The C-glucosyl flavone isoorientin pretreatment attenuates the methylglyoxal-induced mitochondrial dysfunction in the human neuroblastoma SH-SY5Y cells: role for the AMPK-PI3K/Akt/Nrf2/γ-GCL/GSH axis.

The reactive dicarbonyl methylglyoxal (MG) behaves as a pro-oxidant agent, causing redox dysfunction and cell death by different mechanisms in mammalian cells. MG is also a mitochondrial toxicant, impairing the oxidative phosphorylation (OXPHOS) system and leading to bioenergetics and redox collapses. MG induces glycation and exerts an important role in neurodegenerative and cardiovascular diseases. Isoorientin (ISO), a C-glucosyl flavone found in Aspalathus linearis, Fagopyrum esculentum, and Passiflora edulis, among others, is an antioxidant and anti-inflammatory molecule. ISO is a potent inducer of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), the master modulator of the redox environment in mammals. We investigated here whether ISO would prevent the mitochondria-related redox and bioenergetics impairments induced by MG in the human neuroblastoma SH-SY5Y cells. The cells were administrated with ISO at 20 µM for 18 h prior to the exposure to MG at 500 µM for further 24 h. It was observed that ISO efficiently prevented the mitochondrial impairments caused by MG. ISO upregulated the activity of the enzyme γ-glutamate-cysteine ligase (γ-GCL), consequently stimulating the synthesis of glutathione (GSH). The inhibition of γ-GCL, adenosine monophosphate-activated protein kinase (AMPK), and phosphoinositide 3-kinase/Akt (PI3K/Akt) suppressed the beneficial effects induced by ISO on the MG-challenged cells. Moreover, silencing of Nrf2 blocked the ISO-dependent γ-GCL and GSH upregulation and the effects on the mitochondria of the MG-challenged cells. Then, ISO caused mitochondrial protection by an AMPK-PI3K/Akt/Nrf2/γ-GCL/GSH-dependent manner in MG-administrated SH-SY5Y cells.

The isothiocyanate sulforaphane prevents mitochondrial impairment and neuroinflammation in the human dopaminergic SH-SY5Y and in the mouse microglial BV2 cells: role for heme oxygenase-1.

Sulforaphane (SFN) promotes protective effects in different cell types. Nonetheless, it remains to be clarified by which mechanism SFN exerts benefits in mammalian cells. Mitochondria are a major source of adenosine triphosphate (ATP) and reactive species in nucleated cells. Mitochondrial impairment result in cellular redox biology disruption, bioenergetic status collapse, and inflammation. Evidence suggest that mitochondrial dysfunction plays a role in neurological disorders. Since a cure was not discovered yet to some of these diseases, investigating strategies to promote mitochondrial protection is pharmacologically relevant and may improve life quality of patients suffering from these maladies. Natural molecules, such as SFN, are potent inducers of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) and, consequently, stimulate the expression of genes whose products, such as heme oxygenase-1 (HO-1), induce cytoprotective actions in mammalian tissues. In this work, we investigated whether SFN (5 µM) would be capable to prevent the dysfunctions caused by chlorpyrifos (CPF) on the human dopaminergic SH-SY5Y cells. Moreover, we examined the effects of a pretreatment with SFN at the same concentration on the mouse microglial BV2 cells stimulated by lipopolysaccharide (LPS) in an experimental model of neuroinflammation. SFN prevented the mitochondrial impairment and the neuroinflammation caused by the chemical stressors in both cell types. Inhibition of heme oxygenase-1 (HO-1) suppressed the mitochondrial protection and anti-inflammatory action afforded by SFN in this experimental model. Overall, SFN promoted cytoprotection by a mechanism dependent on the HO-1 enzyme in the SH-SY5Y and BV2 cells.

A Pretreatment with Isoorientin Attenuates Redox Disruption, Mitochondrial Impairment, and Inflammation Caused by Chlorpyrifos in a Dopaminergic Cell Line: Involvement of the Nrf2/HO-1 Axis.

The C-glucosyl flavone isoorientin (ISO) is obtained by humans from the diet and exhibits several cytoprotective effects, as demonstrated in different experimental models. However, it was not previously shown whether ISO would be able to prevent mitochondrial impairment in cells exposed to a chemical stressor. Thus, we treated the human neuroblastoma SH-SY5Y cells with ISO (0.5-20 µM) for 18 h before a challenge with chlorpyrifos (CPF) at 100 µM for additional 24 h. We observed that ISO prevented the CPF-induced lipid peroxidation and protein carbonylation and nitration in the membranes of mitochondria extracted from CPF-treated cells. ISO also attenuated the CPF-elicited increase in the production of reactive species in this experimental model. Moreover, ISO prevented the CPF-induced disruption in the activity of components of the oxidative phosphorylation (OXPHOS) system in the SH-SY5Y cells. ISO also promoted an anti-inflammatory action in the cells exposed to CPF. CPF caused a decrease in the activity of the enzyme heme oxygenase-1 (HO-1), a cytoprotective agent. On the other hand, ISO upregulated HO-1 activity in SH-SY5Y cells. Inhibition of HO-1 by zinc protoporphyrin-IX (ZnPP-IX) suppressed the cytoprotection induced by ISO in the CPF-treated cells. Besides, silencing of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) abolished the ISO-induced HO-1 upregulation and mitochondrial benefits induced by this flavone on the CPF-challenged cells. Thus, ISO protected mitochondria of the CPF-treated cells by an Nrf2/HO-1-dependent fashion in the SH-SY5Y cells.

Pinocembrin pretreatment counteracts the chlorpyrifos-induced HO-1 downregulation, mitochondrial dysfunction, and inflammation in the SH-SY5Y cells.

Chlorpyrifos (CPF), an insecticide, induces pro-oxidant, pro-inflammatory, and pro-apoptotic effects in animal cells. Contamination with CPF occurs not only in farms, since CPF is found in the food consumed in homes. Recently, it was demonstrated that CPF affects the mitochondria, inhibiting components of the electron transfer chain (ETC), causing loss of mitochondrial membrane potential (MMP), and reducing the synthesis of adenosine triphosphate (ATP) by the Complex V. Pinocembrin (PB) is found in propolis and exhibits antioxidant, anti-inflammatory, and anti-apoptotic effects in mammalian cells. PB is a potent inducer of the nuclear factor erythroid 2-related factor 2 (Nrf2), which is a major transcription factor controlling the expression of heme oxygease-1 (HO-1), among others. In the present work, we investigated whether PB would be able to prevent the mitochondrial and immune dysfunctions in the human neuroblastoma SH-SY5Y cells exposed to CPF. PB was tested at 1-25 µM for 4 h before the administration of CPF at 100 µM for additional 24 h. We found that PB prevented the CPF-induced inhibition of ETC, loss of MMP, and decline in the ATP synthesis. PB also promoted anti-inflammatory actions in this experimental model. Silencing of Nrf2 or inhibition of HO-1 suppressed the PB-induced effects in the CPF-challenged cells. Thus, PB promoted beneficial effects by a mechanism dependent on the Nrf2/HO-1/CO + BR axis in the CPF-treated cells.

Suppression of Mitochondria-Related Bioenergetics Collapse and Redox Impairment by Tanshinone I, a Diterpenoid Found in Salvia miltiorrhiza Bunge (Danshen), in the Human Dopaminergic SH-SY5Y Cell Line Exposed to Chlorpyrifos.

Tanshinone I (T-I, C18H12O3) is a diterpene found in Salvia miltiorrhiza Bunge (Danshen) and promotes cytoprotection in several experimental models. Chlorpyrifos (CPF) is an agrochemical that causes bioenergetics failure, redox impairment, inflammation, and cell death in animal tissues. Here, we investigated whether T-I would be able to prevent the consequences resulting from the exposure of the human dopaminergic SH-SY5Y cells to CPF. We found that a pretreatment with T-I at 2.5 µM for 2 h suppressed lipid peroxidation and protein carbonylation and nitration on the membranes of mitochondria extracted from the CPF-treated cells. Also, T-I reduced the production of radical superoxide (O2-•) by the mitochondria of the CPF-challenged cells. The production of nitric oxide (NO•) and hydrogen peroxide (H2O2) was also decreased by T-I in the cells exposed to CPF. The CPF-induced decrease in the activity of the complexes I-III, II-III, and V was abolished by a pretreatment with T-I. Loss of mitochondrial membrane potential (ΔΨm) and reduction in the production of adenosine triphosphate (ATP) were also prevented by T-I in the CPF-treated cells. T-I also induced anti-inflammatory effects in the CPF-treated cells by decreasing the levels of interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α) and the activity of the nuclear factor-κB (NF-κB). Inhibition of heme oxygenase-1 (HO-1) or silencing of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) blocked the T-I-promoted mitochondrial protection and anti-inflammatory action. Overall, T-I depended on the Nrf2/HO-1 axis to prevent the deleterious effects caused by CPF in this experimental model.

Astaxanthin prevents mitochondrial impairment in the dopaminergic SH-SY5Y cell line exposed to glutamate-mediated excitotoxicity: Role for the Nrf2/HO-1/CO-BR axis.

Mitochondrial dysfunction has been viewed in several diseases, including neurological disorders. In the glutamate (GLU)-mediated excitotoxicity, it has been described mitochondrial impairment, disrupted redox environment, and increased rates of cell death in the affected brain areas. Astaxanthin (AST) is a potent antioxidant and anti-inflammatory xanthophyll that also promotes beneficial mitochondria-related effects in brain cells. However, it is not completely clear how AST would be able to promote mitochondrial protection in those cell types. Thus, we investigated here how AST would protect mitochondria in the dopaminergic SH-SY5Y cell line exposed to GLU. AST was administrated to the cells at 1-40 µM for 24 h prior to the exposure to GLU at 80 mM for additional 24 h. AST prevented the GLU-induced impairment in the activity of the Complexes I and V, the loss in mitochondrial membrane potential (MMP), and the decline in the synthesis of ATP. AST also induced an antioxidant effect in the membranes of mitochondria obtained from the GLU-treated SH-SY5Y cells. Inhibition of the enzyme heme oxygenase-1 (HO-1) or silencing of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) suppressed the AST-promoted cellular and mitochondrial protection. Either tricarbonyldichlororuthenium(II) dimer (CORM-2, a source of carbon monoxide - CO) or bilirubin (BR), that are products of the HO-1-biliverdin reductase (BVR) axis, blocked some of the effects caused by GLU in the SH-SY5Y cells. Overall, our data demonstrate that AST prevented mitochondrial dysfunction by a mechanism related to the Nrf2/HO-1 axis in GLU-challenged cells.

Effects of nandrolone decanoate on femur morphology. Experimental study.

PURPOSE: To evaluate the immediate and late effects of nandrolone on femur morphology of rats. METHODS: Twenty-eight animals with 20 weeks of age were divided into four groups: C28, control animals that were euthanized eight weeks after the experiment started; C40, control animals euthanized 20 weeks after the experiment started; T28, treated animals receiving nandrolone during eight weeks and euthanized immediately after the treatment period; and T40, animals treated during eight weeks and euthanized 12 weeks after the end of the treatment. Treated animals received nandrolone decanoate during eight weeks and control groups received peanut oil by intramuscular injection. After euthanasia, femurs were removed, dissected, weighted and measured by digital pachymeter. RESULTS: The T40 group presented an increase on distal epiphysis diameter when compared to C40 group. There was no difference between treated and control groups in relation to body and femur absolute weight, relative weight and length of femur. There was also no difference in relation to diameter of proximal epiphysis and diameter of diaphysis among the groups. CONCLUSIONS: Nandrolone decanoate does not produce significant effect on femur, exception on its distal extremity at late period. The effects of such drug may depend on the time after administration.

The signaling pathway PI3K/Akt/Nrf2/HO-1 plays a role in the mitochondrial protection promoted by astaxanthin in the SH-SY5Y cells exposed to hydrogen peroxide.

The mitochondria are the major source of reactive species in the mammalian cells. Hydrogen peroxide (H2O2) is a potent inducer of redox impairment by a mechanism, at least in part, dependent on its ability to impair mitochondrial function. H2O2 plays an important role in several pathological conditions, including neurodegeneration and cardiovascular diseases. Astaxanthin (AST) is a xanthophyll that may be found in microalgae, crustaceans, and salmon and exhibits antioxidant and anti-inflammatory effects in different cell types. Even though there is evidence pointing to a role for AST as mitochondrial protectant agent, it was not clearly demonstrated how this xanthophyll attenuates mitochondrial stress. Therefore, we investigated here whether and how AST would be able to prevent the H2O2-induced mitochondrial dysfunction in the human neuroblastoma SH-SY5Y cells. We found that AST (20 µM) prevented the H2O2-induced loss of mitochondrial membrane potential (MMP) and decrease in the activity of the Complexes I and V. AST pretreatment blocked the mitochondria-related pro-apoptotic effects elicited by H2O2. AST upregulated the enzyme heme oxygenase-1 (HO-1) and the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) by a mechanism dependent on the phosphoinositide 3-kinase/Akt (PI3K/Akt) signaling pathway. Inhibition of the PI3K/Akt or of the HO-1 enzyme abolished the AST-induced mitochondrial protection in cells challenged with H2O2. Silencing of Nrf2 caused similar effects. Thus, we suggest that AST promotes mitochondrial protection by a mechanism dependent on the PI3K/Akt/Nrf2/HO-1 signaling pathway in SH-SY5Y cells exposed to H2O2.

The Isothiocyanate Sulforaphane Depends on the Nrf2/γ-GCL/GSH Axis to Prevent Mitochondrial Dysfunction in Cells Exposed to Methylglyoxal.

Methylglyoxal (MG) is a reactive dicarbonyl presenting both endogenous (e.g. glycolysis) and exogenous (e.g. food cooking) sources. MG induces neurotoxicity, at least in part, by affecting mitochondrial function, including a decline in the oxidative phosphorylation (OXPHOS) system activity, bioenergetics failure, and redox disturbances. Sulforaphane (SFN) is an isothiocyanate found mainly in cruciferous vegetables and exerts antioxidant and anti-inflammatory effects in mammalian cells. SFN also decreases mitochondrial vulnerability to several chemical stressors. SFN is a potent activator of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), which is a master regulator of the mammalian redox biology. Here, we have investigated whether and how SFN would be able to prevent the MG-induced mitochondrial collapse in the human neuroblastoma SH-SY5Y cells. The cells were exposed to SFN at 5 µM for 24 h prior to the administration of MG at 500 µM for additional 24 h. We found that SFN prevented the MG-induced OXPHOS dysfunction and mitochondrial redox impairment. SFN stimulated the activity of the enzyme γ-glutamylcysteine ligase (γ-GCL), leading to increased synthesis of glutathione (GSH). Inhibition of γ-GCL with buthionine sulfoximine (BSO) or silencing of Nrf2 using small interfering RNA (siRNA) against this transcription factor reduced the levels of GSH and abolished the mitochondrial protection promoted by SFN in the MG-treated cells. Thus, SFN protected mitochondria of the MG-challenged cells by a mechanism involving the Nrf2/γ-GCL/GSH axis.

Promotion of Mitochondrial Protection by Emodin in Methylglyoxal-Treated Human Neuroblastoma SH-SY5Y Cells: Involvement of the AMPK/Nrf2/HO-1 Axis.

Mitochondrial dysfunction is part of the mechanism of several human diseases. This negative circumstance may be induced by certain toxicants, as methylglyoxal (MG). MG is a reactive dicarbonyl presenting both endogenous and exogenous sources and is also able to induce protein cross-linking and glycation. Emodin (EM; 1,3,8-trihydroxy-6-methylanthracene-9,10-dione; C15H10O5) is a cytoprotective agent. Nonetheless, it was not previously demonstrated whether EM would be able to promote mitochondrial protection in cells challenged with MG. Therefore, we investigated here whether and how EM would prevent the MG-induced mitochondrial collapse in the human neuroblastoma SH-SY5Y cells. We found that a pretreatment (for 4 h) with EM at 40 µM prevented the MG-induced mitochondrial dysfunction (i.e., decreased activity of the complexes I and V, reduced adenosine triphosphate levels, and loss of mitochondrial membrane potential) in the SH-SY5Y cells. EM also prevented the redox impairment induced by MG in mitochondrial membranes. Inhibiting the adenosine monophosphate-activated protein kinase (AMPK) or silencing of the nuclear factor erythroid 2-related factor 2 (Nrf2), transcription factor abolished the EM-induced protection. Inhibition of heme oxygenase-1 (HO-1) also blocked the EM-induced mitochondrial protection. Therefore, EM protected the mitochondria by a mechanism dependent on the AMPK/Nrf2/HO-1 signaling pathway in MG-challenged SH-SY5Y cells.

Mitochondrial Protection and Anti-inflammatory Effects Induced by Emodin in the Human Neuroblastoma SH-SY5Y Cells Exposed to Hydrogen Peroxide: Involvement of the AMPK/Nrf2 Signaling Pathway.

Emodin (EM; 1,3,8-trihydroxy-6-methylanthracene-9,10-dione; C15H10O5) is an anthraquinone and exerts cytoprotective effects, as observed in both in vitro and in vivo experimental models. Mitochondrial dysfunction induced by reactive species plays a central role in the onset and progression of different human diseases. Thus, we have tested here whether a pretreatment (for 4 h) with EM (at 40 µM) would be able to promote mitochondrial protection in the human neuroblastoma SH-SY5Y cells exposed to the pro-oxidant agent hydrogen peroxide (H2O2). We found that the pretreatment with EM suppressed the effects of H2O2 on the activity of the mitochondrial complexes I and V, as well as on the production of adenosine triphosphate (ATP) and on the mitochondrial membrane potential (MMP). EM also prevented the H2O2-induced collapse in the tricarboxylic acid cycle (TCA) function. An anti-inflammatory role for EM was also observed in this experimental model, since this anthraquinone decreased the secretion of interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α) by the H2O2-challenged cells. Inhibition of the adenosine monophosphate-activated protein kinase (AMPK) or silencing of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) abolished the protection induced by EM in the H2O2-treated cells. Therefore, EM prevented the H2O2-induced mitochondrial dysfunction and pro-inflammatory state in the SH-SY5Y cells by an AMPK/Nrf2-dependent manner.

Nrf2 Mediates the Anti-apoptotic and Anti-inflammatory Effects Induced by Gastrodin in Hydrogen Peroxide-Treated SH-SY5Y Cells.

Redox impairment, inflammation, and increased rates of cell death are central players during neurodegeneration. In that context, activation of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) has been viewed as an interesting strategy in order to reduce the impact of redox dysfunction and neuroinflammation on cell fate. There is evidence indicating that the benefits caused by natural products in the brain may be due to the ability of these agents in upregulating Nrf2. Gastrodin (GAS) induces anti-oxidant, anti-inflammatory, and anti-apoptotic actions in brain cells. Nonetheless, the mechanisms underlying such effects are not clear yet. Therefore, we investigated here whether GAS would affect apoptosis and inflammation in the human neuroblastoma cell line (SH-SY5Y) exposed to hydrogen peroxide (H2O2). GAS at 1-25 µM was administrated to the cells during 30 min before a challenge with H2O2 at 300 µM for additional 24 h. GAS prevented the activation of the intrinsic apoptotic pathway by modulating the levels of Bcl-2 and Bax, causing a decrease in the release of cytochrome c to the cytosol. GAS also prevented the activation of the pro-apoptotic enzymes caspase-9 and caspase-3. Consequently, GAS abrogated poly (ADP-ribose) polymerase (PARP) cleavage and DNA fragmentation in the H2O2-treated SH-SY5Y cells. Moreover, GAS reduced the levels of interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α) and the activity of nuclear factor-κB in H2O2-treated cells. Silencing of Nrf2 by small interfering RNA (siRNA) suppressed the GAS-induced cytoprotection. Thus, GAS elicited anti-apoptotic and anti-inflammatory effects by a mechanism involving Nrf2 in SH-SY5Y cells.

Sulforaphane Attenuated the Pro-Inflammatory State Induced by Hydrogen Peroxide in SH-SY5Y Cells Through the Nrf2/HO-1 Signaling Pathway.

Sulforaphane (SFN), an isothiocyanate obtained from cruciferous vegetables, exerts antioxidant, antiapoptotic, and antitumor activities in different cell types. Moreover, SFN has been viewed as an anti-inflammatory agent. Nonetheless, the mechanism underlying the ability of SFN in modulating the immune response in mammalian cells is not completely understood yet. Therefore, we investigated here whether and how SFN would be effective in preventing inflammation induced by a pro-oxidant agent (hydrogen peroxide, H2O2) in the human neuroblastoma SH-SY5Y cells. The cells were treated with SFN at 5 µM for 30 min before a challenge with H2O2 for an additional 24 h. Pretreatment with SFN reduced the secretion of interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α), as well as decreased the levels of cyclooxygenase-2 (COX-2) in H2O2-treated cells. SFN also decreased the activity of the transcription factor nuclear factor-κB (NF-κB) and the immunocontent of the p65 NF-κB subunit in the cell nucleus. The inhibition of heme oxygenase-1 (HO-1) by ZnPP-IX at 10 µM or the silencing of the nuclear factor erythroid 2-related factor 2 (Nrf2) transcription factor by small interfering RNA targeting Nrf2 attenuated the anti-inflammatory and cytoprotective effects induced by SFN. Therefore, SFN exerted an anti-inflammatory effect in H2O2-challenged SH-SY5Y cells by a mechanism dependent on the Nrf2/HO-1 signaling pathway.

Evaluation of the Mitochondria-Related Redox and Bioenergetics Effects of Gastrodin in SH-SY5Y Cells Exposed to Hydrogen Peroxide.

Mitochondrion is the main site of ATP production in animal cells and also orchestrates signaling pathways associated with cell survival and death. Mitochondrial dysfunction has been linked to bioenergetics and redox impairment in human diseases, such as neurodegeneration and cardiovascular disease. Protective agents able to attenuate mitochondrial impairment are of pharmacological interest. Gastrodin (GAS; 4-hydroxybenzyl alcohol 4-O-beta-D-glucoside) is a phenolic glucoside obtained from the Chinese herbal medicine Gastrodia elata Blume and exhibits antioxidant, anti-inflammatory, and antiapoptotic effects in several cell types. GAS is able to cross the blood-brain barrier, reducing the impact of different stressors on the cognition of experimental animals. In the present work, we investigated whether GAS would protect mitochondria of human SH-SY5Y neuroblastoma cells against an exposure to a pro-oxidant agent. The cells were treated with GAS at 25 µM for 30 min before the administration of hydrogen peroxide (H2O2) at 300 µM for an additional 3 or 24 h, depending on the assay. We evaluated both mitochondrial redox state and function parameters and analyzed the mechanism by which GAS protected mitochondria in this experimental model. Silencing of the nuclear factor erythroid 2-related factor 2 (Nrf2) transcription factor suppressed the GAS-induced mitochondrial protection seen here. Moreover, Nrf2 knockdown abrogated the effects of GAS on cell viability, indicating a potential role for Nrf2 in both mitochondrial and cellular protection promoted by GAS. Further research would be necessary to investigate whether GAS would be able to induce similar effects in in vivo experimental models.

Pinocembrin Suppresses H2O2-Induced Mitochondrial Dysfunction by a Mechanism Dependent on the Nrf2/HO-1 Axis in SH-SY5Y Cells.

Mitochondria are susceptible to redox impairment, which has been associated with neurodegeneration. These organelles are both a source and target of reactive species. In that context, there is increasing interest in finding natural compounds that modulate mitochondrial function and mitochondria-related signaling in order to prevent or to treat diseases involving mitochondrial impairment. Herein, we investigated whether and how pinocembrin (PB) would prevent mitochondrial dysfunction elicited by the exposure of human neuroblastoma SH-SY5Y cells to hydrogen peroxide (H2O2). PB (25 µM) was administrated for 4 h before H2O2 treatment (300 µM for 24 h). PB prevented H2O2-induced loss of cell viability mitochondrial depolarization in SH-SY5Y cells. PB also attenuated redox impairment in mitochondrial membranes. The production of superoxide anion radical (O2-•) and nitric oxide (NO•) was alleviated by PB in cells exposed to H2O2. PB suppressed the H2O2-induced inhibition of the tricarboxylic acid (TCA) cycle enzymes aconitase, α-ketoglutarate dehydrogenase, and succinate dehydrogenase. Furthermore, PB induced anti-inflammatory effects by abolishing the H2O2-dependent activation of the nuclear factor-κB (NF-κB) and upregulation of interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α). The PB-induced antioxidant and anti-inflammatory effects are dependent on the heme oxygenate-1 (HO-1) enzyme and on the activation of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), since HO-1 inhibition (with 0.5 µM ZnPP IX) or Nrf2 silencing (with small interfering RNA (siRNA)) abolished the effects of PB. Overall, PB afforded cytoprotection by the Nrf2/HO-1 axis in H2O2-treated SH-SY5Y cells.

Naringenin Attenuates H2O2-Induced Mitochondrial Dysfunction by an Nrf2-Dependent Mechanism in SH-SY5Y Cells.

Mitochondria are the major site of ATP production in mammalian cells. Furthermore, these organelles are a source and a target of reactive oxygen species (ROS), such as radical anion superoxide (O2-·) and hydrogen peroxide (H2O2). The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) is the master regulator of the mammalian redox biology and controls the expression of antioxidant and phase II detoxifying enzymes in several cell types. Naringenin (NGN, 5,7-dihydroxy-2-(4-hydroxyphenyl)-2,3-dihydrochromen-4-one), a flavanone, exhibits cytoprotective effects by acting as an antioxidant and anti-inflammatory agent. NGN is a potent activator of Nrf2. Nonetheless, it was not examine yet whether NGN would induce mitochondrial protection in cells under redox stress. Therefore, we investigate here whether Nrf2 would be involved in the mitochondrial protection elicited by NGN in SH-SY5Y cells exposed to H2O2. We observed that a pretreatment with NGN at 80 µM for 2 h reduced the levels of lipid peroxidation, protein carbonylation, and protein nitration in the membranes of mitochondria obtained from H2O2-treated SH-SY5Y cells. Additionally, NGN prevented the H2O2-induced impairment in the function of the enzymes aconitase, α-ketoglutarate dehydrogenase, and succinate dehydrogenase. The activites of the complexes I and V, as well as the production of ATP, were restored by NGN. NGN also suppressed the H2O2-induced mitochondria-related apoptosis. Interestingly, NGN promoted an increase in the levels of both total and mitochondrial glutathione (GSH). Silencing of Nrf2 abolished the protective effects induced by NGN. Overall, NGN induced mitochondrial protection by an Nrf2-dependent mechanism in H2O2-treated SH-SY5Y cells.

Maternal folic acid consumption during gestation and its long-term effects on offspring's liver: a systematic review / O consumo materno de ácido fólico durante a gestação e seus efeitos a longo prazo no fígado da prole: uma revisão sistemática

Abstract Objectives: describing the effects of maternal supplementation with folic acid (FA) exclusively during gestation on offspring's liver at later stages in life. Supplementation with FA during gestation has been recommended by the medical society worldwide. The liver has a central role on the substances of metabolism and homeostasis and some studies have shown that a high intake of FA at other periods in life may cause hepatic damage. Methods: a systematic review through which the following databases were consulted: Medline, through platforms of Pubmed, Lilacs and Scielo. The research was performed by keywords such as: "Folic acid", "Gestation", "Rat", "Offspring" and "Liver". Articles which evaluate the effect of FA consumption during both gestation and lactation were excluded. Results: FA consumption avoids disorders on expression of peroxisome proliferator-activated receptor alpha (PPARα) and glucocorticoid receptor (GccR), its lack did not change enzyme activity of the male offspring's liver in adulthood. Supplementation with FA during gestation did not change iron hepatic levels or lipid composition, but had an antioxidant effect on it. Conclusions: supplementation with FA at recommended doses did not cause toxic effects and is very likely to avoid deleterious effects in the liver of the offspring regarding the epigenetic level.

Resumo Objetivos: descrever os efeitos da suplementação materna com ácido fólico (AF) exclusivamente durante a gestação no fígado da prole em fases tardias da vida. A suplementação com ácido fólico durante a gestação tem sido recomendada pela sociedade médica em todo o mundo. O fígado tem papel central no metabolismo de substâncias e alguns estudos mostraram que o consumo de altas doses de ácido fólico em outros períodos da vida causa dano hepático. Métodos: é uma revisão sistemática para a qual foram consultadas as seguintes bases de dados: Pubmed, Lilacs e Scielo. A pesquisa foi realizada pelos descritores: "Folic acid", "Gestation", "Rat", "Offspring" and "Liver". Artigos que avaliaram o consumo de AF durante a gestação e lactação foram excluídos. Resultados: a ingestão de AF evita desordens na expressão de receptores ativados por proliferador de peroxissoma (PPARα) e receptores de glicocorticóides (RG), já sua ausência não alterou a atividade enzimática do fígado da prole macho na idade adulta. AF durante a gestação não alterou os níveis de ferro hepático nem a composição lipídica, mas teve efeito antioxidante neste órgão. Conclusões: a suplementação com ácido fólico nas doses recomendadas não causou efeitos tóxicos e é muito provável que evite efeitos deletérios no fígado da prole em nível epigenético.

The impact of dietary organic and transgenic soy on the reproductive system of female adult rat.

The goal of this article was to compare the effects of a prolonged use of organic and transgenic soy on the lipid profile and ovary and uterus morphology. Wistar rats were fed three different diets from weaning until sacrifice at 15 months of age. The three diets were: casein-based diet control group (CG), organic soy-based diet group (OSG), or transgenic soy-based diet group (GMSG). There were no differences in food consumption or in the diet isoflavone components among the groups. Compared with the CG diet, both the OSG and GMSG diets were associated with significant reductions in body weight, serum triglycerides, and cholesterol (P < 0.05) (CG = 406 +/- 23.1; 104.3 +/- 13.2; 119.9 +/- 7.3 GMSG = 368 +/- 17.6; 60.3 +/- 4.6; 83.3 +/- 5.7 OSG = 389 +/- 23.5; 72.3 +/- 12.5; 95.5 +/- 8.0, respectively). The volume density of endometrial glandular epithelium was greater in the GMSG group (29.5 +/- 7.17, P < 0.001) when compared with the CG (18.5 +/- 7.4) and OSG (20.3 +/- 10.6) groups. The length density of endometrial glandular epithelium was shorter in both GMSG (567.6 +/- 41.1) and OSG (514.8 +/- 144.5) diets compared with the CG (P < 0.05) diet. GMSG also resulted in reduced follicle number and increased corpus luteum number compared to the OSG or CG diets (P < 0.05). In summary, both GMSG and OSG diets resulted in decreased body weight and lower serum triglyceride and cholesterol levels, and alterations in uterine and ovarian morphology were also observed. The prolonged use of soy-based diets and their relation to reproductive health warrants further investigation.