituting the third and fourth groups for 21 days, respectively. Brain cortical and hippocampal samples were taken from the four groups after 21 days. Brain cortical lipid peroxidation (LP) levels and MMCA activity were higher in the alcohol group than in control, although glutathione peroxidase (GSH-Px), vitamin C, vitamin E and β-carotene values were lower in the alcohol group than in control. LP levels were further increased in the acamprosate and alcohol + acamprosate groups compared with the alcohol group. GSH-Px, vitamin A, vitamin C, vitamin E and β-carotene in the acamprosate and alcohol + acamprosate groups were further decreased compared with the alcohol group. Hippocampal NMDAR 2A and 2B subunit concentrations were lower in the alcohol group than in control, although they were increased by acamprosate and alcohol + acamprosate. Brain cortical MMCA activity was higher in the acamprosate group than in the alcohol-treated rats, although its activity was lower in the alcohol + acamprosate group than in the acamprosate group. Brain cortical reduced glutathione levels were not found to be statistically different in any of the groups. Oxidative stress has been proposed to explain the biological side effects of experimental alcohol intake. Acamprosate and alcohol-induced oxidative stress decreased brain antioxidant vitamins in the alcoholic rats.

Neuropathic pain and hippocampal injury can arise from the overload of diabetes-induced calcium ion (Ca