Alpha‐lipoic acid reduces methylmercury‐induced neuronal injury in rat cerebral cortex via antioxidation pathways

Methylmercury (MeHg), an extremely dangerous environmental pollutant, accumulating preferentially in central nervous system, causes a series of cytotoxic effects. The present study explored the mechanisms which contribute to MeHg‐induced neurotoxicity focusing on the oxidative stress in rat cerebral cortex. In addition, the protective effects of alpha‐lipoic acid (LA), a potent antioxidant on MeHg‐mediated neuronal injury, was also investigated in current study. A MeHg poisoning model was established as 64 rats randomly divided into 4 groups of which saline control group, MeHg‐treated groups (4 and 12 μmol kg^?1), and LA pretreatment (35 μmol kg^?1) group, respectively. After administration of 12 μmol kg^?1 MeHg for 4 weeks, it was found that obvious pathological changes and apoptosis in neuronal cells. Meanwhile, total Hg levels elevated significantly, superoxide dismutase (SOD) and gluthathione peroxidase (GSH‐Px) activities were inhibited, and ROS formation elevated, which might be critical to aggravate oxidative stress in cerebral cortex. In addition, NF‐E2‐related factor 2 (Nrf2) pathways were activated, as heme oxygenase‐1 (HO‐1) and γ‐glutamylcysteine synthetase heavy subunit (γ‐GCSh) expressions were up‐regulated obviously by MeHg exposure. Moreover, activities of Na⁺‐K⁺‐ATPase and Ca²⁺‐ATPase were inhibited, leading to intracellular calcium (Ca²⁺) overload. LA pre‐treatment partially reduced MeHg neurotoxic effects via anti‐oxidation pathways. In conclusion, these findings clearly indicated that MeHg aggravated oxidative stress and Ca²⁺ overload in cerebral cortex. LA possesses the ability to prevent MeHg neurotoxicity through its anti‐oxidative properties. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 931–943, 2017.     

Hydroxytyrosol,a dietary phenolic compound forestalls the toxic effects of methylmercury‐induced toxicity in IMR‐32 human neuroblastoma cells

This study demonstrates the protective potential of hydroxytyrosol (HT), an olive oil phenol, against methylmercury (MeHg)‐induced neurotoxicity using IMR‐32 human neuroblastoma cell line. HT inhibited MeHg‐induced cytotoxicity and genotoxicity as confirmed by MTT, micronucleus, and comet assays. Cells preconditioned with HT showed reduction of MeHg‐induced cellular oxidative stress along with the maintenance of glutathione, superoxide dismutase, glutathione‐S‐tranferase, and catalase. Fluorescence microscopy and DNA ladder assays indicated the inhibitory effect of HT against MeHg‐induced apoptosis, which was further established by Western blotting. An effective concentration of 5 µM HT caused downregulation of p53, bax, cytochrome c, and caspase 3 and upregulation of prosurvival proteins including nuclear factor erythroid 2‐related factor 2 (Nrf2) and metallothionein. This work indicates the cytoprotective potential of HT against MeHg‐induced toxicity primarily by the lowering of oxidative stress, which may be endorsed to its antigenotoxic and antiapoptotic potential, in addition to its free radical scavenging ability. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1264–1275, 2016.     

Riluzole prevents morphine-induced apoptosis in rat cerebral cortex

Neuronal apoptosis has been shown to be associated with the development of tolerance to morphine. In the present study, we investigated the effect of intracerebroventricular (icv) administration of an inhibitor of glutamate release, riluzole, on morphine-induced apoptosis in the rat cerebral cortex. Various groups of rats received either morphine (intraperitoneally, ip) and vehicle (icv) or morphine (ip) and different doses of riluzole (icv) once per day for 8 days. An in situ terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL) method was used as an apoptosis assay. Levels of the anti-apoptotic factors Bcl-2 and HSP70 and the pro-apoptotic agent caspase-3 were evaluated by immunoblotting. The glutamate concentration in the cerebral cortex was measured by high performance liquid chromatography (HPLC). The results showed that icv administration of riluzole decreased the number of apoptotic cells in the cerebral cortex compared with the control group, which was treated with morphine (ip) and 1% Tween 80 in 0.9% normal saline (icv). The levels of the anti-apoptotic proteins Bcl-2 and HSP70 were higher in the riluzole groups than in the control. Furthermore, co-administration of riluzole with morphine significantly decreased caspase-3 protein levels and glutamate content of the cerebral cortex compared with the control. In conclusion, we found that icv administration of riluzole attenuates morphine-induced apoptosis in the cerebral cortex after the development of morphine tolerance.     

Epigallocatechin-3-gallate attenuates acrylamide-induced apoptosis and astrogliosis in rat cerebral cortex

The potent neurotoxic agent acrylamide (ACR) is formed during Maillard reaction in food processing. Epigallocatechin-3-gallate (EGCG), a major bioactive component of green tea, is an antioxidant, but its effects on ACR-induced neurotoxicity are unclear. Here, we investigated the neuroprotective effects of EGCG against ACR-induced apoptosis and astrogliosis in the cerebral cortex. Rats were pretreated with EGCG for 4 d and then co-administered ACR for 14 d. Immunohistochemical analysis of glial fibrillary acidic protein and 8-hydroxy-2′-deoxyguanosine indicated that EGCG attenuated astrogliosis and DNA damage in ACR-treated rats. Analysis of DNA fragmentation and protein expression of Bax, Bcl-2, caspase 3, and cytochrome c revealed that EGCG inhibited ACR-induced apoptosis. Furthermore, EGCG inhibited oxidative stress by enhancing the activity of antioxidant enzymes and glutathione levels and reducing the formation of reactive oxygen species and lipid peroxidation. Taken together, our data demonstrate that EGCG inhibits ACR-induced apoptosis and astrogliosis in the cerebral cortex.     

Crocin and quercetin prevent PAT‐induced apoptosis in mammalian cells: Involvement of ROS‐mediated ER stress pathway

Patulin (PAT) is a secondary metabolite produced by several species of the genera of Penicillium, Aspergillus, and Byssochlamys that can be found in rotting fruits, especially in apples and apple‐based products. Exposure to this mycotoxin has been reported to induce intestinal and kidney injuries. The mechanism underlying such toxicity has been linked to the induction of apoptosis which occurred with reactive oxygen species production and endoplasmic reticulum (ER) stress induction. This study aimed to evaluate the effect of the two common dietary compounds Quercetin (QUER), a natural flavonoid, and Crocin (CRO), a natural carotenoid, on PAT‐induced toxicity in human colon carcinoma (HCT116) and embryonic kidney cells (HEK293). We showed that antioxidant properties of QUER and CRO help to prevent ER stress activation and lipid peroxidation as evidenced by the reduction in GRP78 and GADD34 expressions and the decrease in malondialdehyde production. Furthermore, we demonstrated their ability to re‐establish the loss of the mitochondrial membrane potential to inhibit caspase 3 activation and DNA fragmentation. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1851–1858, 2016.     

Silver nanoparticle‐induced oxidative stress,genotoxicity and apoptosis in cultured cells and animal tissues

Silver nanoparticles (AgNPs) have emerged as an important class of nanomaterials for a wide range of industrial and medical applications. However, the unique properties of AgNPs could potentially lead to unexpected hazards to both human health and the well being of the environment. Possible mechanisms of AgNP‐induced toxicity include the stimulation of oxidative stress, genotoxicity and apoptosis. In this study, a number of previous studies are therefore summarized that demonstrate oxidative stress‐, genotoxicity‐ and apoptosis‐related changes brought about by AgNPs in cultured cells and animal tissues. The physicochemical properties of AgNPs that are involved in encouraging such changes are also discussed. Copyright © 2012 John Wiley & Sons, Ltd.     

Acrylonitrile induced apoptosis via oxidative stress in neuroblastoma SH-SY5Y cell

Acrylonitrile (ACN) is a chemical that is widely used in the production of plastics, acrylic fibers, synthetic rubbers and resins. It has been reported that ACN can cause oxidative stress, a condition which is well recognized as an apoptotic initiator; however, information regarding ACN-induced apoptosis is limited. This present study investigated whether ACN induces apoptosis in human neuroblastoma SH-SY5Y cells, and whether its apoptotic induction involves oxidative stress. The results showed that ACN caused activation of caspase-3, a key enzyme involved in apoptosis, in a dose- and time-dependent manner. Detection of sub-G1 apoptotic cell death and apoptotic nuclear condensation revealed that ACN caused an increase in the number of apoptotic cells indicating ACN induces apoptosis in SH-SY5Y cells. ACN dose- and time-dependently increased the level of proapoptotic protein, Bax. Pretreatment with N-acetylcysteine (NAC), an antioxidant, attenuated caspase-3 activation by ACN, as evidenced by a reduction in proteolysis of PARP, a known caspase-3 substrate, as well as in the number of sub-G1 apoptotic cells. Moreover, induction of Bax by ACN was abolished by NAC. Taken together, the results indicate that ACN induces apoptosis in SH-SY5Y cells via a mechanism involving generation of oxidative stress-mediated Bax induction.     

谷氨酸致伤后神经元胞内游离钙的动态变化

目的：探讨谷氨酸致伤后大脑皮层神经元胞内游离钙的动态变化特征,:方法：大鼠大脑皮层神经元原代分离培养方法和光电联合检测技术,培养8天的神经元用于实验,结果：谷氨酸致伤2h内,神经元胞内游防钙降低,60min,90min组比对照组明显降低,2h后胞内游离钙升高,以210min,480min组升高显著,结论：Ca2 稳态破坏参与谷氨酸致伤过程,不仅是Ca2 超载,早期Ca2 降低值得重视。     

Cytotoxicity,genotoxicity, oxidative stress,and apoptosis in HepG2 cells induced by the imidazole ionic liquid 1‐dodecyl‐3‐methylimidazolium chloride

This study purposes to assess the cytotoxicity of 1‐dodecyl‐3‐methylimidazolium chloride ([C₁₂min]Cl) in human hepatocellular carcinoma (HepG2) cells. To this end, HepG2 cells were exposed to a range concentration of [C₁₂min]Cl and evaluated cell viability, genotoxicity, oxidative stress, apoptosis, cell cycle, and apoptosis‐related gene expression to determine cytotoxicity. The outcomes showed that [C₁₂min]Cl curbed HepG2 cell growth and reduced cell viability in a concentration‐ and time‐dependent manner. Moreover, our assay results also revealed that exposure to [C₁₂min]Cl prompted DNA damage and apoptosis, reduced SOD and GSH content, enhanced MDA level, and changed the cell cycle of HepG2 cells. In addition, [C₁₂min] Cl caused alters in the expression levels of p53, Bax, and Bcl‐2, indicating that p53 and Bcl‐2 family may be involved in the cytotoxicity and apoptosis of HepG2 cells induced by [C₁₂min]C1. In summary, these results indicate that [C₁₂min]Cl exerts genotoxicity, physiological toxicity and prompts apoptosis in HepG2 cells, and is not an alleged green solvent.     

Oxidative stress modulation by Rosmarinus officinalis in creosote‐induced hepatotoxicity

Coal tar is a significant product generated from coal pyrolysis. Coal tar can be utilized as raw materials for various industries. It is also a type of raw material from which phenols, naphthalenes, and anthracene can be extracted. The present study was designed to investigate the possibility of coal tar creosote to induce oxidative stress and biochemical perturbations in rat liver and the role of rosemary (Rosmarinus officinalis) in ameliorating its toxic effects. Male Wister Albino rats were randomly divided into four groups of seven each, group I served as control; group II treated with rosemary (10 mL of water extract/kg BW for 21 days), group III received coal tar creosote (200 mg/4 mL olive oil/kg BW for 3 days), and group IV treated with both rosemary and coal tar creosote. The administration of coal tar creosote significantly caused elevation in lipid peroxidation (LPO) and reduction in the activities of glutathione peroxidase (GPx), glutathione reductase (GR), superoxide dismutase (SOD), catalase (CAT), and glutathione S‐transferase (GST). A significant decrease in reduced glutathione (GSH) content was also observed. Liver aminotransferases aspartate transaminase (AST) and alanine transaminase (ALT)] and alkaline phosphatase (AlP) were significantly decreased while lactate dehydrogenase (LDH) was increased. Rosemary pretreatment to coal tar creosote‐treated rats decreased LPO level and normalized GPx, GR, SOD, CAT, and GST activities, while GSH content was increased. Also, liver AST, ALT, AlP, and LDH were maintained near normal level due to rosemary treatment. In conclusion, rosemary has beneficial effects and could be able to antagonize coal tar creosote toxicity. © 2014 Wiley Periodicals, Inc. Environ Toxicol 31: 85–92, 2016.     

The role of GSH in microcystin‐induced apoptosis in rat liver: Involvement of oxidative stress and NF‐κB

Microcystins (MCs) are potent and specific hepatotoxins produced by cyanobacteria in eutrophic waters, representing a health hazard to animals and humans. The objectives of this study are to determine the relationship between oxidative stress and NF‐κB activity in MC‐induced apoptosis in rat liver and the role of glutathione (GSH). Sprague‐Dawley rats were intraperitoneally (i.p.) injected with microcystin‐LR (MC‐LR) at 0.25 and 0.5 LD₅₀ with or without pretreatment of buthionine‐(S,R)‐sulfoximine (BSO), a specific GSH synthesis inhibitor. MC‐LR induced time‐dependent alterations of GSH levels in rat liver. Increased malondialdehyde (MDA) and significant changes of antioxidant enzymes including GSH peroxidase (GPX) and GSH reductase (GR) were also observed, particularly at 24 h post‐exposure. The results indicated that acute exposure to MC‐LR induced oxidative stress, and GSH depletion (BSO pretreatment) enhanced the level of oxidative stress. Furthermore, the modulation of pro‐apoptotic gene p53 and Bax and anti‐apoptotic gene Bcl‐2 was observed in 0.5 LD₅₀ group at 24 h, and the alteration was more pronounced by BSO injection before MC‐LR treatment, suggesting that GSH played a protective role against MC‐induced toxicity. Additionally, electrophoretic mobility shift assay (EMSA) showed that NF‐κB was induced at 0.25 LD₅₀ but inhibited at 0.5 LD₅₀. The above results indicated that the possible crosstalk of oxidative stress and NF‐κB activity was associated with MC‐LR‐induced hepatocytes apoptosis in vivo. Our data will provide a new perspective for understanding the mechanisms of MC‐induced liver injury. © 2014 Wiley Periodicals, Inc. Environ Toxicol 31: 552–560, 2016.     

Excitotoxicity and oxidative damages induced by methylmercury in rat cerebral cortex and the protective effects of tea polyphenols

Methylmercury (MeHg) is a highly neurotoxic environmental pollutant that has a high appetency to the central nervous system. The underlying mechanisms of MeHg‐induced neurotoxicity have not been elucidated clearly until now. Therefore, to explore the mechanisms contribute to MeHg‐induced neurotoxicity, rats were exposed to different dosage of methylmercury chloride (CH₃ClHg) (0, 4, and 12 μmol kg^?1) for 4 weeks to evaluate the neurotoxic effects of MeHg. In addition, considering the antioxidative properties of tea polyphenols (TP), 1 mmol kg^?1 TP was pretreated to observe the possible protective effects on MeHg‐induced neurotoxicity. Then Hg, glutamate (Glu) and glutamine (Gln) levels, glutamine synthetase (GS), phosphate‐activated glutaminase (PAG), Na⁺‐K⁺‐ATPase, and Ca²⁺‐ATPase activities, intracellular Ca²⁺ level were examined, glutathione (GSH), malondialdehyde (MDA), protein sulfhydryl, carbonyl, 8‐hydroxy‐2‐deoxyguanosine (8‐OHdG), and reactive oxygen species (ROS) levels, N‐methyl‐D ‐aspartate receptors (NMDARs) mRNA and protein expressions, apoptosis level and morphological changes in the cerebral cortex were also investigated. Study results showed that compared with those in control, exposure to CH₃ClHg resulted in excitotoxicity in a concentration‐dependent manner, which was shown by the Glu‐Gln cycle disruption and intracellular Ca²⁺ homeostasis disturbance. On the other hand, CH₃ClHg exposure resulted in oxidative damages of brain, which were supported by the significant changes on GSH, MDA, sulfhydryl, carbonyl, 8‐OHdG, and ROS levels. Moreover, apoptosis rate increased obviously and many morphological changes were found after CH₃ClHg exposure. Furthermore, this research indicated that TP pretreatment significantly mitigated the toxic effects of MeHg. In conclusion, findings from this study indicated that exposure to MeHg could induce excitotoxicity and oxidative damage in cerebral cortex while TP might antagonize the MeHg‐induced neurotoxicity. © 2012 Wiley Periodicals, Inc. Environ Toxicol 29: 269–283, 2014.     

Markers of oxidative‐nitrosative stress induced by artesunate are followed by clastogenic and aneugenic effects and apoptosis in human lymphocytes

Artesunate (ARS) is a semi‐synthetic derivative of artemisinin, used as an outstanding antimalarial drug, which also displays antitumor, anti‐inflammatory and immunosuppressive effects. In spite of the numerous reports showing the antitumor activity of ARS, the particular mechanisms associated with its cytotoxicity and genotoxicity in non‐neoplastic human cells remain unclear. Here we aimed to verify the specific chromosome damages and the changes in markers of oxidative‐nitrosative stress and apoptosis triggered by ARS exposure in human peripheral blood lymphocytes. Cultures were incubated in the presence of ARS and the number of binucleated cells was determined. To discriminate between micronuclei (MN) containing a whole chromosome or an acentric chromosome, the MN test was employed in combination with the fluorescence in situ hybridization assay. Alterations in the levels of superoxide anion (O₂^?) and nitric oxide (NO) were measured by the nitroblue tetrazolium and Griess assay, respectively. Changes in the expression of the apoptotic markers were assessed by immunocytochemistry. We found that ARS induced a significant formation of both centromere‐positive MN (C⁺ MN) and centromere‐negative MN (C^– MN). These alterations were accompanied by an increase in both cellular levels of O₂^? and total NO production, and a remarkable enhancement in the expression of the apoptotic markers cytochrome c and caspases 8 and 9. Together these findings reveal that ARS induces changes in the oxidative‐nitrosative status of human lymphocytes, which are followed by apoptosis and clastogenic and aneugenic effects.     

Activation of the N‐methyl‐d‐aspartate receptor is involved in glyphosate‐induced renal proximal tubule cell apoptosis

Glyphosate‐based herbicides have been used worldwide for decades and have been suggested to induce nephrotoxicity, but the underlying mechanism is not yet clear. In this study, we treated a human renal proximal tubule cell line (HK‐2) with glyphosate for 24 hours at concentrations of 0, 20, 40 and 60 μm . Glyphosate was found to reduce cell viability and induce apoptosis and oxidative stress in a dose‐dependent manner. Because the chemical structures of glyphosate and those of its metabolite AMPA are similar to glycine and glutamate, which are agonists of the N‐methyl‐d ‐aspartate receptor (NMDAR), we investigated the potential role of the NMDAR pathway in mediating the proapoptotic effect of glyphosate on proximal tubule cells. We found that NMDAR1 expression, as well as intracellular Ca²⁺ ([Ca²⁺]_i) and reactive oxygen species (ROS) levels, increased after glyphosate treatment. Blocking NMDAR attenuated glyphosate‐induced upregulation of [Ca²⁺]_i and ROS levels as well as apoptosis. Meanwhile, inhibition of [Ca²⁺]_i reduced glyphosate‐induced ROS and apoptosis, and inhibition of ROS alleviated glyphosate‐induced apoptosis. In mice exposed to 400 mg/kg glyphosate, the urine low molecular weight protein levels started to increase from day 7. Upregulation of apoptosis and NMDAR1 expression in renal proximal tubule epithelium and an imbalance of oxidant and antioxidative products were observed. These results strongly suggest that activation of the NMDAR1 pathway, together with its downstream [Ca²⁺]_i and oxidative stress, is involved in glyphosate‐induced renal proximal tubule epithelium apoptosis.     

氧化应激致PC12细胞凋亡的信号传导途径的研究进展

PC12细胞被广泛用于神经细胞功能、分化、凋亡和神经递质分泌,以及潜在的分子机制的研究。氧化应激可导致PC12细胞凋亡,其作用方式为激活对氧化还原反应敏感的细胞信号传导,主要与丝裂原活化蛋白激酶、线粒体凋亡及NF-κB信号传导途径有关。本文综述了氧化应激致PC12细胞凋亡的信号传导途径,旨在为神经系统氧化应激相关疾病的抗氧化剂药物治疗和凋亡信号途径药物干预治疗提供理论依据。     

Ginsenoside Rd prevents glutamate‐induced apoptosis in rat cortical neurons

1. The role of voltage‐independent Ca²⁺ entry in cell apoptosis has recently received considerable attention. It has been found that ginsenoside Rd significantly inhibits voltage‐independent Ca²⁺ entry. The aim of the present study was to investigate the protective effects of ginsenoside Rd against glutamate‐induced apoptosis of rat cortical neurons. 2. Ginsenoside Rd significantly reduced glutamate‐induced apoptotic morphological changes and DNA laddering. In comparison, nimodipine only had a weak effect. 3. Ginsenoside Rd (1, 3 and 10 μmol/L) concentration‐dependently inhibited caspase 3 activation and expression of the p20 subunit of active caspase 3 (by 30 ± 10%, 41 ± 9% and 62 ± 19%, respectively, compared with glutamate alone; P < 0.05), whereas 1 μmol/L nimodipine had no effect. 4. Glutamate decreased cell viability to 37.4 ± 4.7 (n = 8) and evoked cell apoptosis. Ginsenoside Rd (1, 3, 10 and 30 μmol/L) concentration‐dependently inhibited glutamate‐induced cell death, increased cell viability and reduced apoptotic percentage (from 47.5 ± 4.9% to 37.4 ± 6.9%, 28.3 ± 5.2% and 22.5 ± 5.6%, respectively; P < 0.05). At 1 μmol/L, nimodipine had no effect on cell viability. Furthermore, although 1, 3, 10, 30 and 60 μmol/L ginsenoside Rd concentration‐dependently inhibited glutamate‐induced Ca²⁺ entry by 8 ± 2%, 24 ± 4%, 40 ± 7%, 49 ± 8% and 50 ± 8% (P < 0.05), respectively, nimodipine had no effect. 5. In conclusion, the results indicate that ginsenoside Rd prevents glutamate‐induced apoptosis in rat cortical neurons and provide further evidence of the potential of voltage‐independent Ca²⁺ channel blockers as new neuroprotective drugs for the prevention of neuronal apoptosis and death induced by cerebral ischaemia.     

Tri‐ortho‐cresyl phosphate (TOCP)‐induced reproductive toxicity involved in placental apoptosis,autophagy and oxidative stress in pregnant mice

Tri‐ortho‐cresyl phosphate (TOCP) has been widely used as plasticizers, and reported causing reproductive toxicity in mammals. However, little is known about the toxic effect on the placenta. In this study, dams were orally administered different doses of TOCP to explore the effect of TOCP on placental development. Results showed that TOCP exposure significantly reduced numbers of implanted embryo, caused atrophy and collapse of ectoplacental cone, and decreased total areas of placenta and numbers of PCNA‐positive cells. Expression levels of placental development genes were prominently downregulated in the TOCP‐treated groups. Moreover, TOCP administration induced placental apoptosis and autophagy by upregulating P53, Bax, Beclin‐1, ratio of LC3 II/LC3 I and Atg5 and downregulating Bcl‐2 protein. In addition, TOCP exposure markedly inhibited activities of catalase and superoxide dismutase and increased the production of H₂O₂ and malondialdehyde. Collectively, these findings suggest that apoptosis, autophagy and oxidative stress may be involved in the TOCP‐induced reproductive toxicity.     

Epigenetic modification of H3K4 and oxidative stress are involved in MC‐LR‐induced apoptosis in testicular cells of SD rats

Microcystin‐leucine arginine (MC‐LR) is a cyclic heptapeptide, produced by aquatic cyanobacteria such as microcystis, with strong reproductive toxicity which poses greater threat to the reproductive abilities of humans and animals. By exploring the role of trimethylation of histone H3 at lysine 4 (H3K4me3) and the role of oxidative stress in MC‐LR‐induced apoptosis in testicular Sertoli cells in Sprague‐Dawley (SD) rats, this study indicated that MC‐LR increased the expression levels of apoptosis‐related genes by raising the levels of H3K4me3. 5′‐Deoxy‐5′‐methylthioadenosine (MTA), the inhibitor of H3K4me3, reduced apoptosis, indicating for the first time that epigenetic modification is closely related to the testicular reproductive toxicity induced by MC‐LR. MC‐LR also induced oxidative stress by stimulating the generation of reactive oxygen species (ROS), and subsequently triggering mitochondria‐mediated apoptotic pathway by decreasing mitochondrial membrane potential and increasing the levels of Bax, Bcl‐2, Caspase‐3, and so on. MC‐LR‐induced apoptosis of testicular cells could be decreased after pretreatment with oxidative stress inhibitor N‐acetyl‐cysteine (NAC). Furthermore, the pathological damage to mitochondria and testes were observed in SD rats. These results show that MC‐LR can induce apoptosis by raising the levels of H3K4me3, and pretreatment with MTA can ameliorate the MC‐LR‐induced apoptosis of cocultured cells by lowering the levels of H3K4me3. Furthermore, NAC has a protective effect on MC‐LR‐induced apoptosis of testicular cells in SD rats by inhibiting the oxidative stress.     

Oxidative/nitrosative stress,autophagy and apoptosis as therapeutic targets of melatonin in idiopathic pulmonary fibrosis

ABSTRACT

Introduction: Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease associated with disruption of alveolar epithelial cell layer and expansion of fibroblasts/myofibroblasts. Excessive levels of oxidative/nitrosative stress, induction of apoptosis, and insufficient autophagy may be involved in IPF pathogenesis; hence, the targeting of these pathways may ameliorate IPF.

Areas covered: We describe the ameliorative effect of melatonin on IPF. We summarize the research on IPF pathogenesis with a focus on oxidative/nitrosative stress, autophagy and apoptosis pathways and discuss the potential effects of melatonin on these pathways.

Expert opinion: Oxidative/nitrosative stress, apoptosis and autophagy could be interesting targets for therapeutic intervention in IPF. Melatonin, as a potent antioxidant, induces the expression of antioxidant enzymes, scavenges free radicals and modulates apoptosis and autophagy pathways. The effect of melatonin in the induction of autophagy could be an important mechanism against fibrotic process in IPF lungs. Further clinical studies are necessary to determine if melatonin could be a candidate for treating IPF.