Quercetin against Neurodegenerative Diseases Progression: Comparison
View Latest Version
Please note this is a comparison between Version 2 by Vivi Li and Version 1 by Beong Ou Lim.

Berries are well-known fruits for their antioxidant effects due to their high content of flavonoids, and quercetin is one of the potent bioactive flavonoids. Although oxidative stress is an inevitable outcome in cells due to energy uptake and metabolism and other factors, excessive oxidative stress is considered a pivotal mediator for the cell death and leads to the progression of neurodegenerative diseases (NDDs). Furthermore, oxidative stress triggers inflammation that leads to neuronal cell loss. Alzheimer’s, Parkinson’s, Huntington’s disease, amyotrophic lateral sclerosis, multiple sclerosis, and so on are the main neurodegenerative diseases.

  • quercetin
  • oxidative stress
  • cognition
  • amyloid beta
  • tau
  • alpha synuclein

1. Introduction

Neurodegenerative diseases (NDDs) are a heterogeneous group of diseases, as portrayed by leisurely moderate neuronal cell death [1]. The etiology of neurodegenerative diseases has not yet been completely explained; being that as it may, expanded oxidative stress has been recommended as one of the possible normal etiologies in different NDDs. Excessive oxidative stress might incite cell harm, the impedance of the DNA fixed framework, and mitochondrial brokenness, all of which have been known as key components in the speed increase in the maturing system and the advancement of NDDs [2], such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). AD is the most common NDDs and it affects 10% to 50% of the elderly population, PD is the second most common NDD after AD [3]. Therefore, there have been endeavors to discover specialists that can secure against oxidative stress and possibly treat NDDs [4,5][4][5]. WResearchers concentrate on the major pathophysiological pathways of oxidative stress to the onset of NDDs, particularly in AD and PD. Furthermore, weresearchers will layout the current information on the accessible proof for the anticipation and treatment of NDDs and future headings for the ability of cell reinforcement supplementation with improved adequacy.
Mitochondria are the primary cellular producers of oxygen and contain various redox proteins equipped for moving single electrons to oxygen, producing the reactive oxygen species (ROS) superoxide (O2−). Mitochondrial chemicals are so far known to create ROS incorporating tricarboxylic acid (TCA) cycle enzymes aconitase (ACO) and α-ketoglutarate dehydrogenase (KGDH); the electron transport chain (ETC) edifices I, II, and III; pyruvate dehydrogenase (PDH) and glycerol-3-phosphate dehydrogenase (GPDH); dihydroorotate dehydrogenase (DHOH); and the cytochrome b5 reductase (B5R) and monoamine oxidases (MAO). Electron exchange with oxygen, producing superoxide, is more likely when these redox transporters carry many electrons and the probable energy of motion is high, as evidenced by the high mitochondrial membrane potential [6]. ROS is reduced when accessible electrons are few and the exchange energy can be low. Mitochondria also contain a broad cell reinforcement protection framework to detoxify the ROS produced by the responses depicted previously [7,8][7][8]. Nonenzymatic components of the framework incorporate α-tocopherol, cytochrome C, and GSH. Enzymatic parts incorporate MnSOD (manganese superoxide dismutase), glutathione peroxidase (GPX), catalase, phospholipid hydroperoxide glutathione peroxidase, glutathione reductase (GR), peroxiredoxins (PRX3/5), glutaredoxin (GRX2), thioredoxin (TRX2), and thioredoxin reductase (TRXR2) [9,10][9][10]. The recovery of GSH and diminished TRX2 relies upon nicotinamide adenine dinucleotide phosphate (NADPH), which have been acquired from substrates (through isocitrate dehydrogenase, IDH, or malic catalyst, ME) or the film potential through nicotinamide nucleotide transhydrogenase (NNT). In this way, ROS age and cancer prevention agent safeguards are likewise attached to the redox and vigorous conditions of mitochondria. glutathione disulfide (GSSG), lipid hydroxide (LOH), LOOH, and lipid hydroperoxide; o—oxidized state; r—decreased state. In basically and practically flawless mitochondria, a pivotal cancer prevention agent protection limit adjusts the ROS age. Moreover, there is minimal net ROS creation. Mitochondrial harm with the decline of the cancer prevention agent protection limit is essential for net ROS production. When this happens, an endless loop may follow, whereas ROS could be detrimental to mitochondria. This causes the aggravation of the abnormal aging and misfortune or utilization of the cancer prevention agent limit [11]. The nuclear factor erythroid 2–related factor 2 (Nrf2) is a potent antioxidant mediator protein and usually binds to KEAP-1 (cytosol with Kelch-like ECH-associated protein 1) in the cytoplasm [10,12][10][12]. Nrf2 activates through disassociation with the KEAP-1 and translocates into the nucleus [12].

2. Metabolism of Quercetin

2.1. Effects of Quercetin on Cognitive Impairments

Cognition is a neuropsychological term that refers to a range of mental processes for acquiring learning, experiences, perception, thought, memory, and so on. The growing evidence of the neurobiological bases of synaptic plasticity and memory has opened new avenues for the development of cognitive-enhancing drugs that can be used in the treatment of cognitive impairments. Memory is associated with neuropsychological disorders; the neuroregulatory systems that influence memory formation include stress hormones as well as multiple neurotransmitters and neuropeptide signaling pathways. Here, wresearchers review some of the findings on memory enhancement by drugs acting on the neuroregulatory system and discuss possible effects. Cognitive impairments cause lots of neurological and psychological disorders and pivotal symptoms of various NDDs, such as AD, PD, MS, and so on [33][13]. Cognitive impairment refers to turning down intellectualities, memories, reasoning, and so on [34][14]. Cognitive impairments lead to dementia. The etiology of cognitive impairments is not fully understood. Previous studies illustrated that cognitive impairments are caused by oxidative stress, neurotoxicity, inflammations, and many more pathological conditions, and quercetin plays a vital role in mitigating cognitive impairments [33,35][13][15]. Moreover, it has been proven that berries have an improved cognitive function in preclinical and clinical studies [36][16]. Quercetin improves spatial learning, neuroplasticity, and overall cognition in aged and dementia-affected mice [37,38,39][17][18][19]. Quercetin could be the potent bioactive in berries to alleviate cognitive impairments. Quercetin ameliorated learning and memory impairments by improving in the Morris water maze (MWM) test [40,41][20][21], Y-maze test [42][22], radial arm maze [43][23], novel objective recognition (NOR) task [44][24], passive avoidance test [42][22], and elevated plus maze test [41][21] in rodent models.

2.2. Effects of Quercetin on Oxidative Stress

Oxidative stress results from ROS, which is produced by many essential physiological processes such as metabolism, respiration, and intrinsic and extrinsic cellular factors. ROS is a byproduct of aerobic metabolism. Quercetin has been reported for remarkably restored oxidative stress by reducing ROS and reactive nitrogen species (RNS) through modulating cellular antioxidant mechanisms. ROS consists of superoxide anions (O2-), hydrogen peroxide (H2O2), hydroxyl radicals (OH·), and so on. They all have unique chemical properties that give them reactivity against different biological targets. ROS is often related to the principle of oxidative stress, and ROS has been thought to cause pathology by damaging lipids, proteins, DNA, and other macromolecules. H2O2 is made from superoxide produced by mitochondria and NADPH oxidase. Superoxide is formed by the single-electron reduction of molecular oxygen and is rapidly converted intracellularly to H2O2 by superoxide dismutase and then neutralized by the catalase enzyme. SOD is mainly localized in the cell membrane cleft and mitochondria, while SOD is localized in the mitochondrial matrix. SOD prevents the accumulation of superoxide, which damages and inactivates proteins containing iron–sulfur clusters. ROS are neutralized by the cellular antioxidant enzymes that are produced by the cellular antioxidant mechanisms. Apoptosis may take place when the ROS level is imbalanced by exceeding cellular antioxidant activity [45][25]. Antioxidant mediators such as the Nrf2/HO1 pathway are important in protecting against neurodegeneration. An excess of ROS induces the production of inflammatory factors that prolong neuronal cell death and exacerbates mitochondrial function, leading to apoptosis. Several studies have reported that the central cause of NDD is oxidative stress-mediated cell death by disrupting cellular antioxidant pathways [45,46,47,48,49,50][25][26][27][28][29][30]. Oxidative stress triggers a signaling cascade that causes mitochondrial dysfunction, which leads to neuronal cells loss. In addition, oxidation stress can cause chronic inflammation and maintain the death of inflammatory cells. Quercetin mitigates oxidative stress-mediated inflammation in microglia and other neuronal cells [51,52][31][32]. The neurons are protected by quercetin by adjusting the Nrf2 and HO1 antioxidant signal path in vivo and in vitro. Quercetin has placed the route-signaling Nrf2 and HO1 and has specified expression of antioxidant enzymes, such as SOD and GPX, etc., in the brain [53[33][34],54], which is consistent with the quercetin-initiated downregulation of inflammatory cytokines and apoptotic markers by positively modulating the Nrf2/HO1 cellular antioxidant defense mechanism [4]. Drug synergisms are clinically significant when lower-dose combinations produce greater efficacy with fewer side effects than individual doses of each drug. Moreover, quercetin showed synergistic effects with kaempferol and/or pterostilbene and increased the bioavailability [55][35], and it also remarkably attenuated oxidative stress through the Nrf2/ARE pathway.

2.3. Effects of Quercetin on P-53-Mediated Apoptosis

Quercetin is considered a suppressor of hyperactive P-53, which is triggered by several intrinsic and extrinsic factors that lead to cell death [56[36][37][38],57,58], and meanwhile, it also stabilizes P-53 in cancer cells [59][39]. Neurodegeneration is caused by the upregulation of P-53, which was discovered 40 years ago and has been widely studied and causes AD, PD, HD, and so on. P-53 can be triggered by various cellular abnormalities such as damaged DNA, ROS, MAPK, and so on [60,61][40][41], but sometimes without extended stress, P-53 hyperactivation takes place by ROS, which are byproducts of normal respiration and metabolism [62][42]. Potent transcription factor P-53 has many cellular functional activities: it may induce cell cycle arrest, DNA damage, and so on [63][43]. P-53 is an upstream apoptotic mediator, and quercetin significantly ameliorates P-53 and its downstream apoptotic mediators against several stimuli [63,64,65][43][44][45]. The mitochondria are the main energy-producing systems in the cell and regulate key factors of cell death such as P-53, BAX, cytochrome C, and caspases [2,66,67][2][46][47]. Apoptosis is a process of regular programmed cell death. Mitochondrial dysfunction is thought to be a possible key to the deregulation of the apoptotic pathway [67,68][47][48]. The high P-53 level is a marker of neurodegeneration. Indeed, this has been confirmed, for example, in the case of proteolytic products of the precursor protein Aβ, which is a transcriptional regulator of the P-53 gene and has been shown to act as a transcriptional regulator. Oxidative stress is one of the main causes of mitochondrial dysfunction, leading to abnormal apoptosis. Furthermore, mitochondrial dysfunction can also lead to the onset/exaggeration of neurodegenerative diseases (NDDs) by affecting apoptotic pathways, by influencing chronic inflammation, or by apoptosis. The expression of C9orf72(PR)50 in P-53 stable neurons activates genome-wide regulatory factors that are enriched for P-53 binding sites and leads to gene upregulation. As a major P-53 target, wresearchers then sought to directly test whether P-53 is required for C9orf72(PR)50-induced neurodegeneration and proteolytic separation. P-53 KO neurons were able to completely counteract the toxicity of C9orf72(PR)50 accumulation [69][49]. Furthermore, the impaired mitochondrial function also disrupts autophagic clearance (i.e., mitophagy) and induces aggregation of filamentous or misfolding proteins, e.g., amyloid beta (Aβ) and α-synuclein, leading to Alzheimer’s disease and Parkinson’s disease [70][50]. However, excess of cytochrome c, a component of ETC release due to oxidative stress and/or increased P-53 secretion, is an indication of damaged mitochondrial membrane potential [2]. Quercetin has demonstrated neuroprotection by markedly restoring P-53 and downstream apoptotic markers such as BAX, Cyto C, and caspase cascades in neurons [56,64][36][44]. Furthermore, quercetin repairs the P-53 triggering factors. Thus, the downregulation of apoptotic biomarkers in brain tissue could be a significant effect of neuroprotection.

2.4. Effects of Quercetin on Neuroinflammation

Quercetin reduces inflammation in the nervous system by downregulating proinflammatory cytokines (TNF, ILs, IFN, etc.) and mediators. Inflammation is an inevitable immune response towards antigens, pathogens, damaged cells, and so on [70][50]. Precisely, an adverse effect of immune response is called inflammation, and the cells require homeostasis other than the hyperactivation of inflammatory markers. Neuroinflammation is considered the cause of several psychiatric disorders, including anxiety, depression, schizophrenia, AD, and CNS epilepsy. The immune system is more susceptible to age. Long-term, severe post-infection sepsis can lead to depression and anxiety in older patients. Various epidemiological studies have reported that neuroinflammation is an important risk factor and that systemic inflammation is associated with the cause of neuropsychiatric disorders. Recently, targeted treatments for neuroinflammation have been proposed as new therapeutic tools for the control of neuropsychiatric disorders. Inflammation and oxidative stress are interrelated and show detrimental effects on cell survival. For instance, TLR4, LPS activates NADPH oxidase, which is abundantly expressed in macrophages and induces ROS production. This increases macrophage activation and ultimately causes excessive inflammation [71][51], which leads to inflammatory neuronal cell death. Inflammation is an adverse immune response to pathogens, antigens, and so on, and inflammation in neurons is called neuroinflammation. Neuroinflammation is a pivotal factor for neurodegeneration that triggers AD, PD, and other NDDs. Previous studies have shown that LPS administration significantly increases the expression levels of inflammatory cytokines and mediators in the hippocampus. The expression of TNF-α and IL-1β mRNA is dynamically regulated by immune cells in the hippocampal inflammatory response [72,73][52][53]. However, quercetin has shown the ability to mitigate the abnormalities such as anxious behavior and neuroinflammation by consistently lowering LPS-induced IL-6 and IL-1β levels. Furthermore, these results also suggested that the inflammatory response to LPS infiltration significantly increased COX-2 levels by regulating the MAPK/NF-κB signaling pathway in the hippocampus. Previous studies have also shown that NF-κB, which mainly regulates the inflammatory response, is activated by LPS and inflammatory cytokines infiltration. Quercetin addresses LPS and other inflammatory mediator-induced behavioral disorders such as anxiety by significantly inhibiting COX-2 levels through NF-κB regulation [11,74][11][54]. Quercetin alleviates inflammatory markers, attenuates microgliosis and astrogliosis [75][55], and helps to maintain homeostasis as a natural antioxidant and anti-inflammatory agent. Moreover, quercetin promotes autophagic clearance, maintains the neurons in homeostatic conditions, and mitigates inflammatory and oxidative stress-mediated neurodegeneration [76][56]. NLRP3 inflammasome activation is strongly associated with the pathogenesis of NDDS, and quercetin has been shown to remarkably restore inflammasome activation and protect NDDs progression [77][57].

References

  1. Pedersen, J.T.; Chen, S.W.; Borg, C.B.; Ness, S.; Bahl, J.M.; Heegaard, N.H.; Teilum, K. Amyloid-β and α-synuclein decrease the level of metal-catalyzed reactive oxygen species by radical scavenging and redox silencing. J. Am. Chem. Soc. 2016, 138, 3966–3969.
  2. Chan, D.C. Mitochondria: Dynamic Organelles in Disease, Aging, and Development. Cell 2006, 125, 1241–1252.
  3. Zhang, Y.-W.; Thompson, R.; Zhang, H.; Xu, H. APP processing in Alzheimer’s disease. Mol. Brain 2011, 4, 3.
  4. Luo, J.-F.; Shen, X.Y.; Lio, C.K.; Dai, Y.; Cheng, C.S.; Liu, J.X.; Zhou, H. Activation of Nrf2/HO-1 Pathway by Nardochinoid C Inhibits Inflammation and Oxidative Stress in Lipopolysaccharide-Stimulated Macrophages. Front. Pharmacol. 2018, 9, 911.
  5. Arnold, S. Cytochrome c Oxidase and Its Role in Neurodegeneration and Neuroprotection. In Mitochondrial Oxidative Phosphorylation: Nuclear-Encoded Genes, Enzyme Regulation, and Pathophysiology; Kadenbach, B., Ed.; Springer: New York, NY, USA, 2012; pp. 305–339.
  6. Forman, H.J.; Zhang, H. Targeting oxidative stress in disease: Promise and limitations of antioxidant therapy. Nat. Rev. Drug Discov. 2021, 20, 689–709.
  7. Moosecker, S.; Gomes, P.; Dioli, C.; Yu, S.; Sotiropoulos, I.; Almeida, O.F. Activated PPARγ abrogates misprocessing of amyloid precursor protein, Tau missorting and synaptotoxicity. Front. Cell. Neurosci. 2019, 13, 239.
  8. Koh, E.-J.; Kim, K.-J.; Choi, J.; Kang, D.-H.; Lee, B.-Y. Spirulina maxima extract prevents cell death through BDNF activation against amyloid beta 1-42 (Aβ 1-42) induced neurotoxicity in PC12 cells. Neurosci. Lett. 2018, 673, 33–38.
  9. Bayazid, A.B.; Jang, Y.A.; Kim, Y.M.; Kim, J.G.; Lim, B.O. Neuroprotective Effects of Sodium Butyrate through Suppressing Neuroinflammation and Modulating Antioxidant Enzymes. Neurochem. Res. 2021, 46, 2348–2358.
  10. Tonelli, C.; Chio, I.I.C.; Tuveson, D.A. Transcriptional Regulation by Nrf2. Antioxid. Redox Signal. 2018, 29, 1727–1745.
  11. Jabri, M.-A.; Rtibi, K.; Sebai, H. Chamomile decoction mitigates high fat diet-induced anxiety-like behavior, neuroinflammation and cerebral ROS overload. Nutr. Neurosci. 2020, 25, 1350–1361.
  12. Brandes, M.S.; Gray, N.E. NRF2 as a Therapeutic Target in Neurodegenerative Diseases. ASN Neuro 2020, 12, 1759091419899782.
  13. Bakoyiannis, I.; Daskalopoulou, A.; Pergialiotis, V.; Perrea, D. Phytochemicals and cognitive health: Are flavonoids doing the trick? Biomed. Pharmacother. 2019, 109, 1488–1497.
  14. Robertson, D.A.; Savva, G.M.; Kenny, R.A. Frailty and cognitive impairment—A review of the evidence and causal mechanisms. Ageing Res. Rev. 2013, 12, 840–851.
  15. Broman-Fulks, J.J.; Canu, W.H.; Trout, K.L.; Nieman, D.C. The effects of quercetin supplementation on cognitive functioning in a community sample: A randomized, placebo-controlled trial. Ther. Adv. Psychopharmacol. 2012, 2, 131–138.
  16. Subash, S.; Essa, M.M.; Al-Adawi, S.; Memon, M.A.; Manivasagam, T.; Akbar, M. Neuroprotective effects of berry fruits on neurodegenerative diseases. Neural Regener. Res. 2014, 9, 1557–1566.
  17. Wang, D.-M.; Li, S.-Q.; Wu, W.-L.; Zhu, X.-Y.; Wang, Y.; Yuan, H.-Y. Effects of Long-Term Treatment with Quercetin on Cognition and Mitochondrial Function in a Mouse Model of Alzheimer’s Disease. Neurochem. Res. 2014, 39, 1533–1543.
  18. Yang, S.; Wang, G.; Ma, Z.F.; Qin, L.-Q.; Zhai, Y.-J.; Yu, Z.-L.; Xue, M.; Zhang, Y.-H.; Wan, Z. DietaryAdvancedGlycationEnd Products-InducedCognitive Impairment in Aged ICR Mice: Protective Role of Quercetin. Mol. Nutr. Food Res. 2019, 64, e1901019.
  19. Zingales, V.; Sirerol-Piquer, M.S.; Fernández-Franzón, M.; Ruiz, M.-J. Role of quercetin on sterigmatocystin-induced oxidative stress-mediated toxicity. Food Chem. Toxicol. 2021, 156, 112498.
  20. Halder, S.; Kar, R.; Galav, V.; Mehta, A.K.; Bhattacharya, S.K.; Mediratta, P.K.; Banerjee, B.D. Cadmium exposure during lactation causes learning and memory-impairment in F1 generation mice: Amelioration by quercetin. Drug Chem. Toxicol. 2015, 39, 272–278.
  21. Priprem, A.; Watanatorn, J.; Sutthiparinyanont, S.; Phachonpai, W.; Muchimapura, S. Anxiety and cognitive effects of quercetin liposomes in rats. Nanomed. Nanotechnol. Biol. Med. 2008, 4, 70–78.
  22. Choi, G.N.; Kim, J.H.; Kwak, J.H.; Jeong, C.-H.; Jeong, H.R.; Lee, U.; Heo, H.J. Effect of quercetin on learning and memory performance in ICR mice under neurotoxic trimethyltin exposure. Food Chem. 2011, 132, 1019–1024.
  23. Pu, F.; Mishima, K.; Irie, K.; Motohashi, K.; Tanaka, Y.; Orito, K.; Egawa, T.; Kitamura, Y.; Egashira, N.; Iwasaki, K.; et al. Neuroprotective Effects of Quercetin and Rutin on Spatial Memory Impairment in an 8-Arm Radial Maze Task and Neuronal Death Induced by Repeated Cerebral Ischemia in Rats. J. Pharmacol. Sci. 2007, 104, 329–334.
  24. Mert, D.G.; Turgut, N.H.; Arslanbas, E.; Gungor, H.; Kara, H. The influence of quercetin on recognition memory and brain oxidative damage in a ketamine model of schizophrenia. Psychiatry Clin. Psychopharmacol. 2018, 29, 1–7.
  25. Cavaliere, G.; Trinchese, G.; Penna, E.; Cimmino, F.; Pirozzi, C.; Lama, A.; Annunziata, C.; Catapano, A.; Mattace Raso, G.; Meli, R.; et al. High-Fat Diet Induces Neuroinflammation and Mitochondrial Impairment in Mice Cerebral Cortex and Synaptic Fraction. Front. Cell. Neurosci. 2019, 13, 509.
  26. Emerit, J.; Edeas, M.; Bricaire, F. Neurodegenerative diseases and oxidative stress. Biomed. Pharmacother. 2003, 58, 39–46.
  27. Khoubnasabjafari, M.; Ansarin, K.; Jouyban, A. Reliability of malondialdehyde as a biomarker of oxidative stress in psychological disorders. BioImpacts 2015, 5, 123–127.
  28. Gumeni, S.; Papanagnou, E.-D.; Manola, M.S.; Trougakos, I.P. Nrf2 activation induces mitophagy and reverses Parkin/Pink1 knock down-mediated neuronal and muscle degeneration phenotypes. Cell Death Dis. 2021, 12, 671.
  29. Butterfield, D.A.; Drake, J.; Pocernich, C.; Castegna, A. Evidence of oxidative damage in Alzheimer’s disease brain: Central role for amyloid β-peptide. Trends Mol. Med. 2001, 7, 548–554.
  30. Yousof Ali, M.; Zaib, S.; Jannat, S.; Khan, I. Discovery of potent and selective dual cholinesterases and β-secretase inhibitors in pomegranate as a treatment for Alzheimer’s disease. Bioorganic Chem. 2022, 129, 106137.
  31. Le, K.; Song, Z.; Deng, J.; Peng, X.; Zhang, J.; Wang, L.; Zhou, L.; Bi, H.; Liao, Z.; Feng, Z. Quercetin alleviates neonatal hypoxic-ischemic brain injury by inhibiting microglia-derived oxidative stress and TLR4-mediated inflammation. Agents Actions 2020, 69, 1201–1213.
  32. Benameur, T.; Soleti, R.; Porro, C. The Potential Neuroprotective Role of Free and Encapsulated Quercetin Mediated by miRNA against Neurological Diseases. Nutrients 2021, 13, 1318.
  33. Yu, X.; Li, Y.; Mu, X. Effect of quercetin on PC12 Alzheimer’s disease cell model induced by Aβ25-35 and its mechanism based on sirtuin1/Nrf2/HO-1 pathway. BioMed Res. Int. 2020, 2020, 8210578.
  34. Song, J.; Du, G.; Wu, H.; Gao, X.; Yang, Z.; Liu, B.; Cui, S. Protective effects of quercetin on traumatic brain injury induced inflammation and oxidative stress in cortex through activating Nrf2/HO-1 pathway. Restor. Neurol. Neurosci. 2021, 39, 73–84.
  35. Saw, C.L.L.; Guo, Y.; Yang, A.Y.; Paredes-Gonzalez, X.; Ramirez, C.; Pung, D.; Kong, A.-N.T. The berry constituents quercetin, kaempferol, and pterostilbene synergistically attenuate reactive oxygen species: Involvement of the Nrf2-ARE signaling pathway. Food Chem. Toxicol. 2014, 72, 303–311.
  36. Ahmad, A.; Khan, M.M.; Hoda, N.; Raza, S.S.; Javed, H.; Ishrat, T.; Ashafaq, M.; Ahmad, E.; Safhi, M.M.; Islam, F. Quercetin Protects Against Oxidative Stress Associated Damages in a Rat Model of Transient Focal Cerebral Ischemia and Reperfusion. Neurochem. Res. 2011, 36, 1360–1371.
  37. Jembrek, M.J.; Vlainić, J.; Čadež, V.; Šegota, S. Atomic force microscopy reveals new biophysical markers for monitoring subcellular changes in oxidative injury: Neuroprotective effects of quercetin at the nanoscale. PLoS ONE 2018, 13, e0200119.
  38. Roshanzamir, F.; Yazdanparast, R. Quercetin attenuates cell apoptosis of oxidant-stressed SK-N-MC cells while suppressing up-regulation of the defensive element, HIF-1α. Neuroscience 2014, 277, 780–793.
  39. Tanigawa, S.; Fujii, M.; Hou, D.-X. Stabilization of p53 Is Involved in Quercetin-Induced Cell Cycle Arrest and Apoptosis in HepG2 Cells. Biosci. Biotechnol. Biochem. 2008, 72, 797–804.
  40. Agarwal, M.L.; Taylor, W.R.; Chernov, M.V.; Chernova, O.B.; Stark, G.R. The p53 Network. J. Biol. Chem. 1998, 273, 1–4.
  41. Xue, W.; Zender, L.; Miething, C.; Dickins, R.A.; Hernando, E.; Krizhanovsky, V.; Cordon-Cardo, C.; Lowe, S.W. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 2007, 445, 656–660.
  42. Sablina, A.A.; Budanov, A.V.; Ilyinskaya, G.V.; Agapova, L.S.; Kravchenko, J.E.; Chumakov, P. The antioxidant function of the p53 tumor suppressor. Nat. Med. 2005, 11, 1306–1313.
  43. Hafner, A.; Bulyk, M.L.; Jambhekar, A.; Lahav, G. The multiple mechanisms that regulate p53 activity and cell fate. Nat. Rev. Mol. Cell Biol. 2019, 20, 199–210.
  44. Sharma, D.; Wani, W.; Sunkaria, A.; Kandimalla, R.; Sharma, R.; Verma, D.; Bal, A.; Gill, K. Quercetin attenuates neuronal death against aluminum-induced neurodegeneration in the rat hippocampus. Neuroscience 2016, 324, 163–176.
  45. Fridman, J.S.; Lowe, S.W. Control of apoptosis by p53. Oncogene 2003, 22, 9030–9040.
  46. Li, X.; Gu, S.; Ling, Y.; Shen, C.; Cao, X.; Xie, R. p53 inhibition provides a pivotal protective effect against ischemia-reperfusion injury in vitro via mTOR signaling. Brain Res. 2015, 1605, 31–38.
  47. Wolff, S.; Erster, S.; Palacios, G.; Moll, U.M. p53’s mitochondrial translocation and MOMP action is independent of Puma and Bax and severely disrupts mitochondrial membrane integrity. Cell Res. 2008, 18, 733–744.
  48. Sun, J.; Wang, F.; Li, H.; Zhang, H.; Jin, J.; Chen, W.; Pang, M.; Yu, J.; He, Y.; Liu, J.; et al. Neuroprotective Effect of Sodium Butyrate against Cerebral Ischemia/Reperfusion Injury in Mice. BioMed Res. Int. 2015, 2015, 395895.
  49. Maor-Nof, M.; Shipony, Z.; Lopez-Gonzalez, R.; Nakayama, L.; Zhang, Y.-J.; Couthouis, J.; Blum, J.A.; Castruita, P.A.; Linares, G.R.; Ruan, K.; et al. p53 is a central regulator driving neurodegeneration caused by C9orf72 poly(PR). Cell 2021, 184, 689–708.e20.
  50. Bayazid, A.B.; Kim, J.G.; Azam, S.; Jeong, S.A.; Kim, D.H.; Park, C.W.; Lim, B.O. Sodium butyrate ameliorates neurotoxicity and exerts anti-inflammatory effects in high fat diet-fed mice. Food Chem. Toxicol. 2021, 159, 112743.
  51. Wu, H.; Wang, Y.; Zhang, Y.; Xu, F.; Chen, J.; Duan, L.; Zhang, T.; Wang, J.; Zhang, F. Breaking the vicious loop between inflammation, oxidative stress and coagulation, a novel anti-thrombus insight of nattokinase by inhibiting LPS-induced inflammation and oxidative stress. Redox Biol. 2020, 32, 101500.
  52. Xu, J.; Gao, H.; Zhang, L.; Rong, S.; Yang, W.; Ma, C.; Chen, M.; Huang, Q.; Deng, Q.; Huang, F. Melatonin alleviates cognition impairment by antagonizing brain insulin resistance in aged rats fed a high-fat diet. J. Pineal Res. 2019, 67, e12584.
  53. Bayazid, A.B.; Jeong, S.A.; Park, C.W.; Kim, D.H.; Lim, B.O. The Anti-Inflammatory Activities of Fermented Curcuma That Contains Butyrate Mitigate DSS-Induced Colitis in Mice. Molecules 2022, 27, 4745.
  54. Lee, B.; Yeom, M.; Shim, I.; Lee, H.; Hahm, D.-H. Protective Effects of Quercetin on Anxiety-Like Symptoms and Neuroinflammation Induced by Lipopolysaccharide in Rats. Evidence-Based Complement. Altern. Med. 2020, 2020, 4892415.
  55. Wu, M.; Liu, F.; Guo, Q. Quercetin attenuates hypoxia-ischemia induced brain injury in neonatal rats by inhibiting TLR4/NF-κB signaling pathway. Int. Immunopharmacol. 2019, 74, 105704.
  56. Ashrafizadeh, M.; Ahmadi, Z.; Farkhondeh, T.; Samarghandian, S. Autophagy as a molecular target of quercetin underlying its protective effects in human diseases. Arch. Physiol. Biochem. 2019, 128, 200–208.
  57. Han, X.; Xu, T.; Fang, Q.; Zhang, H.; Yue, L.; Hu, G.; Sun, L. Quercetin hinders microglial activation to alleviate neurotoxicity via the interplay between NLRP3 inflammasome and mitophagy. Redox Biol. 2021, 44, 102010.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)
Video Production Service
Feedback