Teratogenic Effects of Drugs on Primary Lymphocytes Assessed by Flow Cytometry.

Peripheral blood lymphocytes as primary cells can be isolated from human, animal, fetus, and placenta. These cells are an excellent cellular model for the assessment of cytotoxicity, genotoxicity, oxidative stress, and mitochondrial and lysosomal dysfunction induced by drug and chemicals. Moreover, peripheral blood lymphocytes are an easily available source of primary cells appropriate for basic research and in cellular studies regarding teratogenic, genotoxic, and cytotoxic effect of drugs and chemicals. Most drugs and other chemicals that produce birth defects, known as teratogenic agents, produce reactive oxygen species (ROS) formation and mitochondrial and lysosomal dysfunction. It seems that there is an important mechanistic link between oxidative stress, mitochondrial damages, lysosomal integrity, and teratogenic drug-induced birth defects. One of the most sensitive periods in the embryo is transition from an important developmental event to another such as transition from proliferation to differentiation. Mitochondria, lysosomes, and cellular ROS have an important role in proliferative, differentiative, and apoptotic activities during the development. Therefore, disruption of the function of mitochondria, lysosomes, oxidative stress, and redox imbalance leads to cellular dysfunctions and subsequently poor developmental outcomes in the fetus. In this chapter, we will focus on evaluation of mitochondrial/lysosomal functions and estimation of ROS formation using flow cytometry methods in isolated lymphocytes and their isolated mitochondria.

Maintenance of mitochondrial function by sinapic acid protects against tramadol-induced toxicity in isolated mitochondria obtained from rat brain.

It is reported that tramadol can induce neurotoxic effects with the production of DNA damage, mitochondrial dysfunction, and oxidative stress. The current study aimed to evaluate the potential role of mitochondrial impairment in the pathogenesis of tramadol-induced neurotoxicity, and protective effect of sinapic acid (SA) against it in isolated mitochondria from rat brain. Mitochondria were isolated and were incubated with toxic concentrations (100 µM) of tramadol and then cotreated with tramadol + SA (10, 50, and 100 µM). Biomarkers of mitochondrial toxicity including succinate dehydrogenases (SDH) activity, reactive oxygen species (ROS), lipid peroxidation (LPO), mitochondrial membrane potential (MMP), GSH depletion, and mitochondrial swelling were assessed. Our results showed a significant decrease in SDH activity, and a significant increase in ROS, LPO, GSH depletion, MMP collapse, and mitochondrial swelling was detected in tramadol group. We observed that 50 and 100 µM SA cotreatment for 1 h efficiently ameliorated tramadol-caused damage in mitochondrial dysfunction, accumulation of ROS, LPO, GSH depletion, depolarization of mitochondrial membrane potential, and mitochondrial swelling. These data suggest that mitochondrial impairment and oxidative stress are mechanisms involved in the pathogenesis of tramadol-induced neurotoxicity. Also, results indicate that SA antagonizes against tramadol-induced mitochondrial toxicity and suggest SA may be a preventive/therapeutic agent for tramadol-induced neurotoxicity complications.

Hesperidin Protects Alcohol-induced Mitochondrial Abnormalities via the Inhibition of Oxidative Stress and MPT Pore opening in Newborn Male Rats as Fetal Alcohol Syndrome Model.

OBJECTIVE: Prenatal alcohol exposure causes fetal developmental abnormalities via mitochondrial dysfunction, ROS formation, oxidative stress. Therefore, we aimed to investigate the potential of hesperidin as a mitochondrial protective and anti-oxidative agent in newborn male rats as fetal alcohol syndrome (FAS) model. METHODS: Newborns male rats were divided randomly into 5 groups; sham group (receiving 27.8 ml/kg milk solution, orally), ethanol group (5.25 g/kg, orally, 2-10 days after birth in milk solution), ethanol + hesperidin group (25 mg/kg per day orally), ethanol + hesperidin group (50 mg/kg per day orally), and ethanol + hesperidin group (100 mg/kg per day orally). Thirty-six days after birth, newborns male rats were sacrificed and brain mitochondria were isolated using differential centrifugation. Mitochondrial toxicity biomarkers of including: succinate dehydrogenases (SDH) activity, mitochondrial swelling, mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) were measured. RESULTS: Offspring neonatally exposed to ethanol showed a significant reduction of SDH activity, mitochondrial swelling, MMP collapse, induction of ROS formation and lipid peroxidation in isolated mitochondria. Orally administration of hesperidin restored SDH activity, improved MMP collapse, mitochondrial swelling, and reduced ROS formation. CONCLUSIONS: This study demonstrates that hesperidin exerts a potent mitochondria protective effect against alcohol-induced mitochondrial toxicity in FAS model. Moreover, these findings indicates that hesperidin might be a useful compound for prevention of alcohol-induced fetal developmental abnormalities during pregnancy.

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.

Hesperidin via maintenance of mitochondrial function and antioxidant activity protects lithium toxicity in rat heart isolated mitochondria.

Lithium is commonly used in the treatment of bipolar disorders (BD) and consumer electronics. It has been reported that lithium exposure is associated with mitochondrial dysfunction and oxidative stress in isolated cardiac mitochondria. Mitochondrial protection has a key role in myocardial tissue homeostasis, cardiomyocyte survival and inhibition of cardiotoxicity. Hesperidin as a flavanone and cardioprotective agent has shown high potential in antioxidant activity and restoration of mitochondrial dysfunction in different models. Therefore, we aimed to evaluate the ameliorative effects of hesperidin against lithium-induced mitochondrial toxicity in rat cardiac mitochondria. Isolated mitochondria were classified into six groups; control, lithium carbonate (125 µM), three groups of lithium + hesperidin-treated received lithium (125 µM) and hesperidin with various concentrations (10, 50, and 100 µM) and hesperidin (100 µM). Succinate dehydrogenases (SDH) activity, mitochondrial swelling, mitochondrial membrane potential (MMP), reactive oxygen species (ROS), mitochondrial glutathione (GSH) and lipid peroxidation (LPO) were measured. The mitochondria received lithium showed a significant reduction of SDH activity, MMP collapse, mitochondrial swelling, induction of ROS formation and lipid peroxidation. However, we observed that the administration of hesperidin (50 and 100 µM) resulted in the increase of SDH activity, improved MMP collapse, mitochondrial swelling, and reduced ROS formation and lipid peroxidation. Also, there were no obvious changes in cardiac mitochondria received of hesperidin. These findings suggest that hesperidin could reduce lithium-induced mitochondrial dysfunction through antioxidant activities in cardiac mitochondria, may be beneficial for prevention and treatment of lithium toxicities, either as a drug to treat BD or as an environmental pollutant.

Pretreatment of ellagic acid protects ifosfamide-induced acute nephrotoxicity in rat kidneys: A mitochondrial, histopathological and oxidative stress approaches.

Ifosfamide (IFO) kidney damage is an important organ toxicity in children and adults undergoing chemotherapy. Previous evidence has shown that IFO toxic metabolites such as acrolein and are associated with mitochondrial dysfunction, depletion of antioxidants, oxidative stress and may predispose the kidney to IFO toxicity. Bioactive food compounds such as ellagic acid (EA) found in fruits has been described as antioxidant and mitochondrial protective agents against toxicity-related mitochondrial damage and oxidative stress. In current study, the protective effects of EA on IFO-induced nephrotoxicity in male Wistar rats were investigated with histopathological, biochemical, and mitochondrial methods. The rats were randomly divided into four groups, control, IFO, IFO + EA, and EA groups. EA (25 mg/kg, i.p. daily) were administered to animals for 2 consecutive days and IFO (500 mg/kg, i.p.) was administered on third day. The results showed that pretreatment EA significantly increased mitochondrial succinate dehydrogenases (SDH) activity, and protected mitochondrial swelling, mitochondrial membrane potential (MMP), reactive oxygen species (ROS) formation, lipid peroxidation (LPO) and depletion glutathione (GSH). Histopathological findings demonstrated that EA had protective effects and reduced histopathological abnormalities caused by IFO. These results showed that EA administration protects the kidneys against mitochondrial dysfunction, oxidative stress and histopathological abnormality induced by IFO. Taken together, our results demonstrated that EA played a protective role against IFO-induced nephrotoxicity through mitochondrial protection and antioxidant properties.

Vanillic acid alleviates methamphetamine-induced mitochondrial toxicity in cardiac mitochondria via antioxidant activity and inhibition of MPT Pore opening: an in-vitro study.

BACKGROUND: Methamphetamine is widely abused in all parts of the world. It has been reported that short-term and long-term methamphetamine exposure could damage the dopaminergic system and induce cardiomyopathy and cardiotoxicity via mitochondrial dysfunction and oxidative stress. Vanillic acid (VA), a phenolic acid compound derived from plants, is known for its antioxidant and mitochondrial protection properties. METHODS: In the current study we used VA for attenuating of Methamphetamine-induced mitochondrial toxicity in cardiac mitochondria. Isolated mitochondria obtained from rat heart were grouped as: control, methamphetamine (250 µM), VA (10, 50 and 100 µM) was cotreated with methamphetamine (250 µM) and VA (100 µM) alone. After 60 min, mitochondrial fraction including: succinate dehydrogenases (SDH) activity, mitochondrial membrane potential (MMP), mitochondrial swelling, mitochondrial glutathione (GSH), reactive oxygen species (ROS) and lipid peroxidation (LPO) were evaluated. RESULTS: Methamphetamine exposure significantly disrupted mitochondrial function and induced ROS formation, lipid peroxidation, GSH depletion, MMP collapse and mitochondrial swelling, while VA significantly increased SDH activity as indicator of mitochondrial toxicity and dysfunction. VA also significantly decreased ROS formation, lipid peroxidation, mitochondrial swelling, MMP collapse and depletion of GSH in cardiac mitochondria in the presence of methamphetamine. CONCLUSION: These findings suggested that VA is able to reduce methamphetamine-induced mitochondrial dysfunction and oxidative stress. Our results demonstrate that VA could potentially serve as a promising and accessible cardioprotective agent against methamphetamine-induced cardiotoxicity, via antioxidant and mitochondrial protection properties.

Lapse and Relapse Rates in Narcotics Anonymous versus Methadone Maintenance Treatment: A 12-Month Prospective Study.

Objective: The present study aimed to compare lapse and relapse-free survival between patients treated in Narcotics Anonymous (NA) groups and Methadone Maintenance Treatment (MMT) centers and to determine the relationship between social support scale and treatment outcome. Method: This study was a prospective, 12-month cohort study using the random sampling method to select 100 newcomer patients treated by the NA Association as well as 100 patients in MMT centers. The data were collected using a demographic questionnaire and Social Support Appraisals (SSA) scale at the onset of the study along with follow-up phone calls every other week. Results: All participants were male, aged between 18 and 65 with a mean (SD) age of 38.98 (± 10.85) years. Prevalence of relapse in 12 months was 60.5%. The lapses in the MMT group and relapses in the NA group were significantly higher (P < 0.001). The younger patients with lower levels of education are at greater risk of lapse/relapse. The mean score of SSA was significantly higher in the MMT group than the NA group in all subscales, including friends, family, and the others' support (P < 0.001). The mean scores of SSA subscales for the participants without relapse in the NA group was significantly higher in comparison to the MMT group. Conclusion: Detection of factors related to drug abuse relapse/lapse may help addiction therapists to identify drug abuse patients with lapse/relapse and to develop treatment and policy guidelines to prevent relapse in addiction recovery.

The Association of Opioid Use Disorder and COVID-19, a Longitudinal Study.

Background: Coronavirus disease 2019 (COVID-19) quickly spread to the world, causing a pandemic. While some studies have found no link between opioid use disorder (OUD) and COVID-19, the role of opioid on COVID-19 is challenging. The present study aimed to determine the relationship between OUD and COVID-19. Methods: This was a prospective cohort study. We used data from the third phase of the Shahroud Eye Cohort Study on 4394 participants which started in September 2019 and ended before the COVID-19 epidemic in Shahroud in February 2020. The participants were followed for about 13 months till March 26, 2021. COVID-19 was detected by RT-PCR on swap samples from the oropharynx and nasopharynx. The incidence of COVID-19 compared in OUD and non-OUD participants, and relative risk was calculated in log-binomial regression models. Results: Among the 4394 participants with a mean age of 61.1 years, 120 people had OUD. The incidence of COVID-19 in participants with OUD and non-OUD was 4.17% and 6.22%, respectively (P-value: 0356). The relative risk of OUD for COVID-19 was 0.60 (95% confidence intervals: 0.25-1.44; P value: 0.251). Conclusions: OUD was not associated with COVID-19. The claim that people with OUD are less likely to develop COVID-19 is not supported by these data.

Celecoxib decreases mitochondrial complex IV activity and induces oxidative stress in isolated rat heart mitochondria: An analysis for its cardiotoxic adverse effect.

In spite of the cardiotoxic effect of selective cyclooxygenase-2 inhibitors, they are most widely used as anti-inflammatory and analgesic drugs. Today, valdecoxib and rofecoxib have been withdrawn in the market but celecoxib remains. In this study, we focused on an analysis of celecoxib toxic effects on isolated mitochondria. Isolated rat heart mitochondria were obtained using differential centrifugation. Using flow cytometry and biochemical assays, we searched succinate dehydrogenases, mitochondrial membrane potential (MMP), reactive oxygen species (ROS) formation, mitochondrial swelling, ATP/ADP ratio, lipid peroxidation, and mitochondrial complexes activity in rat heart isolated mitochondria. Herein, our results indicated a significant decrease in the activity of complex IV after exposure with celecoxib (16 µg/ml). This decrease in the activity of complex IV is paralleled by the MMP collapse, ROS formation, mitochondrial swelling, depletion of ATP, and lipid peroxidation. For the first time, this introductory study has shown a significant decrease in the activity of complex IV and mitochondrial dysfunction after exposure with celecoxib in rat heart isolated mitochondria.

Selenium and L-carnitine protects from valproic acid-Induced oxidative stress and mitochondrial damages in rat cortical neurons.

Oxidative stress and mitochondrial dysfunction have been associated with valproic acid (VPA) induced neurotoxicity. Mitochondria are vulnerable to oxidative damage and are also a major source of superoxide free radicals. Therefore, the need for mitochondrial protective and antioxidant agents for reducing valporic acid toxicity in central nerve system (CNS) is essential. In the present study, we investigated the potential beneficial effects of sodium selenite (SS) and L-carnitine (LC) against valproic acid -induced oxidative stress and mitochondrial dysfunction in isolated rat cortical neurons. Valproic acid (50, 100 and 200 µM) treatment caused a significant decrease in cellular viability, which was accompanied by increases in reactive oxygen species (ROS) generation, GSSG and GSH content, lipid peroxidation and lysosomal and mitochondrial damages. Sodium selenite (1 µM) and L-carnitine (1 mM) pretreatment attenuated valproic acid-induced decrease in cell viability. In addition, sodium selenite (1 µM) and L-carnitine (1 mM) pretreatment significantly protected against valproic acid-induced raise in oxidative stress, mitochondrial and lysosomal dysfunction, lipid peroxidation levels and depletion of GSH content. Our results in the current study provided insights into the protective mechanism by L-carnitine and sodium selenite, which is liked, to neuronal ROS generation and mitochondrial and lysosomal damages.

Antioxidant Potential and Inhibition of Mitochondrial Permeability Transition Pore by Myricetin Reduces Aluminium Phosphide-Induced Cytotoxicity and Mitochondrial Impairments.

Oxidative stress and mitochondrial dysfunction are involved in the mechanisms of cardiac toxicity induced by aluminum phosphide (AlP). AlP-induced cardiotoxicity leads to cardiomyocyte death, cardiomyopathy, cardiac dysfunction, and eventually severe heart failure and death. Importantly, protecting cardiomyocytes from death resulting from AlP is vital for improving survival. It has been reported that flavonoids such as myricetin (Myr) act as modifiers of mitochondrial function and prevent mitochondrial damage resulting from many insults and subsequent cell dysfunction. In this study, the ameliorative effect of Myr, as an important antioxidant and mitochondrial protective agent, was investigated in cardiomyocytes and mitochondria isolated from rat heart against AlP-induced toxicity, oxidative stress, and mitochondrial dysfunction. Treatment of AlP (20 µg/ml) significantly increased cytotoxicity; reduced glutathione (GSH) depletion, cellular reactive oxygen species (ROS) formation, malondialdehyde (MDA) level, ATP depletion, caspase-3 activation, mitochondrial membrane potential (ΔΨm) collapse, and lysosomal dysfunction; and decreased the activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) in intact cardiomyocytes. Also, treatment of AlP (20 µg/ml) significantly increased mitochondrial dysfunction and swelling in isolated mitochondria. Myr (80 µM) appeared to ameliorate AlP-induced cytotoxicity in isolated cardiomyocytes; significantly lessened the AlP-stimulated intracellular ROS and MDA production and depletion of GSH; and increased the activities of SOD, CAT, and GSH-Px. Furthermore, Myr (40 and 80 µM) lowered AlP-induced lysosomal/mitochondrial dysfunction, ATP depletion, and caspase-3 activation. In the light of these findings, we concluded that Myr through antioxidant potential and inhibition of mitochondrial permeability transition (MPT) pore exerted an ameliorative role in AlP-induced toxicity in isolated cardiomyocytes and mitochondria, and it would be valuable to examine its in vivo effects.

Calcitriol attenuates the cytotoxicity induced by aluminium phosphide via inhibiting mitochondrial dysfunction and oxidative stress in rat isolated cardiomyocytes.

These days, poisoning with aluminium phosphide (AlP), is one of the main health threats in human societies. Previous studies have been reported that cardiotoxicity induced by AlP, via mitochondrial dysfunction and oxidative stress is the main cause of death in victims. On the other, collectively, multiple lines of evidence strongly suggest that calcitriol has mitochondrial protective and antioxidant effects. Therefore, we assumed that calcitriol could presumably ameliorate AlP-induced oxidative stress and mitochondrial dysfunction in cardiomyocytes. Mitochondria and cardiomyocytes were isolated by differential centrifugation and collagenase perfusion respectively from rat heart. The isolated cardiomyocytes and mitochondria were cotreated with different concentrations of calcitriol (0.2, 0.4 and 1 µg/ml) and AlP (20 µg/ml) for 3 h. The parameters of cellular toxicity including; cytotoxicity, reactive oxygen species (ROS) formation, malondialdehyde (MDA) level, mitochondria membrane potential (ΔΨm) collapse, lysosomal membrane integrity, the level of oxidized and reduced glutathione (GSH and GSSG), and mitochondrial toxicity parameters including; succinate dehydrogenase (SDH) activity and mitochondrial swelling were analyzed using biochemical and flow cytometric evaluations. Administration of AlP significantly increased cytotoxicity, GSH depletion, cellular ROS formation, MDA level, mitochondrial and lysosomal dysfunction in isolated cardiomyocytes. In isolated mitochondria, AlP decreased SDH activity and mitochondrial swelling. The cotreatment of isolated cardiomyocytes and mitochondria with calcitriol (0.4 and 1 µg/ml) and AlP (20 µg/ml) showed the ability to reduce the toxic effects of AlP. These findings suggest a potential therapeutic role of calcitriol in protecting cardiomyocytes and cardiac mitochondria from oxidative damage induced by AlP. According to the results, calcitriol exerted ameliorative effects against AlP-induced cytotoxicity and mitochondrial toxicity, and the effect was attributed to the antioxidant properties.

Thymoquinone reduces mitochondrial damage and death of cardiomyocytes induced by clozapine.

The generation of a reactive nitrenium ion by microsomal/mitochondrial cytochrome P450 (CYPs) from clozapine (CLZ) has been suggested as the main cause of cardiotoxicity by this drug. Previous studies indicated that thymoquinone (TQ) as an active constituent of Nigella sativa has pharmacological effects such as antioxidant, reactive oxygen species (ROS) scavenger, and inhibitory effect on CYPs enzymes. Therefore, we hypothesized that TQ with these pharmacological effects can reduce CLZ-induced toxicity in isolated cardiomyocytes and mitochondria. Rat left ventricular cardiomyocytes and mitochondria were isolated by collagenase perfusion and differential centrifugation respectively. Then, isolated cardiomyocytes and mitochondria were pretreated with different concentrations of TQ (1, 5, and 10 µmol/l) for 30 min and then followed by exposure to CLZ (50 µmol/l) for 6 h. After 6 h of incubation, using biochemical evaluations and flow cytometric analysis, the parameters of cellular toxicity including cytotoxicity, the level of oxidized/reduced glutathione (GSH/GSSG), malondialdehyde (MDA), reactive oxygen species (ROS) formation, lysosomal membrane integrity, mitochondria membrane potential (ΔΨm) collapse, and mitochondrial toxicity including succinate dehydrogenase (SDH) activity and mitochondrial swelling were analyzed. We observed a significant toxicity in isolated cardiomyocytes and mitochondria after exposure with CLZ which was related to ROS formation, oxidative stress, GSH depletion, lysosomal and mitochondrial damages, and mitochondrial dysfunction and swelling, while TQ pretreatment reverted the above toxic effect of CLZ on isolated cardiomyocytes and mitochondria. Our results indicate that TQ prevents and reverses CLZ-induced cytotoxicity and mitochondrial damages in isolated cardiomyocytes and mitochondria, providing an experimental basis for clinical treatment on CLZ-induced cardiotoxicity.

Mesalazine Induces Oxidative Stress and Cytochrome c Release in Isolated Rat Heart Mitochondria: An Analysis of Cardiotoxic Effects.

Mesalazine is widely used in the management of inflammatory bowel disease. Previous studies reported that mesalazine-induced cardiotoxicity is a rare, potentially fatal complication. Mitochondria play an important role in myocardial tissue homeostasis. Deterioration in mitochondrial function will eventually lead to cardiomyocyte death and consequently cardiovascular dysfunction. The aim of the current study was to investigate the effects of mesalazine on rat heart mitochondria. Rat heart mitochondria were isolated by mechanical lysis and differential centrifugation. Parameters of mitochondrial toxicity including succinate dehydrogenase (SDH) activity, reactive oxygen species (ROS) formation, mitochondrial membrane potential (MMP) collapse, mitochondrial swelling, and cytochrome c release were evaluated. Results revealed that mesalazine induced a concentration- and time-dependent rise in mitochondrial ROS formation, inhibition of SDH, MMP collapse, mitochondrial swelling, and cytochrome c release in rat heart mitochondria. These results indicate that the cardiotoxic effects of mesalazine are most likely associated with mitochondrial dysfunction and ROS formation, which finally ends in cytochrome c release signaling and induction of apoptosis.

Pathogenic Mechanisms and Therapeutic Implication in Nickel-Induced Cell Damage.

BACKGROUND: Nickel (Ni) is mostly applied in a number of industrial areas such as printing inks, welding, alloys, electronics and electrical professions. Occupational or environmental exposure to nickel may lead to cancer, allergy reaction, nephrotoxicity, hepatotoxicity, neurotoxicity, as well as cell damage, apoptosis and oxidative stress. METHODS: In here, we focused on published studies about cell death, carcinogenicity, allergy reactions and neurotoxicity, and promising agents for the prevention and treatment of the toxicity by Ni. RESULTS: Our review showed that in the last few years, more researches have focused on reactive oxygen species formation, oxidative stress, DNA damages, apoptosis, interaction with involving receptors in allergy and mitochondrial damages in neuron induced by Ni. CONCLUSION: The collected data in this paper provide useful information about the main toxicities induced by Ni, also, their fundamental mechanisms, and how to discover new ameliorative agents for prevention and treatment by reviewing agents with protective and therapeutic consequences on Ni induced toxicity.