Mitotherapy inhibits against tenofovir induced nephrotoxicity on rat renal proximal tubular cells.

Tenofovir, as nucleotide reverse transcriptase inhibitors (NRTIs), is used to prevent and cure HIV/AIDS. Ample evidence confirmed that the nephrotoxicity of tenofovir has been linked to mitochondrial dysfunction. It seems that transplantation with healthy mitochondria instead of damaged mitochondria may be a beneficial approach to therapy. Therefore, it decided to investigate the impact of mitotherapy on tenofovir against renal proximal tubular cells (RPTCs) toxicity by measurement of oxidative stress and cytotoxicity biomarkers and restoring of mitochondrial function on isolated mitochondria. EC50 of tenofovir was achieved at 40 µM following 2 h incubation in Earle's solution (pH = 7.4; 37 °C). Freshly isolated mitochondria (80 µg/ml) were added to damage RPTCs affected by tenofovir in treated groups. One Way ANOVA analysis showed that healthy mitochondrial transplantation decreased oxidative stress biomarkers following tenofovir toxicity in RPTCs. Our data revealed that mitotherapy makes cell survival possible in RPTCs affected by tenofovir. In addition, it supposed that a novel and ideal strategy for the treatment of chemicals-induced nephrotoxicity.

The Effect of Donor Rat Gender in Mitochondrial Transplantation Therapy of Cisplatin-Induced Toxicity on Rat Renal Proximal Tubular Cells.

Background: Cisplatin-induced nephrotoxicity has been linked to a fundamental mechanism of mitochondrial dysfunction. A treatment called mitochondrial transplantation therapy can be used to replace damaged mitochondria with healthy mitochondria. Mitochondrial-related diseases may benefit from this approach. Objectives: We investigated the effect of mitochondrial transplantation on cisplatin-induced nephrotoxicity using freshly isolated mitochondria obtained from renal proximal tubular cells (RPTCs). Methods: Based on our previous findings, we hypothesized that direct exposure of healthy mitochondria to cisplatin-affected RPTCs might improve cytotoxicity markers and restore mitochondrial function. Therefore, the primary objective of this study was to determine whether newly isolated mitochondrial transplantation protected RPTCs from cisplatin-induced cytotoxicity. The supply of exogenous rat kidney mitochondria to cisplatin-affected RPTCs was also a goal of this study to investigate the possibility of gender differences. After the addition of cisplatin (100 µM), rat RPTCs (106 cells/mL) were suspended in Earle's solution (pH = 7.4) at 37°C for two hours. Freshly isolated mitochondria were extracted at 4°C and diluted in 100 and 200 µg/mL mitochondrial protein. Results: Statistical analysis revealed that transplantation of healthy mitochondria decreased ROS level, mitochondrial membrane potential (MMP) collapse, MDA level, glutathione depletion, lysosomal membrane damage, and caspase-3 activity induced by cisplatin in rat RPTCs. In addition, our results demonstrated that transplantation of female rat kidney mitochondria has higher protective activity at reducing toxicity parameters than male mitochondria. Conclusions: The findings reaffirmed that mitochondrial transplantation is a novel, potential, and promising therapeutic strategy for xenobiotic-induced nephrotoxicity.

The Effect of Physical Exercise Pretreatment on Spatial Memory and Learning and Function of Mitochondria in the Brain in Type 2 Diabetic Rats.

Background: The prevalence of type 2 diabetes mellitus (T2DM) is increasing worldwide, and this issue is one of the major concerns in the pending years. T2DM causes numerous complications, including cognition, learning, and memory impairments. The positive effect of physical exercise as a popular approach has been shown in many chronic diseases. Further, the improvement effects of exercise on cognition and memory impairment have been noticed. Objectives: This study examines the possible preventative effects of physical exercise on spatial memory attenuation and brain mitochondrial dysfunction caused by T2DM. Methods: Male Wistar rats received treadmill exercise (30 min per day, five days per week for two or four weeks). Then, T2DM was induced by a high-fat diet and an injection of streptozotocin (30 mg/kg). Spatial learning and memory were assessed by the Morris water maze test. Further, brain mitochondrial function, including reactive oxygen species (ROS) generation, mitochondrial membrane potential (MMP), mitochondrial swelling, outer membrane damage, cytochrome c release, and ADP/ATP ratio, were measured. Results: Impaired spatial memory in T2DM rats was observed. Furthermore, brain mitochondrial dysfunction was demonstrated proved by increased ROS generation, MMP collapse, mitochondrial swelling, outer membrane damage, cytochrome c release, and ADP/ATP ratio. Conversely, physical exercise, before diabetes onset, significantly ameliorated spatial memory impairment and brain mitochondrial dysfunction. Conclusions: This study reveals that physical exercise could prevent diabetes-induced spatial memory impairment. Moreover, it could ameliorate brain mitochondrial dysfunction as one of the possible underlying mechanisms of spatial memory impairment in T2DM.

Toxicity of superparamagnetic iron oxide nanoparticles on retinoblastoma mitochondria.

PURPOSE: Retinoblastoma (RB) is one of the most important cancers in children with a higher rate of prevalence in developing countries. Despite different approaches to the treatment of RB, it seems necessary to discover a new approach to its treatment. Today, mitochondria are recognised as an important target in the treatment of cancer. Superparamagnetic iron oxide nanoparticles (SPIONs) have been studied by researchers due to their important biological effects. METHODS: In this study, the effects of SPIONs on mitochondria isolated from Y79 retinoblastoma cells were investigated. RESULTS: The results showed that SPIONs were able to increase the reactive oxygen species (ROS) level and subsequently damage the mitochondrial membrane and release cytochrome c a as one of the important pro-apoptotic proteins of RB mitochondria. Furthermore, the results indicated a decrease in cell viability and an increase in caspase-3 activity in Y79 retinoblastoma cells. CONCLUSIONS: These events can lead to the killing of cancerous mitochondria. Our results suggest that SPIONs can cause mitochondrial dysfunction and death in RB mitochondria.

Protective effect of a standardized Allium jesdianum extract in an Alzheimer's disease induced rat model.

Alzheimer's disease (AD) is a complex disorder with multiple underlying mechanisms. Existing treatment options mostly address symptom management and are associated with numerous side effects. Therefore, exploring alternative therapeutic agents derived from medicinal plants, which contain various bioactive compounds with diverse pharmacological effects, holds promise for AD treatment. This study aims to assess the protective effects of the hydroalcoholic extract of Allium jesdianum on cognitive dysfunction, mitochondrial and cellular parameters, as well as genetic parameters in an intracerebroventricular Streptozotocin (icv-STZ) induced rat model of AD. Male Wistar rats were injected with a single dose of STZ (3 mg/kg, icv) to establish a sporadic AD model. A. jesdianum extract (100, 200, and 400 mg/kg/day) and donepezil (5 mg/kg/day) were orally administered for 14 days following model induction. Cognitive function was evaluated using the radial arm water maze test. Mitochondrial toxicity parameters in various brain regions (whole brain, frontal cortex, hippocampus, and cerebellum) were assessed. Gene expression analysis of miR-330, miR-132, Bax, and Bcl-2 in isolated rat brain neurons was performed using RT-qPCR. A. jesdianum extract significantly attenuated cognitive dysfunction and mitigated mitochondrial toxicity induced by icv-STZ administration. Following STZ injection, there was upregulation of Bax gene expression and downregulation of miR-330, miR-132, and Bcl-2 gene expression. Treatment with A. jesdianum extract resulted in the reversal of the expression of these microRNAs and genes, indicating its potential for improving AD and reducing neuronal apoptosis. This study demonstrates the neuroprotective capabilities of A. jesdianum against STZ-induced oxidative stress and cognitive impairment in rats, highlighting its therapeutic potential in the management of AD.

Mitochondrial transplantation attenuates toxicity in rat renal proximal tubular cells caused by Favipiravir.

OBJECTIVES: Exogenous mitochondria transplantation or mitotherapy can be used to swap out unhealthy mitochondria for functioning ones. Treatment of mitochondrial diseases using this approach may be beneficial. METHODS: In this study, we looked at the effect of transplanting newly isolated mitochondria on the toxicity that favipiravir (FAV) causes in renal proximal tubular cells (RPTCs). In this study, parameters such as lactate dehydrogenase (LDH) leakiness, reactive oxygen species (ROSs) production, damage to the lysosome membrane, reduced glutathione (GSH) content, extracellular oxidized glutathione (GSSG) content, GSH/GSSG ratio, ATP level, mitochondrial membrane potential (MMP) collapse, Bcl-2 content, and caspase-3 activity were used to assess the protective effects of mitochondrial transplantation against FAV-induced mitochondrial toxicity. KEY FINDINGS: The statistical analysis showed that the cytotoxicity, ROS production, MMP collapse, lysosomal damage, GSSG levels, and caspase-3 activity brought on by FAV in RPTCs were reduced by transplanting the healthy mitochondria. In addition, it led to an increase in ATP level, GSH content, Bcl-2 content, and GSH/GSSG ratio in RPTCs. CONCLUSIONS: A recent study found that mitochondrial transplantation is a powerful therapeutic approach for treating nephrotoxicity brought on by xenobiotics.

Inhalation of multi-wall carbon nanotubes changes the expression of apoptosis and cancer genes in rat brain and lungs.

One of the important issues in urban areas is air pollution which causes respiratory disorders. A significant association between exposure to inhaled particulate matter (PM), mainly ultrafine particles, and increased neurological and pulmonary morbidity and mortality was observed in some research. This study aimed to demonstrate the relation between multi-wall carbon nanotubes (MWCNTs) inhalation and the carcinogenic effect of these materials in the brain and lungs. For this purpose, we investigated gene expression in rat brain and lung tissues induced by exposure to MWCNTs. Rats were exposed to MWCNTs in diameters of 10 and 100 nm (pure and impure) at a concentration of 5 mg/m3. Exposure was done through a whole-body exposure chamber for 5 h/day, 5 days/week for 14 days. After exposure, both brain and lung tissues were isolated to evaluate certain gene expressions including Bax, Bcl2, Rac1, Tp53, Mmp12, and Arc. The results showed that exposure to impure and pure MWCNTs (10 and 100 nm) at a concentration of 5 mg/m3 causes up-regulation or down-regulation of some of these genes. The results suggest that impure and pure MWCNTs (10 and 100 nm) can increase the risk of central nervous system disorders such as Alzheimer's disease and increase the risk of carcinogenesis in the lung tissues of rats exposed to MWCNTs (Tab. 2, Fig. 2, Ref. 64). Text in PDF www.elis.sk Keywords: multi-wall carbon nanotube, inhalation, gene expression, carcinogenicity, brain, lung.

Antioxidants and mitochondrial/lysosomal protective agents reverse toxicity induced by titanium dioxide nanoparticles on human lymphocytes.

Most of the literature has focused on titanium dioxide (TiO2) nanoparticles (NPs) toxicity, showing the importance of oxidative stress, mitochondrial dysfunction, and cell death in TiO2-induced toxicity. For this purpose, in the current study, we investigated the protective role of antioxidant and mitochondrial/lysosomal protective agents to minimize TiO2 NPs-induced toxicity in human lymphocytes. Human lymphocytes were obtained from heathy individuals and treated with different concentrations (80, 160, and 320 µg/mL) of TiO2 NPs, and then human lymphocytes preincubated with butylated hydroxytoluene (BHT), cyclosporin A (CsA), and chloroquine separately were exposed to TiO2 NPs for 6 h. In all the above-mentioned treated groups, adverse parameters such as cytotoxicity, reactive oxygen species (ROS), mitochondrial membrane potential (MMP), lysosomal membrane destabilization, the levels of malondialdehyde (MDA), and glutathione (GSH) were measured. The results showed that TiO2 nanoparticles induced cytotoxicity through ROS formation, MMP collapse, lysosomal damages, depletion of GSH, and lipid peroxidation. However, BHT as an antioxidant, CsA as a mitochondrial permeability transition (MPT) pore sealing agent, and chloroquine as a lysosomotropic agent, significantly inhibited all the TiO2 NPs-induced cellular and organelle toxicities. Thus, it seems that antioxidant and mitochondrial/lysosomal protective agents are promising preventive strategies against TiO2 NPs-induced toxicity.

The Selective Cytotoxicity of Quercus Brantii Lindl. Galls on A375 and SK-MEL-3 Human Malignant Melanoma Cell Lines.

This study aimed to find out the mechanism of cytotoxic effects of galls of Quercus Brantii on A375 and SK-MEL-3 melanoma and AGO-1522 normal human fibroblast cell lines for the first time. Therefore, cell viability and cytotoxic activities were evaluated. Furthermore, ROS formation, lipid peroxidation, and release of cytochrome-c were also assessed. The results revealed that the extract of these galls at a concentration of 0.05 mg/ml significantly (P<0.001) increased cytotoxicity, ROS formation, TBARS formation, and cytochrome-c release in A375 and SK-MEL-3 melanoma cell lines compared to AGO-1522 normal human fibroblast. These results demonstrated that these galls can be considered a promising candidate which acts in synergy with anticancer agents used in the clinical treatment of human malignant melanoma.

Toxicity of para-phenylenediamine (PPD;1, 4 diaminobenzene) on isolated human lymphocytes: The key role of intracellular calcium enhancement in PPD-induced apoptosis.

Para-phenylenediamine (PPD) is a derivative of benzene used as an ingredient in dyes, a photographic developing agent, and a component of engineered polymers. The carcinogenicity of PPD, which has been documented in several studies, may be related to its toxic effects on different compartments of the immune system. The main goal of this research was to evaluate the mechanism of the toxicity of PPD on human lymphocytes by exploiting the accelerated cytotoxicity mechanism screening (ACMS) technique. Lymphocytes were isolated from the blood of healthy persons using a Ficoll-Paque PLUS standard method. Assessment of cell viability was carried out 12 h following treatment of human lymphocytes with 0.25-1 mM PPD. For determination of cellular parameters, isolated human lymphocytes were incubated with 1/2 the IC50 (0.4 mM), the IC50 (0.8 mM), and twice the IC50 (1.6 mM) for 2, 4, and 6 h. Half maximal inhibitory concentration (IC50) is the concentration that reduces cell viability approximately 50% following treatment. The results of this study demonstrated that PPD-associated apoptosis in human lymphocytes was mainly through the enhancement of intracellular calcium, oxidative stress, and following adverse effect on lymphocyte organelles (like mitochondria and lysosomes). Lipid peroxidation, activation of caspase-3, and stimulation of cytokines (IL2, interferon-gamma (IFN-γ), and TNF-alpha) production were also observed in PPD-treated lymphocytes. Considering the results of this study, we can suggest an association between PPD carcinogenicity and its toxic effects on different compartments of the immune system.

Alpha pyrrolidinovalerophenone (α-PVP) administration impairs spatial learning and memory in rats through brain mitochondrial dysfunction.

Novel psychoactive substances (NPS) consumption has increased in recent years, thus NPS-induced cognitive decline is a current source of concern. Alpha-pyrrolidinovalerophenone (α-PVP), as a member of NPS, is consumed throughout regions like Washington, D.C., Eastern Europe, and Central Asia. Mitochondrial dysfunction plays an essential role in NPS-induced cognitive impairment. Meanwhile, no investigations have been conducted regarding the α-PVP impact on spatial learning/memory and associated mechanisms. Consequently, our study investigated the α-PVP effect on spatial learning/memory and brain mitochondrial function. Wistar rats received different α-PVP doses (5, 10, and 20 mg/kg) intraperitoneally for 10 sequential days; 24 h after the last dose, spatial learning/memory was evaluated by the Morris Water Maze (MWM). Furthermore, brain mitochondrial protein yield and mitochondrial function variables (Mitochondrial swelling, succinate dehydrogenase (SDH) activity, lipid peroxidation, Mitochondrial Membrane Potential (MMP), Reactive oxygen species (ROS) level, brain ADP/ATP proportion, cytochrome c release, Mitochondrial Outer Membrane (MOM) damage) were examined. α-PVP higher dose (20 mg/kg) significantly impaired spatial learning/memory, mitochondrial protein yield, and brain mitochondrial function (caused reduced SDH activity, increased mitochondrial swelling, elevated ROS generation, increased lipid peroxidation, collapsed MMP, increased cytochrome c release, elevated brain ADP/ATP proportion, and MOM damage). Moreover, the lower dose of α-PVP (5 mg/kg) did not alter spatial learning/memory and brain mitochondrial function. These findings provide the first evidence regarding impaired spatial learning/memory following repeated administration of α-PVP and the possible role of brain mitochondrial dysfunction in these cognitive impairments.

Cardiotoxicity of chloroquine and hydroxychloroquine through mitochondrial pathway.

BACKGROUND: Medical therapies can cause cardiotoxicity. Chloroquine (QC) and hydroxychloroquine (HQC) are drugs used in the treatment of malaria and skin and rheumatic disorders. These drugs were considered to help treatment of coronavirus disease (COVID-19) in 2019. Despite the low cost and availability of QC and HQC, reports indicate that this class of drugs can cause cardiotoxicity. The mechanism of this event is not well known, but evidence shows that QC and HQC can cause cardiotoxicity by affecting mitochondria and lysosomes. METHODS: Therefore, our study was designed to investigate the effects of QC and HQC on heart mitochondria. In order to achieve this aim, mitochondrial function, reactive oxygen species (ROS) level, mitochondrial membrane disruption, and cytochrome c release in heart mitochondria were evaluated. Statistical significance was determined using the one-way and two-way analysis of variance (ANOVA) followed by post hoc Tukey to evaluate mitochondrial succinate dehydrogenase (SDH) activity and cytochrome c release, and Bonferroni test to evaluate the ROS level, mitochondrial membrane potential (MMP) collapse, and mitochondrial swelling. RESULTS: Based on ANOVA analysis (one-way), the results of mitochondrial SDH activity showed that the IC50 concentration for CQ is 20 µM and for HCQ is 50 µM. Based on two-way ANOVA analysis, the highest effect of CQ and HCQ on the generation of ROS, collapse in the MMP, and mitochondrial swelling were observed at 40 µM and 100 µM concentrations, respectively (p < 0.05). Also, the highest effect of these two drugs has been observed in 60 min (p < 0.05). The statistical results showed that compared to CQ, HCQ is able to cause the release of cytochrome c from mitochondria in all applied concentrations (p < 0.05). CONCLUSIONS: The results suggest that QC and HQC can cause cardiotoxicity which can lead to heart disorders through oxidative stress and disfunction of heart mitochondria.

Mitochondrial transplantation against gentamicin-induced toxicity on rat renal proximal tubular cells: the higher activity of female rat mitochondria.

Mitochondrial dysfunction is a fundamental mechanism leading to drug nephrotoxicity, such as gentamicin-induced nephrotoxicity. Mitochondrial therapy (mitotherapy) or exogenous mitochondria transplantation is a method that can be used to replace dysfunctional mitochondria with healthy mitochondria. This method can help in the treatment of diseases related to mitochondria. In this research, we studied the transplantation effect of freshly isolated mitochondria on the toxicity induced by gentamicin on renal proximal tubular cells (RPTCs). Furthermore, possible gender-related effects on supplying exogenous rat kidney mitochondria on gentamicin-induced RPTCs were investigated. At first, the normality and proper functioning of fresh mitochondria were assessed by measuring mitochondrial succinate dehydrogenase activity (SDH) and changes in mitochondrial membrane potential (MMP). Then, the protective effects of mitochondrial transplantation against gentamicin-induced mitochondrial toxicity were evaluated through parameters including lactate dehydrogenase (LDH) leakiness, reactive oxygen species (ROS) production, lipid peroxidation (LPO) content, reduced glutathione (GSH) level, extracellular oxidized glutathione (GSSG) level, ATP level, MMP collapse, and caspase-3 activity. According to the statistical analysis, transplanting the healthy mitochondria decreased the cytotoxicity, ROS production, MMP collapse, LPO content, GSSG levels, and caspase-3 activity caused by gentamicin in RPTCs. Also, it has caused an increase in the level of ATP and GSH in the RPTCs. Furthermore, higher preventive effects were observed for the female group. According to the current study, mitochondrial transplantation is a potent therapeutic method in xenobiotic-caused nephrotoxicity.

Comparative Toxic Effect of Bulk Copper Oxide (CuO) and CuO Nanoparticles on Human Red Blood Cells.

Destruction of red blood cell is associated with anemia and other pathological status; hence, the hemolytic effects of all chemicals and particles which come into contact with blood components must be considered. Nanomaterials and nanoparticles are potential substitutes for common material and particles, and assessment of their effect on blood components is a necessary part of their safety evaluation. High surface-to-volume ratio of nanoparticles may cause their toxic effects differ from those observed for bulk material. The aim of this study was to compare the hemolytic effects of CuO nanoparticles and bulk CuO. Red blood cells were isolated from blood of healthy subjects and hemolytic effects assayed following treatment of cells with 0.005-0.25 mM of CuO (bulk and nanoparticles) for 6 h. For assessment of other parameters, cells were incubated with 0.01, 0.05, and 0.25 mM of CuO nanoparticles and bulk CuO for 1, 2, and 3 h. Our results demonstrate that CuO nanoparticles, in particular, caused toxic hemolytic effects in concentration-dependent manner, and this effect maybe through formation of ROS, glutathione depletion, and lipid peroxidation. In conclusion, CuO nanoparticles are shown to effectively destruct human red blood cells in comparison to bulk CuO.

Mitochondrial Transplantation Therapy against Ifosfamide Induced Toxicity on Rat Renal Proximal Tubular Cells.

Mitochondrial dysfunction is a basic mechanism leading to drug nephrotoxicity. Replacement of defective mitochondria with freshly isolated mitochondria is potentially a comprehensive tool to inhibit cytotoxicity induced by ifosfamide on renal proximal tubular cells (RPTCs). We hypothesize that the direct exposure of freshly isolated mitochondria into RPTCs affected by ifosfamide might restore mitochondrial function and reduce cytotoxicity. So, the aim of this study was to assess the protective effect of freshly isolated mitochondrial transplantation against ifosfamide-induced cytotoxicity in RPTCs. Therefore, the suspension of rat RPTCs (106 cells/ml) in Earle's solution with the pH of 7.4 at 37°C was incubated for 2 h after ifosfamide (4 mM) addition. Fresh mitochondria were isolated from the rat kidney and diluted to the needed concentrations at 4°C. The media containing suspended RPTCs was replaced with mitochondrial-supplemented media, which was exposed to cells for 4 hours in flasks-rotating in a water bath at 37°C. Statistical analysis demonstrated that mitochondrial administration reduced cytotoxicity, lipid peroxidation (LPO), reactive oxygen species (ROS) production, mitochondrial membrane potential (MMP) collapse, lysosomal membrane damage, extracellular oxidized glutathione (GSSG) level, and caspase-3 activity induced by ifosfamide in rat RPTCs. Moreover, mitochondrial transplantation increased the intracellular reduced glutathione (GSH) level in RPTCs affected by ifosfamide. According to the current study, mitochondrial transplantation is a promising therapeutic method in xenobiotic-caused nephrotoxicity pending successful complementary in vivo and clinical studies.

Toxicity of Persian Gulf shell-less marine mollusc (Peronia peronii) methanolic extract on melanoma tumor mitochondria.

INTRODUCTION: Melanoma is known as an aggressive and highly lethal cancer. The poor prognosis and resistance to treatment are characteristics of melanoma. In melanoma cells, apoptosis signaling which relies heavily on the acute activity of mitochondria and reactive oxygen species (ROS) formation is suppressed. Studies have shown that compounds isolated from marine herbs and animals, have been shown to have cytotoxic consequences on cancerous cells in prior research. This study was designed to evaluate the apoptotic effect of methanolic extract of Persian Gulf shell-less marine mollusc (Peronia peronii) on skin mitochondria isolated from animal model of melanoma. PURPOSE: Melanoma mitochondria obtained from skin of melanoma animal model are studied in this research to see whether extracts from Persian Gulf shell-less marine mollusc (Peronia peronii), has a cytotoxic impact on them. MATERIAL AND METHOD: In this study, the mitochondria were isolated from melanoma cells via differential centrifugation were treated with various concentrations (650, 1300 and 2600 µg/ml) of methanolic extract of Peronia peronii. Then MTT(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) viability assay, Reactive oxygen species (ROS) determination, Mitochondrial Membrane Potential (MMP) decline assay, mitochondrial swelling and cytochrome c release determination were performed. Flow cytometry assay of % apoptotic vs necrotic phenotypes was also performed on extract treated melanoma cells. RESULTS: The results of MTT assay showed that different concentrations of Peronia peronii extract significantly (P < 0.05) decreased the SDH activity in cancerous skin mitochondria with the IC50(1300 µg/ml). The ROS results also showed that all concentrations of Peronia peronii extracts significantly increased ROS production, MMP decline and the release of cytochrome c in cancer groups mitochondria. The swelling of mitochondria was significantly increased compared to the control group. In addition, the results of apoptosis assay showed that addition of root extract of Peronia peronii on melanoma cells increased apoptosis, while it had no effect on control non tumour cells. DISCUSSION AND CONCLUSION: Based on these results, the presence of potentially bioactive compounds in Peronia peronii make this Persian Gulf coastal herb a strong candidate for further molecular studies and clinical research in the field of melanoma cancer therapy.

Correlation between coenzyme Q10 content and the nutrient sensors in AKI induced by Hemiscorpius lepturus envenomation.

Introduction: Acute kidney injury (AKI) may have a negative effect on mitochondrial hemostasis and bioenergetics as well as coenzyme Q10 (CoQ10) content. PGC-1α, AMPK, sirtuin 1 (Sirt1), and Sirt3, as the key metabolic regulators under nutritional stress, stimulate energy production via mitochondrial biogenesis during AKI. However, no report is available on the relationship between CoQ10 level and nutrient sensors in the pathophysiology of AKI caused by Hemiscorpius lepturus scorpion envenomation. Methods: Three doses of venoms (1, 5, and 10 mg/kg) were administered by subcutaneous (SC) injection to male albino mice. The animals were sacrificed 1 day or 7 days after administration of venom and their kidneys were collected to analyze gene expression involved in AKI, nutrient sensors, and apoptosis signaling activation by real-time polymerase chain reaction (PCR) and the measurement of CoQ10 level using the High-performance liquid chromatography (HPLC) method. Results: The data indicated a significant decrease in CoQ10 level after the administration of venom in 5 and 10 mg/kg. In addition, 1 day after the treatment, a significant over-expression of Sirt1 (5 and 10 mg/kg) was observed compared with normal mice. Overexpression of Sirt3 occurred 1 day and 7 days after treatment only at the dose of 5.0 mg/kg of venom. Furthermore, over-expression of AMPK as an important mitochondrial energetic sensor happened 1 day and 7 days after the injection of venom (5 mg/kg) (P < 0.01). The significant increase in the gene expression of caspase-9 and 3 after the injection of venom (5 and 10 mg/kg) confirmed the role of cell death signaling. Conclusion: The venom-induced energy-sensing pathways have a key role in gene expression of PGC-1α, AMPK, Sirt3, and CoQ10 content after venom-induced AKI.

Antiproliferative activity of new derivatives of pyrazino[1,2-a]benzimidazole: Integrated cell-based assay and computational studies with divalent magnesium, iron, and copper ions.

Magnesium, iron, and copper are three vital metals that play essential roles in cancer cell proliferation. This study aimed to evaluate the metal chelation of new derivatives of pyrazino[1,2-a]benzimidazole and investigate their antiproliferative properties. The density functional theory method has been employed to evaluate the complexation properties of new synthetic pyrazino[1,2-a]benzimidazole derivatives possessing the 4-OMe, 2,4-dimethyl, and 3,4,5-trimethoxy substitution on N-2 phenyl ring with divalent magnesium, iron, and copper. The free energies for the water-ligand exchange reactions were employed to investigate the thermodynamic stability, water exchange properties, and electronic properties in the gas phase. Natural population analysis was employed to estimate atomic partial charges, second-order interactions between the filled and vacant orbitals, and the occupancies of the metals' valence s, p, and d orbitals. Among pyrazino[1,2-a]benzimidazole derivatives, the 3,4,5-trimethoxy substituted pyrazino[1,2-a]benzimidazole shows better electron donor ability. This compound also reduced proliferation and increased the apoptosis of human glioblastoma cancer cells.

Selective toxicity of Cistanche tubulosa root extract on cancerous skin mitochondria isolated from animal model of melanoma.

INTRODUCTION: As a major public health issue, skin cancer is a leading reason of death and has resulted in significant financial and human losses globally. Numerous environmental and internal variables may both drive and exacerbate the pathophysiology of skin cancer. Marine herbs and animals, including marine sponges, cucumbers, and squirts, have been shown to have cytotoxic consequences on cancerous cells in prior research. PURPOSE: melanoma mitochondria obtained from the skin of melanoma animal models are studied in this research to see whether extracts from Cistanche tubulosa, a plant endemic to the northern coasts of the Persian Gulf, have a cytotoxic impact on them. MATERIAL AND METHOD: In this study, the mitochondria were isolated from melanoma cells via differential centrifugation and treated with various concentrations (1250, 2500 and 5000 µg/ml) of methanolic extract of C. tubulosa. Then MTT, ROS, MMP decline, mitochondrial swelling, cytochrome c release and flow cytometry assays were performed on them. RESULTS: The results of the MTT assay showed that the IC50 of C. tubulosa extract is 2500 µg/ml and C. tubulosa extract induced a selectively significant (P < 0.05) concentration-dependent decrease in the SDH activity in cancerous skin mitochondria. The ROS results also showed that all concentrations of C. tubulosa extracts significantly increased ROS production, MMP decline and the release of cytochrome c in cancer group mitochondria. The swelling of mitochondria isolated from the cancer group was significantly increased compared to the control group. In addition, the results of the apoptosis assay showed that the addition of root extract of C. tubulosa on melanoma cells increased apoptosis, while it had no effect on control non-tumour cells. DISCUSSION AND CONCLUSION: Based on these results, the presence of potentially bioactive compounds in C. tubulosa makes this Persian Gulf coastal herb a strong candidate for further molecular studies and clinical research in the field of melanoma cancer therapy.

Risperidone Toxicity on Human Blood Lymphocytes in Nano molar Concentrations.

Risperidone is an atypical antipsychotic drug used for the pharmacotherapy of psychiatric disorders. Some reports indicate that risperidone is toxic to various systems of the body, including the immune system. This study evaluated the toxicity effect of risperidone on human blood lymphocytes. To achieve this aim, lymphocytes were isolated using Ficoll paque plus. The results showed that risperidone (12, 24 and 48 nM) causes toxicity in human blood lymphocytes by increasing the level of intracellular reactive oxygen species (ROS), damage to lysosomal membrane, the collapse of the mitochondrial membrane potential (MMP), and increased extracellular oxidized glutathione (GSSG). Also, exposure of human blood lymphocytes to risperidone is associated with a decrease in intracellular glutathione (GSH) levels. Finally, it could be concluded that oxidative stress is one of the mechanisms of risperidone-induced toxicity in human blood lymphocytes.