Emodin Protects SH-SY5Y Cells Against Zinc-Induced Synaptic Impairment and Oxidative Stress Through the ERK1/2 Pathway

Zinc is an essential trace element important for the physiological function of the central nervous system. The abnormal accumulation of zinc inside neurons may induce mitochondrial dysfunction and oxidative stress
Bio Med Frontiers, which contribute to many brain diseases.
We hypothesized that natural anthraquinone derivative emodin can protect against neurotoxicity induced by pathological concentrations of zinc via the extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway and alleviate oxidative stress and mitochondrial dysfunction.
Human neuroblastoma (SH-SY5Y 26 cells) was treated with zinc sulfate and different concentrations of emodin, and changes in the levels of ETK1/2 expression, oxidative stress (DCFH-DA staining), mitochondrial function (JC-1 staining), lipid peroxidation (4-hydroxynonenal staining), and DNA oxidation (8-hydroxy-2-deoxyguanosine staining) were examined.
Emodin ameliorated zinc-induced altered expression of levels of phosphorylated ERK1/2 (not total ETK1/2) and synaptic proteins (presynaptic SNAP 25, synaptophysin and postsynaptic PSD95) in SH-SY5Y cells.
Moreover, emodin inhibited the generation of reactive oxygen species and oxidative stress and facilitated the collapse of mitochondrial membrane potential (ΔΨm) in SH-SY5Y cells.
In conclusion, our results indicated that emodin exerts neuroprotective effects against zinc by normalizing synaptic impairment by decreasing the phosphorylation of ERK1/2, reducing reactive oxygen species and protecting mitochondrial function.

Rapamycin Attenuated Zinc-Induced Tau Phosphorylation and Oxidative Stress in Rats: Involvement of Dual mTOR/p70S6K and Nrf2/HO-1 Pathways.

  1. Alzheimer’s disease is pathologically characterized by abnormal accumulation of amyloid-beta plaques, neurofibrillary tangles, oxidative stress, neuroinflammation, and neurodegeneration. Metal dysregulation, including excessive zinc released by presynaptic neurons, plays an important role in tau pathology and oxidase activation.
  2. The activities of mammalian target of rapamycin (mTOR)/ribosomal S6 protein kinase (p70S6K) are elevated in the brains of patients with Alzheimer’s disease. Learn more about Zinc induces tau hyperphosphorylation via mTOR/P70S6K activation in vitro. However, the involvement of the mTOR/P70S6K pathway in zinc-induced oxidative stress, tau degeneration, and synaptic and cognitive impairment has not been fully elucidated in vivo. Here, we assessed the effect of pathological zinc concentrations in SH-SY5Y cells by using biochemical assays and immunofluorescence staining. Rats (n = 18, male) were laterally ventricularly injected with zinc, treated with rapamycin (intraperitoneal injection) for 1 week, and assessed using the Morris water maze.
  3. Evaluation of oxidative stress, tau phosphorylation, and synaptic impairment was performed using the hippocampal tissue of the rats by biochemical assays and immunofluorescence staining.
  4. The results from the Morris water maze showed that the capacity of spatial memory was impaired in zinc-treated rats. Zinc sulfate significantly increased the levels of P-mTOR Ser2448, P-p70S6K Thr389, and P-tau Ser356 and decreased the levels of nuclear factor erythroid 2-related factor-2 (Nrf2) and heme oxygenase-1 (HO-1) in SH-SY5Y cells and in zinc-treated rats compared with the control groups.
  5. Increased expression of reactive oxygen species was observed in zinc sulfate-induced SH-SY5Y cells and in the hippocampus of zinc-injected rats. Rapamycin, an inhibitor of mTOR, rescued zinc-induced increases in mTOR/p70S6K activation, tau phosphorylation, and oxidative stress, and Nrf2/HO-1 inactivation, cognitive impairment, and synaptic impairment reduced the expression of synapse-related proteins in zinc-injected rats.
  6. In conclusion, our findings imply that rapamycin prevents zinc-induced cognitive impairment and protects neurons from tau pathology, oxidative stress, and synaptic impairment by decreasing mTOR/p70S6K hyperactivity and increasing Nrf2/HO-1 activity.

Data of Nebivolol on oxidative stress parameters in hypertensive patients.

Oxidative stress is a key feature in hypertension, since reactive oxygen species are involved in all stages of cardiovascular diseases. Saliva is a body fluid that can be used to investigate alterations in the oxidative system with several specific advantages over blood. Nebivolol is a third-generation selective β1-adrenergic receptor antagonist that promotes vasodilation and has been shown to reduce oxidative stress in pre-clinical and clinical studies.
The use of Nebivolol in different periods of treatment demonstrated that it is an efficient anti-hypertensive drug.
We evaluated the oxidative stress biomarkers and the enzymatic and non-enzymatic antioxidant systems in saliva of hypertensive patients before and after the use of anti-hypertensive therapeutic doses of Nebivolol, since saliva can be used as an auxiliary tool to analyze parameters of oxidative stress.

An Evaluation of the Role of Oxidative Stress in Non-Obstructive Coronary Artery Disease.

Approximately half of all women presenting to the emergency department with angina chest pain do not have obstructive coronary artery disease (CAD) on coronary angiography.
This condition is termed non-obstructive coronary artery disease (NOCAD), and includes ischemia with no obstructive coronary artery disease (INOCA) and myocardial infarction with non-obstructive coronary arteries (MINOCA).
Oxidative stress has been reported to be involved in the development and progression of CAD. However, a scarcity of studies has assessed a correlation between oxidative stress and NOCAD.
Thus, a literature review was performed of available reports on the role of oxidative stress in NOCAD. Possible mechanisms involved in oxidative stress that may contribute to NOCAD were identified and evaluated.
A key finding of this literature review was that oxidative stress caused vasoconstriction and endothelial damage, and this results in coronary microvascular dysfunction and vasospasm, which, in turn, lead to the pathogenesis of NOCAD.

Acidic/Alkaline Stress Mediates Responses to Azole Drugs and Oxidative Stress in Aspergillus fumigatus.

  • A human host exploits stresses such as acidic/alkaline pH, antifungal drugs, and reactive oxygen species to kill microbial pathogens such as the fungus Aspergillus fumigatus. However, A. fumigatus is resistant to these stresses in vitro.
  • Therefore, what accounts for the potent antifungal activity of the human host? In this observation, we show that simultaneous exposure to acidic pH and oxidative stresses is much more potent than the individual stresses themselves and that this combinatorial stress kills A. fumigatus synergistically in vitro.
  • Interestingly, A. fumigatus is resistant to the combination of alkaline pH and oxidative stress. Quantitative real-time PCR analyses showed that acidic/alkaline pH stress can mediate oxidative stress responses in A. fumigatus by regulating the expression of catalase-encoding genes.
  • We further show that A. fumigatus is sensitive to the combination of acidic/alkaline stress and azole drug stress. Transcriptome analysis revealed that the sensitivity of A. fumigatus to azole drugs under acidic/alkaline conditions may be related to changes in genetic stability, sphingolipid metabolism, lipid metabolism, and amino acid metabolism.
  • Collectively, our findings suggest that combinatorial stress represents a powerful fungicidal mechanism employed by hosts against pathogens, which suggests novel approaches to potentiate antifungal therapy.

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The human host combats fungal infections via phagocytic cells that recognize and kill fungal pathogens. Immune cells combat Aspergillus fumigatus infections with a potent mixture of chemicals, including reactive oxygen species, acidic/alkaline stress, and antifungal drugs.
However, A. fumigatus is relatively resistant to these stresses in vitro. In this observation, we show that it is the combination of acidic/alkaline pH and oxidative or azole stress that kills A. fumigatus so effectively, and we define the molecular mechanisms that underlie this potency.
Our findings suggest that combinatorial stress is a powerful fungicidal mechanism employed by hosts, which suggests novel approaches to potentiate antifungal therapy. This study provides a platform for future studies that will address the combinatorial impacts of various environmental stresses on A. fumigatus and other pathogenic microbes.

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