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.
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.
•H2O2 induced mitochondria-related redox and bioenergetics impairments in SH-SY5Y cells.•AST increased the activity of HO-1 and Nrf2 in SH-SY5Y cells.•AST prevented the H2O2-induced mitochondrial dysfunction in SH-SY5Y cells.•AST promoted mitochondrial protection by a PI3K/Akt/Nrf2/HO-1-dependent manner.
We report the synthesis of twelve indole derivatives bearing nitro or amide groups via Fischer indole methodology followed by reduction/acetylation and amidation reactions. After thorough ...characterization, these indoles were subjected to a number of studies in order to evaluate their bioactive potential as photosynthesis and plant growth inhibitors. Firstly, these molecular hybrids were evaluated as photosystem II (PSII) inhibitors through chlorophyll a (Chl a) fluorescence measurement. In this study, 6‐chloro‐8‐nitro‐2,3,4,9‐tetrahydro‐1H‐carbazole (15a) and 5‐chloro‐2,3‐dimethyl‐7‐nitro‐1H‐indole (15b) showed the best results by reducing the phenomenological parameters of reaction centers ABS/RC, TR0/RC and ET0/RC of PSII. Electron chain blockage by these compounds may lead to diminished ATP synthesis and CO2 fixation which interrupt the plant development. The compounds 15a and 15b both act as postemergent herbicides, reducing the dry biomass of Ipomoea grandifolia and Senna alata weeds by an average of 40% and 37%, respectively, corroborating the fluorescence results. Additionally, the molecular docking study revealed that the presence of strong electron‐withdrawing groups at the indole phenyl ring is important for the ligand’s interaction with the binding pocket of protein D1 on PSII. The optimization of these molecular features is the goal of our research group in further understanding and development of new potent herbicides.
This work reports the synthesis of indole nitrogen hybrids and their bioactive potential as photosystem inhibitors. The molecular hybrids were evaluated as photosystem II inhibitors through chlorophyll a fluorescence measurements and plant growth inhibitors. Compounds 6‐Chloro‐8‐nitro‐2,3,4,9‐tetrahydro‐1H‐carbazole and 5‐chloro‐2,3‐dimethyl‐7‐nitro‐1H‐indole showed the best results by reducing the phenomenological parameters of the reaction center, diminishing ATP synthesis and CO2 fixation which interrupt the plant development. Additionally, the molecular docking study revealed that the presence of strong electron withdrawing groups at the indole phenyl ring are important for the ligands’ interaction with the binding pocked of protein D1.
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 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.
Tanshinone I (T-I, C
18
H
12
O
3
) 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 (O
2
−•
) by the mitochondria of the CPF-challenged cells. The production of nitric oxide (NO
•
) and hydrogen peroxide (H
2
O
2
) 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 (ΔΨ
m
) 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-1β (IL-1β) 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.
The intake of almonds and nuts demonstrates benefits to human health due to their bioactive compounds. In Brazil, baru almonds and Brazil nuts are largely explored in communities through ...cooperatives. The objective of the present work was to develop and evaluate a nutritive bar with Brazil nut (BN) and baru almond (BA) byproducts at concentrations of 0, 25, 50, 75, and 100% in formulations. Baru almonds showed higher protein content (24.95 g/100 g) than Brazil nuts (14.74 g/100 g), while Brazil nuts showed higher lipidic content (59.36 g/100 g). All the nutritive bar formulations could be classified as high mineral content, mainly iron, calcium, phosphorus, zinc, and magnesium. The firmness (instrumental texture) was the highest for BA100 (217.9 N), while the adhesiveness was the lowest (−23.62 N). The highest acceptability indexes for taste and texture (59 and 67%, respectively) were observed for BN25:BA75 while BA100 achieved the highest acceptability index for odor, color, and global perception (71, 73, and 72%, respectively). Therefore, BN25:BA75 could be the most suitable formulation to be produced as it had a good nutritional content balance and obtained higher acceptance and preference in the sensory evaluation.
•Brazil nut and baru almond byproducts are good raw material for nutritive bars production.•Ready-to-eat food with Brazil nut and baru almond.•Nutritive bars had good sensory acceptability.
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.
PHOTOSYSTHEM II INHIBITORS: AN ALLELOCHEMICAL PERSPECTIVE. The process of photosynthesis involves the absorption of light energy by photosynthetic pigments found in the thylakoid membrane of ...chloroplasts in order to produce chemical energy. In the presence of photosynthetic inhibitors, plant development is affected mainly by the reduction of the electron chain, which leads to growth inhibition. In this context, chlorophyll a (Chl a) fluorescence is an important technique used to identify the effects of inhibitors on the photosynthetic apparatus employing the JIP-test, which correlates the Chl a fluorescence transient to biophysical parameters, providing valuable information about the efficiency of photosystems I and II. Natural products have been highlighted as photosynthesis inhibitors due to the continued use of synthetic herbicides, which leads to the development of invasive plants resistant to these pesticides, in addition to the toxicity caused to humans and the environment. Thus, this review describes the main applications of extracts and isolated secondary metabolites obtained from plants and microorganisms in the investigation of electron transport inhibition on photosystem II.
Calophyllum brasiliense Camb., Clusiaceae, is commonly known as “guanandi” and its stem bark is used in Brazilian traditional medicine to treat rheumatism, vein problems, hemorrhoids and gastric ...ulcers. The aim of this study was to evaluate the toxicity of hexane extract of Calophyllum brasiliense stem bark (HECb) using in vitro and in vivo experimental models.
In vitro toxicity was evaluated by Alamar Blue cytotoxicity assay and micronucleus test, using Chinese hamster ovary (CHO-k1) epithelial cells. in vivo toxicity was evaluated by oral acute and subchronic toxicity assays. In the oral acute toxicity screening, a single dose of HECb was administered to mice at doses ranging from 250 to 1000mg/kg. In the subchronic study, HECb was administered orally for 30 days to Wistar rats at doses of 100mg/kg and 500mg/kg. Phytochemical analyses were performed by HPLC/UV–vis, secondary metabolites were quantified by spectrophotometric methods.
HECb presented IC50=119.94±4.31µg/mL after a 24h cytotoxicity test using CHO-k1 cells, showing low cytotoxicity. However, when the cells were exposed to HECb for 72h, the IC50 value was 8.39±2.00µg/mL, showing in this case, a pronounced cytotoxic effect. In the oral acute toxicity studies, doses up to 500mg/kg of HECb did not cause any changes in both male and female mice. At 1000mg/kg, male mice showed signs typical of depression and stimulation that were reversed at 72h. Besides, female mice were more sensitive to the toxic effect of HECb at 1000mg/kg, which initially presented typical agitation signals, followed by depression signals, leading to death of all the animals at 24h. In subchronic assay with rats, HECb administered orally at doses of 100 and 500mg/kg did not cause significant changes in all clinical parameters evaluated. Histopathological analyses showed no deleterious effect in the vital organs of rats. Preliminary phytochemical analysis revealed the presence of phenolic compounds, steroids, and volatile coumarins. Analysis by HPLC showed two major peaks characteristic of chromanones.
In vitro toxicological tests showed that HECb exhibited cytotoxicity especially after 72h of exposition, and mutagenicity on the highest tested dose. The in vivo studies demonstrated that HECb produced some toxicity signs at the highest dose tested, particularly, in the acute toxicity test but showed no significant signs of toxicity in the subchronic assay. Based on these and previous pharmacological studies, it is possible to say that HECb did not exhibit significant toxicity at its effective dose. This suggests that HECb is relatively safe in humans at its effective dose.
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