The mechanism of protective effect of crocin against liver mitochondrial toxicity caused by arsenic III

In this study, we want to understand whether crocin could prevent mitochondrial damage caused by As III. For this purpose, we determined different mitochondrial toxicity endpoints caused by As III. We evaluated mitochondrial ROS formation, lipid peroxidation, mitochondrial membrane potential (MMP) collapse, mitochondrial outer membrane integrity and cytochrome c release. Our results showed that pretreatment with crocin at a concentration of 25?µg/ml significantly (p?相似文献   

Chrysin ameliorates aluminum phosphide‐induced oxidative stress and mitochondrial damages in rat cardiomyocytes and isolated mitochondria

Apart from the anticancer, antioxidant, anti‐inflammatory effects, and inhibition of aromatase, chrysin is involved in the protection of cardiovascular disorders. Cardiovascular complications are the main cause of death induced by aluminum phosphide (AlP) which is related to oxidative stress and mitochondrial damages. For this purpose, we investigated the effect of chrysin as an antioxidant and mitochondrial protective agent against AlP‐induced toxicity in isolated cardiomyocytes and mitochondria obtained from rat heart ventricular. Using by biochemical and flow cytometry, cell viability, reactive oxygen species (ROS) formation, mitochondria membrane potential (MMP), lysosomal membrane integrity, malondialdehyde (MDA) content, and glutathione (GSH) and oxidized glutathione (GSSG) content were measured in isolated cardiomyocytes. Also, mitochondrial toxicity parameters such as mitochondrial NADH/succinate dehydrogenase activity, mitochondrial swelling, ROS formation, MMP collapse, and lipid peroxidation were analyzed in isolated mitochondria. Our results showed that the administration of chrysin (up to 10 μM) efficiently decreased (P < 0.05) cytotoxicity, oxidative, lysosomal, and mitochondrial damages induced by AlP, in isolated cardiomyocytes. Also, our finding in isolated mitochondria showed that chrysin (up to 10 μM) significantly (P < 0.05) decreased AlP‐induced mitochondrial toxicity. These findings demonstrated that chrysin as an antioxidant and mitochondrial protective agent exert protective effect in wild‐type cardiomyocyte treated with AlP. It was concluded that chrysin significantly reduced the toxicity of AlP in isolated cardiomyocytes and mitochondria. Due to the very low toxicity of chrysin for humans, it could be a promising agent in treatment of AlP poisoning.     

Atorvastatin induces mitochondrial dysfunction and cell apoptosis in HepG2 cells via inhibition of the Nrf2 pathway

Atorvastatin (ATO) is a 3‐hydroxy‐3‐methylglutaryl‐CoA reductase inhibitor widely used to treat hypercholesterolemia. However, clinical application is limited by potential hepatotoxicity. Nuclear factor‐erythroid 2‐related factor 2 (Nrf2) is a master regulator of cellular antioxidants, and oxidative stress is implicated in statin‐induced liver injury. This study investigated mechanisms of ATO‐induced hepatotoxicity and potential mitigation by Nrf2 signaling. ATO reduced Nrf2 and antioxidant enzyme superoxide dismutase‐2 (SOD2) expression in human hepatocarcinoma HepG2 cells. ATO also induced concentration‐dependent HepG2 cell toxicity, reactive oxygen species (ROS) accumulation, and mitochondrial dysfunction as evidenced by decreased mitochondrial membrane potential (MMP) and cellular adenosine triphosphate (ATP). Further, ATO induced mitochondria‐dependent apoptosis as indicated by increased Bax/Bcl‐2 ratio, cleaved caspase‐3, mitochondrial cytochrome c release and Annexin V‐fluorescein isothiocyanate/propidium iodide staining. Tert‐butylhydroquinone enhanced Nrf2 and SOD2 expression, and partially reversed ATO‐induced cytotoxicity, ROS accumulation, MMP reduction, ATP depletion and mitochondria‐dependent apoptosis. In conclusion, the present study demonstrates that ATO induces mitochondrial dysfunction and cell apoptosis in HepG2 cells, at least in part, via inhibition of the Nrf2 pathway. Nrf2 pathway activation is a potential prevention for ATO‐induced liver injury.     

Protective effects of Sesamum indicum extract against oxidative stress induced by vanadium on isolated rat hepatocytes

Vanadium toxicity is a challenging problem to human and animal health with no entirely understanding cytotoxic mechanisms. Previous studies in vanadium toxicity showed involvement of oxidative stress in isolated liver hepatocytes and mitochondria via increasing of ROS formation, release of cytochrome c and ATP depletion after incubation with different concentrations (25–200 µM). Therefore, we aimed to investigate the protective effects of Sesamum indicum seed extract (100–300 μg/mL) against oxidative stress induced by vanadium on isolated rat hepatocytes. Our results showed that quite similar to Alpha‐tocopherol (100 µM), different concentrations of extract (100–300 μg/mL) protected the isolated hepatocyte against all oxidative stress/cytotoxicity markers induced by vanadium in including cell lysis, ROS generation, mitochondrial membrane potential decrease and lysosomal membrane damage. Besides, vanadium induced mitochondrial/lysosomal toxic interaction and vanadium reductive activation mediated by glutathione in vanadium toxicity was significantly (P < 0.05) ameliorated by Sesamum indicum extracts. These findings suggested a hepato‐protective role for extracts against liver injury resulted from vanadium toxicity. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 979–985, 2016.     

The role of oxidative stress in citreoviridin‐induced DNA damage in human liver‐derived HepG2 cells

We hypothesize that citreoviridin (CIT) induces DNA damage in human liver‐derived HepG2 cells through an oxidative stress mechanism and that N‐acetyl‐l ‐cysteine (NAC) protects against CIT‐induced DNA damage in HepG2 cells. CIT‐induced DNA damage in HepG2 cells was evaluated by alkaline single‐cell gel electrophoresis assay. To elucidate the genotoxicity mechanisms, the level of oxidative DNA damage was tested by immunoperoxidase staining for 8‐hydroxydeoxyguanosine (8‐OHdG); the intracellular generation of reactive oxygen species (ROS) and reduced glutathione (GSH) were examined; mitochondrial membrane potential and lysosomal membranes' permeability were detected; furthermore, protective effects of NAC on CIT‐induced ROS formation and CIT‐induced DNA damage were evaluated in HepG2 cells. A significant dose‐dependent increment in DNA migration was observed at tested concentrations (2.50–10.00 µM) of CIT. The levels of ROS, 8‐OHdG formation were increased by CIT, and significant depletion of GSH in HepG2 cells was induced by CIT. Destabilization of lysosome and mitochondria was also observed in cells treated with CIT. In addition, NAC significantly decreased CIT‐induced ROS formation and CIT‐induced DNA damage in HepG2 cells. The data indicate that CIT induces DNA damage in HepG2 cells, most likely through oxidative stress mechanisms; that NAC protects against DNA damage induced by CIT in HepG2 cells; and that depolarization of mitochondria and lysosomal protease leakage may play a role in CIT‐induced DNA damage in HepG2 cells. © 2014 The Authors. Published by Wiley Periodicals Inc. Environ Toxicol 30: 530–537, 2015.     

Selective toxicity of persian gulf sea cucumber holothuria parva on human chronic lymphocytic leukemia b lymphocytes by direct mitochondrial targeting

Natural products isolated from marine environment are well known for their pharmacodynamic potential in diversity of disease treatments such as cancer or inflammatory conditions. Sea cucumbers are one of the marine animals of the phylum Echinoderm. Many studies have shown that the sea cucumber contains antioxidants and anti‐cancer compounds. Chronic lymphocytic leukemia (CLL) is a disease characterized by the relentless accumulation of CD5⁺ B lymphocytes. CLL is the most common leukemia in adults, about 25–30% of all leukemias. In this study B lymphocytes and their mitochondria (cancerous and non‐cancerous) were obtained from peripheral blood of human subjects and B lymphocyte cytotoxicity assay, and caspase 3 activation along with mitochondrial upstream events of apoptosis signaling including reactive oxygen species (ROS) production, collapse of mitochondrial membrane potential (MMP) and mitochondrial swelling were determined following the addition of Holothuria parva extract to both cancerous and non‐cancerous B lymphocytes and their mitochondria. Our in vitro finding showed that mitochondrial ROS formation, MMP collapse, and mitochondrial swelling and cytochrome c release were significantly (P < 0.05) increased after addition of different concentrations of H. parva only in cancerous BUT NOT normal non‐cancerous mitochondria. Consistently, different concentrations of H. parva significantly (P < 0.05) increased cytotoxicity and caspase 3 activation only in cancerous BUT NOT normal non‐cancerous B lymphocytes. These results showed that H. parva methanolic extract has a selective mitochondria mediated apoptotic effect on chronic lymphocytic leukemia B lymphocytes hence may be promising in the future anticancer drug development for treatment of CLL. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1158–1169, 2017.     

1,25-dihydroxyvitamin D3 prevents deleterious effects of erythromycin on mitochondrial function in rat heart isolated mitochondria

Erythromycin (ERY) is a risk factor for cardiotoxicity through the mitochondria pathway. In the current study, we tested the hypothesis that erythromycin could impair mitochondrial function and oxidative stress and 1,25-dihydroxivitamin D3 (calcitriol) treatment could prevent these effects in rat heart isolated mitochondria. Rat heart mitochondria were isolated with mechanical lysis and differential centrifugation. Then isolated mitochondria were first pretreated with three different concentrations of 1,25-dihydroxivitamin D3 (2.5, 5 and 10 µmol/L) for 5 minutes at 37°C, after which erythromycin (10 µmol/L) was added to promote deleterious effects on mitochondria. During 1 hour of incubation, using by flow cytometry and biochemical evaluations, the parameters of mitochondrial toxicity were evaluated, including: succinate dehydrogenase (SDH) activity, mitochondrial swelling, mitochondrial membrane potential (MMP) collapse, reactive oxygen species (ROS) formation and lipid peroxidation (LP). The results showed that erythromycin (10 µmol/L) caused a significant change in mitochondrial function, ROS formation, mitochondrial swelling, MMP collapse, increasing lipid peroxidation and oxidative stress. 1,25-dihydroxivitamin D3 (10 µmol/L) reverted the effect of erythromycin on the tested parameters . In this study, we showed that erythromycin impairs mitochondrial function and induces mitochondrial toxicity in rat heart isolated mitochondria, which were reverted by calcitriol. These findings suggest that 1,25-dihydroxivitamin D3 may be a preventive/therapeutic strategy for cardiotoxicity complications caused by erythromycin.     

A new approach on methamphetamine-induced hepatotoxicity: involvement of mitochondrial dysfunction

Abstract

1.?Methamphetamine (METH) is a highly addictive stimulant that is among the most widely abused illicit drugs. Clinical evidence has shown that the liver is a target of METH toxicity. The exact cellular and molecular mechanisms involved in METH-induced hepatotoxicity have not yet been completely understood.

2.?In this study, the cellular pathways involved in METH liver toxicity were investigated in freshly isolated rat hepatocytes. METH cytotoxicity was associated with reactive oxygen species (ROS) formation, lipid peroxidation and rapid glutathione (GSH) depletion which is a third marker of cellular oxidative stress. Our results showed that the hepatocyte mitochondrial membrane potential (ΔΨm) was rapidly decreased by METH, which was prevented by antioxidants and ROS scavenger, suggesting that mitochondrial membrane damage was a consequence of ROS formation. Incubation of hepatocytes with METH also caused release of cytochrome c from mitochondria into the cytosol before cell lysis ensued.

3.?Our findings showed that cytotoxic action of METH is mediated by oxidative stress and subsequent changes in mitochondrial membrane conformation and cytochrome c release into the cytosol which causes mitochondrial collapse of ΔΨm.     

Toxicity of new synthetic amphetamine drug mephedrone On Rat Heart mitochondria: a warning for its abuse

Abstract

1.?Mephedrone, a new and popular amphetamine drug, is widely abused and is still legal in some parts around the world. Little data on mechanisms involved in mephedrone induced cardiotoxicity are available.

2.?Therefore, we decided to explain the mechanisms of mephedrone cardiotoxicity by using mitochondria isolated from rat heart. The isolated heart mitochondria were incubated with different concentrations of mephedrone (5, 10 and 20?µM).

3.?Results showed that mephedrone induced mitochondrial dysfunction via an increase in mitochondrial reactive oxygen species (ROS) production, mitochondrial membrane potential (MMP) collapse, mitochondrial swelling and damage in the mitochondrial outer membrane (MOM) which is associated with the cytochrome c release. Our results showed that decrease of ATP levels is an indicator of disturbance in oxidative phosphorylation. Also, mephedrone increased the caspase-3 activity.

4.?According to the results, we suggest that mephedrone induced cardiotoxicity is the result of a disruptive effect on the mitochondrial respiratory chain and induction of ROS-mediated apoptosis signaling in heart cardiomyocytes.     

Induction of mitochondrial permeability transition (MPT) pore opening and ROS formation as a mechanism for methamphetamine-induced mitochondrial toxicity

During the past 10 years, the use of methamphetamine (METH) has significantly increased in Iran and around the world. The widespread use of 3,4-methylenedioxymethamphetamine as a recreational drug has been responsible for the incidence of several cases of liver failure in young people. This issue made researchers focus on METH toxicity due to the lack of effective treatment and human health risk assessment. There are several reports showing that its long-term use increases the risk for dopamine depletion, but the toxicity mechanisms of METH in liver are not well understood. Therefore, we aimed to investigate the mitochondrial toxicity mechanisms of METH on isolated mitochondria. Rat liver mitochondria were obtained by differential ultracentrifugation, and the isolated mitochondria were then incubated with different concentrations of METH (2.5–20 μM). Our results showed that this agent could induce oxidative stress via rising in mitochondrial reactive oxygen species (ROS) formation, lipid peroxidation, mitochondrial membrane potential collapse, and mitochondrial swelling. In addition, collapse of mitochondrial membrane potential, mitochondrial swelling, and release of cytochrome c following METH treatment were well inhibited by pretreatment of mitochondria with cyclosporin A and butylated hydroxytoluene. Finally, it is suggested that METH could interact with respiratory complexes (II and III) and METH-induced liver toxicity may be the result of its disruptive effect on mitochondrial respiratory chain that is the obvious cause of ROS formation, mitochondrial membrane potential decline, and cytochrome c expulsion which start cell death signaling.     

Protective effects of coenzyme Q10 nanoparticles on dichlorvos‐induced hepatotoxicity and mitochondrial/lysosomal injury

Development of biocompatible antioxidant nanoparticles for xenobiotic‐induced liver disease treatment by oral or parenteral administration is of great interest in medicine. In the current study, we demonstrate the protective effects of coenzyme Q10 nanoparticles (CoQ10‐NPs) on hepatotoxicity induced by dichlorvos (DDVP) as an organophosphate. Although CoQ10 is an efficient antioxidant, its poor bioavailability has limited the applications of this useful agent. First, CoQ10‐NPs were prepared then characterized using dynamic light scattering (DLS) and transmission electron microscopy (TEM). In DDVP‐treated and non‐treated hepatocytes in the presence of CoQ10‐NPs, cell viability, the level of reactive oxygen species (ROS), lipid peroxidation (LPO), mitochondrial membrane potential (MMP), lysosome membrane integrity, and cellular glutathione (GSH) content were measured. The prepared CoQ10‐NPs were mono‐dispersed and had narrow size distribution with average diameter of 54 nm. In the in vivo study, we evaluated the enzymes, which are involved in the antioxidant system for maintenance of normal liver function. In comparison to nonparticulate CoQ10, the CoQ10‐NPs efficiently decreased the ROS formation, lipid peroxidation and cell death. Also, particulate form of CoQ10 improved MMP, GSH level and lysosome membrane integrity. In the in vivo, study, we revealed that CoQ10‐NPs were better hepatoprotective than its nonparticulate form (P < .05). Altogether, we propose that the CoQ10‐NPs have potential capability to be used as a therapeutic and prophylactic agent for poisoning that is induced by organophosphate agents, especially in the case of DDVP. Furthermore, these positive remarks make this nanoparticle amenable for the treatment of xenobiotic‐induced liver diseases.     

Methotrexate induced mitochondrial injury and cytochrome c release in rat liver hepatocytes

Methotrexate (MTX) is a folic acid antagonist that is widely used to treat a variety of diseases. One of the most serious side effects of MTX therapy is hepatotoxicity. The potential molecular cytotoxic mechanisms of MTX toward isolated rat hepatocytes were investigated using Accelerated Cytotoxicity Mechanism Screening (ACMS) techniques. A concentration and time dependent increase in cytotoxicity and reactive oxygen species (ROS) formation and a decrease in mitochondrial membrane potential (MMP) were observed with MTX. Furthermore, a significant increase in MTX (300?μM)-induced cytotoxicity and ROS formation were observed when glutathione (GSH)-depleted hepatocytes were used whereas addition of N-acetylcysteine (a GSH precursor) decreased cytotoxicity. Catalase inactivation also increased MTX-induced cytotoxicity, while the direct addition of catalase to the hepatocytes decreased cytotoxicity. MTX treatment in isolated rat mitochondria caused swelling and significantly decreased adenosine triphosphate (ATP) and GSH content, and cytochrome c release. Potent antioxidants such as mesna, resveratrol and Trolox decreased MTX-induced cytotoxicity and ROS formation and increased MMP. This study suggests that MTX-induced cytotoxicity caused by ROS formation and GSH oxidation leads to oxidative stress and mitochondrial injury in rat hepatocytes.     

Hydroxyapatite nanoparticle‐induced mitochondrial energy metabolism impairment in liver cells: in vitro and in vivo studies

Hydroxyapatite nanoparticles (HAP‐NPs) have been extensively developed as drug carriers, bone implants, coating materials, etc. in the human body. However, research focusing on the potential side effects of HAP‐NPs on the mitochondria‐associated energy metabolism in liver cells is lacking. In this study, HAP‐NPs with a long diameter of 80 nm and a short diameter of 20 nm were evaluated for their ability to induce mitochondrial energy metabolism dysfunction in vitro and in vivo . In the in vitro system, the buffalo rat hepatocyte (BRL) cell line was directly exposed to the HAP‐NPs. The results of these experiments showed that the HAP‐NPs induced inhibition of mitochondrial dehydrogenase activity, which was accompanied by a decrease in the mitochondrial membrane potential (MMP). In addition, HAP‐NPs elevated the hepatic levels of reactive oxygen species (ROS) and malondialdehyde (MDA) and decreased the levels of GSH and SOD. These data indicated that HAP‐NPs induced a lowered rate of electron transfer in the mitochondrial respiratory chain, accompanied by a decrease in the activity of the mitochondrial respiratory chain complexes I, II and III. Furthermore, HAP‐NPs induced a decline in the enzymatic expression in the Krebs cycle. We also investigated the role of Kupffer cells (KCs, rat‐derived) in the effects induced by the HAP‐NPs. The supernatant from the HAP‐NP‐treated KCs was used to stimulate the BRL cells. We observed that the HAP‐NPs had the ability to induce KC activation. The activation of KCs then led to the release of tumor necrosis factor‐α (TNF‐α), nitric oxide (NO) and reactive oxygen species (ROS), and induced the inhibition of mitochondrial respiratory chain complexes I, II and III in the BRL cells. In the in vivo study, the TEM examination revealed mitochondrial swelling and vacuolar degeneration in the HAP‐NP‐treated hepatocytes. In addition, the amount of succinate (Suc), an intermediate in the mitochondrial Krebs cycle, also declined in the ¹H NMR spectroscopic measurements. Copyright © 2017 John Wiley & Sons, Ltd.     

Cardiotoxin III induces apoptosis in T24 cells via reactive oxygen species‐independent mitochondrial death pathway

Cardiotoxin III (CTX III), a basic polypeptide with 60 amino acid residues isolated from Naja naja atra venom, has been reported to have anticancer activity. CTX III inhibited the growth of T24 cells in a time‐ and dose‐dependent manner with an IC₅₀value of 1.7 µg/mL and displayed several features of apoptosis including apoptotic body formation, increase of sub G₁ population, DNA fragmentation, and poly (ADP‐ribose) polymerase (PARP) cleavage. Using apoptosis analysis, measurement of reactive oxygen species (ROS) and assessment of mitochondrial membrane potentials (ΔΨm), CTX III was found to be a potent inducer of apoptosis, transducing apoptotic signals via a decrease in mitochondrial membrane potential (ΔΨm) and release of cytochrome c from mitochondria into cytosol. However, CTX III did not generate reactive oxygen species (ROS). Taken together, the present data indicate that CTX III induces apoptosis in T24 cells through an ROS‐independent mitochondrial dysfunction pathway and resultant cytochrome c release. This is the first report on the mechanism of the anticancer effect of CTX III on T24 cells. Drug Dev. Res. 63:219–224, 2004. © 2004 Wiley‐Liss, Inc.     

The role of mitochondria-mediated intrinsic death pathway in gingerdione derivative I6-induced neuronal apoptosis

Neuronal death induced by I6 displayed apoptotic characteristics but the precise mechanism has not been fully elucidated. In the present studies, I6 at 24 h after intraperitoneal administration significantly decreased the density of surviving neurons and increased caspase-3 activity in frontal cortex, suggesting that peripherally administered I6 may cross BBB to induce CNS toxicity. In rat embryonic primary cortical cells, I6-induced reduction of mitochondrial viability and neuronal apoptosis was inhibited by vitamin E. In addition, I6-induced reactive oxygen species (ROS) caused the disruption of mitochondria membrane potential (MMP), the release of cytochrome c, the activation of caspase-9 and caspase-3, and cleavage of poly(ADP-ribose) polymerase (PARP), resulting in activation of mitochondrial-mediated intrinsic death pathway. Pre-treatment with antioxidant vitamin E or N-acetylcysteine (NAC) completely abolished the I6-induced generation of ROS, loss of MMP, release of cytochrome c, activation of caspase-9 and caspase-3, and cleavage of PARP. Carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone (FCCP), a mitochondrial uncoupler, significantly reduced I6-induced neuronal death as well as caspase-3 activation and PARP cleavage. These results suggest that I6 induces neuronal death by promoting intracellular ROS production to cause a loss of MMP that result in release of cytochrome c and activation of mitochondria-mediated intrinsic death pathway.     

The effects of para-phenylenediamine (PPD) on the skin fibroblast cells

Abstract

1. Para-phenylenediamine (PPD) is the commonest and most well-known component of hair dyes. PPD is found in more than 1000 hair dye formulations and is the most frequently used permanent hair dye component in Europe, North America and East Asia. PPD containing hair dyes have been associated with cancer and mutagenicity. Apart from that, PPD has potential toxicity which includes acute toxicity such as allergic contact dermatitis and subacute toxicity.

2. In this study, we examined the effects of the PPD composition on the skin-isolated fibroblast cells. Fibroblast cells were isolated from the skin and cell viability, reactive oxygen species (ROS) production, the collapse of mitochondrial membrane potential (MMP), lipid peroxidation (LPO), damage to the lysosome release of lactate dehydrogenase (LDH) and finally release of cytochrome c were examined following the exposure to various concentrations of PPD.

3. Our results showed that exposure to PPD increased ROS generation, LPO, the collapse of MMP, LDH release and cytochrome c release. Our results suggest that PPD can induce damage to the lysosomal membrane.

4. These results showed that PPD composition has a selective toxicity on skin fibroblasts cell and mitochondria are considered one of the goals of its toxicity.     

A novel 7‐azaisoindigo derivative‐induced cancer cell apoptosis and mitochondrial dysfunction mediated by oxidative stress

This research focused on a novel 7‐azaisoindigo derivative [namely N¹‐(n‐butyl)‐7‐azaisoindigo, 7‐AI‐b], and investigated its molecular antitumor mechanism by exploring the means of cell death and the effects on mitochondrial function. 7‐AI‐b inhibited cancer cell proliferation in a dose‐ and time‐dependent way. The morphological and nuclei changes in H₂B‐GFP‐labeled HeLa cells were observed using a live cell system. The results suggested that cell death induced by 7‐AI‐b is closely related to apoptosis. 7‐AI‐b induced release of cytochrome C from mitochondria to cytosol and activation of caspase‐3, showing that the apoptosis is mediated by the mitochondrial pathway. Furthermore, our data indicated that 7‐AI‐b triggers apoptosis through reactive oxygen species (ROS): cellular ROS levels were increased after 3 h exposure of 7‐AI‐b, which was reversed by the ROS scavenger N‐acetyl‐l ‐cysteine. As a consequence, 7‐AI‐b‐mediated cell death, mitochondrial transmembrane potential collapse and ATP level were partly blocked by N‐acetyl‐l ‐cysteine. Further study showed that 7‐AI‐b could induce mitochondrial dysfunction: collapse of the mitochondrial transmembrane potential and reduction of intracellular ATP level. In summary, the novel synthesized 7‐AI‐b was demonstrated to be effective in killing cancer cells via an ROS‐promoted and mitochondria‐ and caspase‐dependent apoptotic pathway. Copyright © 2010 John Wiley & Sons, Ltd.     

Toxicity of Atorvastatin on Pancreas Mitochondria: A Justification for Increased Risk of Diabetes Mellitus

Statins (including atorvastatin) are a widely used class of drugs, and like all medications, they have a potential for adverse effects. Recently, it has been shown that statins also exert side effects on the pancreas. In vitro studies have suggested that this class of drugs induced a reduction in insulin secretion. Also, the use of statins is associated with a raised risk of diabetes mellitus (DM), but the mechanisms underlying statin‐induced diabetes are poorly known. Literature data indicate that several statins are able to induce apoptosis signalling. This study was designed to examine the mechanism of atorvastatin on mitochondria obtained from rat pancreas. In our study, mitochondria were obtained from the pancreas and then exposed to atorvastatin and vehicle to investigate probable toxic effects. The results showed that atorvastatin (25, 50, 75, 100 and 125 μM) increased reactive oxygen species (ROS) production, mitochondrial swelling, collapse of mitochondrial membrane potential and cytochrome c release, the orchestrating factor for mitochondria‐mediated apoptosis signalling. Atorvastatin also reduced the ATP levels. These results propose that the toxicity of atorvastatin on pancreas mitochondria is a key point for drug‐induced apoptotic cell loss in the pancreas and therefore a justification for increased risk of DM.     

镉诱发HEK293细胞凋亡的线粒体途径

目的研究镉引起的HEK293细胞凋亡与线粒体的关系。方法分别以2′,7′-二氯荧光素二酯和若丹明123为荧光探针,经流式细胞仪检测胞浆内活性氧含量和线粒体膜电位的变化;Western印迹法检测线粒体细胞色素c的释放。结果在镉诱导HEK293细胞的凋亡过程中,胞浆内的活性氧水平升高,但能被抗氧化剂N-乙酰-L-半胱氨酸(NAC)抑制;同时,镉使线粒体膜电位下降和线粒体细胞色素c释放进入胞浆,二者都被NAC加剧。结论镉诱导HEK293细胞的凋亡可能通过线粒体途径。     

Involvement of mitochondrial alteration and reactive oxygen species generation in Taiwan cobra cardiotoxin-induced apoptotic death of human neuroblastoma SK-N-SH cells

Naja naja atra cardiotoxin 3 (CTX3) induced apoptotic death on human neuroblastoma SK-N-SH cells. The apoptosis signals of CTX3 included reactive oxygen species (ROS) generation, disruption of mitochondrial membrane potential (DeltaPsim), cytochrome c release to the cytosol and activation of caspase-9 and -3. However, CTX3-induced increase in mitochondrial permeability transition was not initiated by proteins of the Bcl-2 family. The collapse of DeltaPsim, release of cytosolic cytochrome c, production of ROS and subsequent apoptotic cell death in CTX-treated cells could not be completely abolished by either N-acetylcysteine (ROS scavenger) or cyclosporin A (an inhibitor of mitochondrial permeability transition). Co-incubation with rotenone, an inhibitor of mitochondrial electron transport chain complexes I, resulted in partial inhibition of CTX3-induced ROS generation but not the loss of DeltaPsim. Obviously, the dissipation of DeltaPsim was not an upstream event for ROS generation or vice versa. Given that CTX3 was able to induce the leakage of isolated mitochondria, our data indicate that CTX3-induced apoptotic death of SK-N-SH cells is mediated through mitochondrial alteration and ROS generation.