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| Hypothetical scenarios for the role of NGF after systemic oxidative stress. NGF levels increase in peripheral tissues and is secreted into the circulation, resulting in autocrine/paracrine effects. Peripheral NGF activates the TrkA pathway in brain endothelial cells, which induces the transcription of transporters of the sulfhydryl AAs L-cys/L-cys2 in neurons and glial cells. In addition, NGF synthesis is increased in brain endothelial cells (BECs), and NGF is secreted into the brain parenchyma, activating the NGF/TrkA/PI3K/Akt/Nrf2 pathway that increases the expression of antioxidant genes in the CNS. TJ, tight junctions.
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Glutathione (GSH) is the most abundant intracellular antioxidant. GSH depletion leads to oxidative stress and neuronal damage in the central nervous system (CNS). In mice, the acute systemic inhibition of GSH synthesis by L-buthionine-S-R-sulfoximine (BSO) triggers a protective response and a subsequent increase in the CNS GSH content. This respons...
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Context 1
... into account these results and our previous studies (Limón-Pacheco et al., 2007;Valdovinos-Flores and Gonsebatt, 2013;Garza-Lombó et al., 2018), it is possible that changes in the systemic redox state induce tissue-specific responses through Nrf2 or NF-κB that include the synthesis of NGF, which increases circulating NGF levels in the blood. Then, although at the time evaluated here it was not observed, it is possible that peripheral NGF activates the NGF/TrkA signaling pathway in brain endothelial cells and enables the entrance of the sulfhydryl AAs L-cys/L-cys2 into the brain parenchyma and the subsequent secretion of NGF in the brain, where it plays a critical role in the antioxidant response via the NGF/TrkA pathway (Figure 6) in neurons and glial cells. In fact, xCT mRNA and protein expression have been shown along brain blood vessels, including endothelial cells, meninges and astrocytes, EAAC1 is expressed in neurons and LAT1 in microvascular cells of the BBB and neurons ( Burdo et al., 2006;Muller and Heuer, 2014;Ottestad-Hansen et al., 2018). ...
Citations
... We found that AA de ciency increases ROS generation and expression of the oxidative stress response element Nrf2 (Fig. 7B). The transcription of LAT1 has been reported to be increased by activation of the Nrf2 pathway in the striatum 31 . Expression of LAT1 in A549 cells may be upregulated by the ROS-dependent Nrf2 pathway. ...
Claudin-1 (CLDN1) is highly expressed in human lung adenocarcinoma-derived A549 cells and is involved in the augmentation of chemoresistance. However, the mechanism of chemoresistance is not fully understood. In the tumor microenvironment, cancer cells are exposed to stress conditions such as hypoxia and malnutrition. Here, we investigated the effect of CLDN1 expression on amino acid (AA) flux and chemoresistance using A549 cells. L-type AA transporters, LAT1 and LAT3, were highly expressed in three-dimensional spheroid cells compared with in two-dimensional (2D) cultured cells. The expression of these transporters was increased by AA deprivation in 2D cultured cells. The paracellular AA flux except for Ser, Thr, and Tyr was enhanced by CLDN1 silencing. The expression of AA transporters and AA contents in spheroids were decreased by CLDN1 silencing. These results suggest that CLDN1 forms a paracellular AA barrier, leading to a compensatory increase in LAT1/3 expression in spheroids. The production of reactive oxygen species in the mitochondria and cytosol was decreased by CLDN1 silencing in spheroids, resulting in downregulation of the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and its target antioxidant genes. CLDN1 silencing enhanced the cytotoxicity of doxorubicin, an anthracycline antitumor agent, which was blocked by sulforaphane, an Nrf2 activator. In 2D cultured cells, the cytotoxicity of doxorubicin was attenuated by a reduction in extracellular AA concentration or treatment with sulforaphane. We suggest that CLDN1 forms an AA barrier in spheroids, leading to the augmentation of Nrf2-dependent chemoresistance in A549 cells.
... Hence, Gas7 has become a potential therapeutic target [3]. NGF plays an important role in regulating the development, differentiation, plasticity, cell death, and survival, of neurons [4]. EA stimulation can induce NGF to play a therapeutic role in cerebral ischemia. ...
Objective:
To investigate the potential mechanisms underlying the migration of endogenous neural stem cells (eNSCs) to the frontal cortex to differentiate into neurons, and to monitor the effect of electroacupuncture (EA) regulation of focal cerebral ischemia (FCI) in rats on the expression of growth arrest-specific protein 7 (Gas7) and nerve growth factor (NGF) in the prefrontal cortex (PFC).
Methods:
Randomly, forty-eight male Sprague-Dawley rats were divided into four groups: Normal, Sham operation, Model, and EA. The right middle cerebral artery was embolized utilizing the thread-embolism technique. In the EA group, "Baihui" and "Zusanli" points were treated with electroacupuncture for 30 minutes, once a day, for 21 days. Nissl staining revealed the neuronal morphology of the PFC. Using immunohistochemistry and Western blot, the expression of Gas7 and NGF in the right PFC was observed.
Results:
Nissl staining showed clear PFC neurons with centered nuclei and distinct nucleoli in the Normal and Sham groups. In the Model group, the PFC nuclei were distinctively smaller. The neuronal morphology in the EA group resembled that of the Normal group. Results from Western blot and immunohistochemistry were comparable. The expression of Gas7 and NGF in the Sham surgery group did not differ significantly from the Normal group. However, the expression of Gas7 and NGF in the Model group was significantly lower than in the Normal group. The expression of Gas7 and NGF was significantly higher in the EA group than in the Model group.
Conclusions:
EA can increase the expressions of Gas7 and NGF in the ischemic prefrontal cortex, which may be one of the mechanisms by which EA promotes the differentiation of eNSCs into neurons in the injured area.
... Cell ferroptosis is mainly manifested as decreased glutathione peroxidase 4 (GPX4) activity and glutathione (GSH) depletion at the molecular level [50]. GSH is the most abundant intracellular antioxidant that protects DNA, proteins, lipids, and other biomolecules from oxidative damage [51]. As a selenoprotein that repairs oxidative damage of lipid cells in mammals, GPX4 can catalyze the conversion of GSH to GSSG, and, at the same time, reduce intracellular toxic lipid peroxides to non-toxic hydroxyl compounds or convert free H 2 O 2 into the water, protecting cell membrane structure and function from interference and damage by peroxides [52]. ...
Mycotoxin contamination has become one of the biggest hidden dangers of food safety, which seriously threatens human health. Understanding the mechanisms by which mycotoxins exert toxicity is key to detoxification. Ferroptosis is an adjustable cell death characterized by iron overload and lipid reactive oxygen species (ROS) accumulation and glutathione (GSH) depletion. More and more studies have shown that ferroptosis is involved in organ damage from mycotoxins exposure, and natural antioxidants can alleviate mycotoxicosis as well as effectively regulate ferroptosis. In recent years, research on the treatment of diseases by Chinese herbal medicine through ferroptosis has attracted more attention. This article reviews the mechanism of ferroptosis, discusses the role of ferroptosis in mycotoxicosis, and summarizes the current status of the regulation of various mycotoxicosis through ferroptosis by Chinese herbal interventions, providing a potential strategy for better involvement of Chinese herbal medicine in the treatment of mycotoxicosis in the future.
... Compound 28 exhibits improved Nrf2 activation when co-stimulated with tumor necrosis factor [100]. Treatment with a sulfoximine derivative L-buthionine-S-R-sulfoxime reportedly upregulated γglutamylcysteine ligase mRNA and L-cys/L-cys2 transporter via the activation of Nrf2 and other pathways in the striatum [139]. ...
Nuclear factor erythroid 2-related factor 2 (Nrf2) signaling has become a key pathway for cellular regulation against oxidative stress and inflammation, and therefore an attractive therapeutic target. Several organosulfur compounds are reportedly activators of the Nrf2 pathway. Organosulfur compounds constitute an important class of therapeutic agents in medicinal chemistry due to their ability to participate in biosynthesis, metabolism, cellular functions, and protection of cells from oxidative damage. Sulfur has distinctive chemical properties such as a large number of oxidation states and versatility of reactions that promote fundamental biological reactions and redox biochemistry. The presence of sulfur is responsible for the peculiar features of organosulfur compounds which have been utilized against oxidative stress-mediated diseases. Nrf2 activation being a key therapeutic strategy for oxidative stress is closely tied to sulfur-based chemistry since the ability of compounds to react with sulfhydryl (-SH) groups is a common property of Nrf2 inducers. Although some individual organosulfur compounds have been reported as Nrf2 activators, there are no papers with a collective analysis of these Nrf2-activating organosulfur compounds which may help to broaden the knowledge of their therapeutic potentials and motivate further research. In line with this fact, for the first time, this review article provides collective and comprehensive information on Nrf2-activating organosulfur compounds and their therapeutic effects against oxidative stress, thereby enriching the chemical and pharmacological diversity of Nrf2 activators.
... On the other hand, Nrf2 activates GCLC and xCT which maintain intracellular GSH levels by regulating the rate-limiting steps for GSH synthesis. Furthermore, GSH depletion increases the transcription of Nrf2 and xCT [55][56][57]. Therefore, GSH concentration and the Nrf2 system may be reciprocally regulated by each other. ...
P2X7 receptor (P2X7R) regulates inducible nitric oxide synthase (iNOS) expression/activity in response to various harmful insults. Since P2X7R deletion paradoxically decreases the basal glutathione (GSH) level in the mouse hippocampus, it is likely that P2X7R may increase the demand for GSH for the maintenance of the intracellular redox state or affect other antioxidant defense systems. Therefore, the present study was designed to elucidate whether P2X7R affects nuclear factor-erythroid 2-related factor 2 (Nrf2) activity/expression and GSH synthesis under nitrosative stress in response to lipopolysaccharide (LPS)-induced neuroinflammation. In the present study, P2X7R deletion attenuated iNOS upregulation and Nrf2 degradation induced by LPS. Compatible with iNOS induction, P2X7R deletion decreased S-nitrosylated (SNO)-cysteine production under physiological and post-LPS treated conditions. P2X7R deletion also ameliorated the decreases in GSH, glutathione synthetase, GS and ASCT2 levels concomitant with the reduced S-nitrosylations of GS and ASCT2 following LPS treatment. Furthermore, LPS upregulated cystine:glutamate transporter (xCT) and glutaminase in P2X7R+/+ mice, which were abrogated by P2X7R deletion. LPS did not affect GCLC level in both P2X7R+/+ and P2X7R−/− mice. Therefore, our findings indicate that P2X7R may augment LPS-induced neuroinflammation by leading to Nrf2 degradation, aberrant glutamate-glutamine cycle and impaired cystine/cysteine uptake, which would inhibit GSH biosynthesis. Therefore, we suggest that the targeting of P2X7R, which would exert nitrosative stress with iNOS in a positive feedback manner, may be one of the important therapeutic strategies of nitrosative stress under pathophysiological conditions.
... Nerve growth factor (NGF), the first neurotrophic drug to be discovered, plays an active role in regulating neuronal development, differentiation, plasticity, cell death and survival [23]. However, the molecular weight of NGF is approximately 13.4 kDa, making it difficult to cross the BBB under normal conditions and reach its effective drug concentration to exert its therapeutic effect [24]. ...
Background:
The blood-brain barrier (BBB) maintains the balance of the internal environment of the brain and strictly controls substance exchange between the brain and blood dynamically but stably. Transient increases in the permeability of the BBB plays an important role in helping macromolecular drugs enter the brain to exert their pharmacological effects. Previous research has revealed that electronic acupuncture (EA) stimulation connecting Baihui (GV20) and Shuigou (GV26) at a specific frequency can enhance the permeability of the BBB at 8 minutes after the intervention and induce the entry of 20 kDa fluorescein isothiocyanate-dextran (FITC-dextran) into the cerebral cortex, but whether it can also allow drugs to pass the BBB remains unknown. We hypothesized that EA at a specific frequency could open the BBB and induce the entry of nerve growth factor (NGF) into the brain to exert its therapeutic effect.
Methods:
First, the middle cerebral artery occlusion (MCAO) model is adopted and changes in the permeability and structure of the BBB are assessed by measuring both the intensity of Evans blue (EB) staining and the cerebral infarction volume, and by evaluating the ultrastructure of the BBB. Then, a laser spectrometer and immunofluorescence are used to observe entry of NGF into the brain. Finally, the learning and memory ability of rats are assessed and the DeadEndTM Fluorometric TUNEL System is applied to assess apoptosis in the hippocampus.
Results:
Our results showed that, in the first, the BBB was essentially repaired three weeks after MCAO operation. Secondly, Electronic Acupuncture (EA) stimulation at a specific frequency can enhance BBB permeability in the prefrontal cortex and induce NGF uptake by prefrontal neurons. Finally, in the presence of EA stimulation, entry of NGF into the brain promoted learning and memory in rats and inhibited the apoptosis of neurons in the hippocampus.
Conclusions:
In this study, the timing of BBB repair in the MCAO model was determined under pathological conditions and the EA stimulation can induce the entry of NGF into the brain to exert its therapeutic effect. EA could serve as a new strategy for delivering therapeutics to the central nervous system (CNS), given that EA stimulation at a specific frequency was shown to increase the permeability of the BBB. Further study of the mechanism underlying the opening of the BBB and its timing is needed.
... Nerve growth factor (NGF), the rst neurotrophic drug to be discovered, plays an active role in regulating neuronal development, differentiation, plasticity, cell death and survival (23). However, the molecular weight of NGF is approximately 13.4 kDa, making it di cult to cross the BBB under normal conditions and reach its effective drug concentration to exert its therapeutic effect (24). ...
The blood-brain barrier (BBB) maintains the balance of the internal environment of the brain and strictly controls substance exchange between the brain and blood dynamically but stably. Transient increases in the permeability of the BBB plays an important role in helping macromolecular drugs enter the brain to exert their pharmacological effects. Previous research has revealed that electronic acupuncture (EA) stimulation at a specific frequency can enhance the permeability of the BBB and induce the entry of 20 kDa fluorescein isothiocyanate-dextran (FITC-dextran) into the cerebral cortex, but whether it can also allow drugs to pass the BBB remains unknown. We hypothesized that EA at a specific frequency could open the BBB and induce the entry of nerve growth factor (NGF) into the brain to exert its therapeutic effect. To simulate the clinical apoplexy sequelae observed in patients and determine the basic timing of BBB repair under pathological conditions, we employed the middle cerebral artery occlusion (MCAO) model and assessed changes in the permeability and structure of the BBB by measuring both the intensity of Evans blue (EB) staining and the cerebral infarction volume and evaluating the ultrastructure of the BBB. Then, we used a laser spectrometer and immunofluorescence to observe entry of NGF into the brain. Finally, we assessed the learning and memory ability of rats and used the DeadEnd TM Fluorometric TUNEL System to assess apoptosis in the hippocampus. Our results showed that the BBB was essentially repaired three weeks after MCAO, indicating that EA stimulation at a specific frequency can enhance BBB permeability and induce NGF uptake by prefrontal neurons. In the presence of EA stimulation, entry of NGF into the brain promoted learning and memory in rats and inhibited the apoptosis of neurons in the hippocampus. In this study, the MCAO model was used to determine the timing of BBB repair under pathological conditions and assess the EA stimulation-induced entry of NGF into the brain to exert its therapeutic effect. EA could serve as a new strategy for delivering therapeutics to the central nervous system (CNS), given that EA stimulation at a specific frequency was shown to increase the permeability of the BBB. Further study of the mechanism underlying the opening of the BBB and its timing is needed.
... TrkA is the major high-affinity receptor of NGF and has an irreplaceable role in the growth and development of the nervous system and the maintenance of neuronal characteristics (29). The combination of NGF and TrkA may further activate the MAPK signaling pathway and promote stem cell proliferation and differentiation (30,31). ...
Patients with diabetes frequently suffer from periodontitis, which progresses rapidly and is difficult to cure. Mesenchymal stem cell (MSC) transplantation may effectively treat periodontitis, but high glucose limits its therapeutic effect in diabetes. Nerve growth factor (NGF) has the functions of cell protection, anti-apoptosis and immune regulation, and may have potential application in diabetic periodontitis. In the present study, flow cytometry indicated that NGF inhibited MSC apoptosis induced by high glucose. Of note, high glucose promoted the transformation of MSCs into the proinflammatory type. NGF inhibited this transformation of MSCs under diabetic conditions and further decreased the proportion of T cells and monocytes/macrophages among lymphocytes. An animal model of diabetic periodontitis was constructed and MSC transplantation was demonstrated to reduce alveolar bone loss caused by diabetes. NGF enhanced the therapeutic effect of MSCs and maintained transplanted MSC survival in periodontal tissue of diabetic mice. Immunohistochemical analysis of periodontal tissues suggested that in the NGF group, infiltration of T cells and macrophages was reduced. Neurotrophic receptor tyrosine kinase 1 was indicated to have a key role in these effects of NGF. In conclusion, NGF may enhance the therapeutic effect of MSCs on diabetic periodontitis by protecting the cells and promoting the transformation of MSCs into the immunosuppressive type.
... After treatment with NAC for 12 weeks, diabetic ApoE -/mice fed a HLD exhibited enhanced aortic GSH levels compared with those in the DM + HLD group (Fig. 3A). BSO is an inhibitor of GSH (39). In vitro, NAC significantly reduced MG-induced ROS elevation compared with that in the MG group. ...
In diabetic animal models, high plasma/tissue levels of methylglyoxal (MG) are implicated in atherosclerosis. N‑acetylcysteine (NAC) is a cysteine prodrug that replenishes intracellular glutathione (GSH) levels, which can increase the elimination of MG in diabetes mellitus (DM). The present study investigated the anti‑atherosclerotic role of NAC in DM and aimed to determine whether the mechanism involved GSH‑dependent MG elimination in the aorta. Apolipoprotein‑E knockdown (ApoE‑/‑) mice injected with streptozotocin for 5 days exhibited enhanced atherosclerotic plaque size in the aortic root; notably, a high‑lipid diet aggravated this alteration. NAC treatment in the drinking water for 12 weeks decreased the size of the atherosclerotic lesion, which was associated with a reduction in MG‑dicarbonyl stress and oxidative stress, as indicated by decreased serum malondialdehyde levels, and increased superoxide dismutase‑1 and glutathione peroxidase‑1 levels in the diabetic aorta. Endothelial damage was also corrected by NAC, as indicated by an increase in the expression levels of phosphorylated (p‑)Akt and p‑endothelial nitric oxide synthase (eNOS) in the aorta, as well as nitric oxide (NO) in the serum. In addition, MG‑treated human umbilical vein endothelial cells (HUVECs) exhibited increased reactive oxygen species and decreased antioxidant enzyme expression levels. NAC treatment corrected the alteration in HUVECs induced by MG, whereas the protective role of NAC was blocked via inhibition of GSH. These findings indicated that the diabetic aorta was more susceptible to atherosclerotic lesions compared with non‑diabetic ApoE‑/‑ mice. Furthermore, NAC may offer protection against atherosclerotic development in DM by altering aortic and systemic responses via correcting GSH‑dependent MG elimination, leading to decreased oxidative stress and restoration of the p‑Akt/p‑eNOS pathway in the aorta.
... In addition, one way to support DA neurons is to transfer Nrf2-regulated gene products from astrocytes to neurons via microvesicles or exsosomes. Nerve growth factor (NGF) and glial cell-derived neurotrophic factor (GDNF) produced by either astrocytes or neurons enhances Nrf2 gene expression via an autocrine or paracrine manner Valdovinos-Flores et al. 2019). One of the possibilities is the formation of positive feedback loop between NGF and Nrf2 (Naveilhan et al. 1994;Mimura et al. 2011). ...
Traditionally, hydrogen peroxide (H2O2) was formed from cellular oxidative metabolism and often viewed as toxic waste. In fact, H2O2 was a benefit messenger for neuron-glia signaling and synaptic transmission. Thus, H2O2 was a double-edged sword and neuroprotection vs. neurotoxicity produced by H2O2 was difficult to define. Nuclear factor erythroid 2-related factor 2 (Nrf2) has been implicated as an intracellular regulator of neuronal growth. Inactivation of Nrf2 participated in the development of Parkinson's disease (PD). Thus, suitable activation of Nrf2 was essential for the prevention and treatment of PD. This study aimed to explore whether H2O2-conferred neuroprotective effects to support neuronal survival. H2O2 were added into primary neuron-glia, neuron-astroglia and neuron-microglia co-cultures in concentration- and time-dependent manners. H2O2 increased dopamine (DA) neuronal survival in concentration- and time-dependent manners. In addition, glial cells Nrf2 activation involved in H2O2-supported DA neuronal survival with the following phenomenons. First, H2O2 activated Nrf2 signaling pathway. Second, H2O2 generated beneficial neuroprotection in neuron-glia, neuron-astroglia and neuron-microglia co-cultures but not in neuron-enriched cultures. Third, silence of Nrf2 in glial cells abolished H2O2-conferred DA neuronal survival. This study demonstrated that physiological concentration of H2O2-supported DA neuronal survival via activation of Nrf2 signaling in glial cells. Our data permit to re-evaluate the role of H2O2 in the pathogenesis and therapeutic strategies for PD.
Graphic Abstract
