bims-nurfan 2023-11-19 papers

bims-nurfan

Biomed News

on NRF2 and Neurological Diseases

Issue of 2023‒11‒19
sixteen papers selected by
Arif Kamil Salihoğlu, Karadeniz Technical University

Regulation of NRF2 by Phosphoinositides and Small Heat Shock Proteins.
Mild Oxidative Stress Induced by Sodium Arsenite Reduces Lipocalin-2 Expression Levels in Cortical Glial Cells.
Demethylnobiletin ameliorates cerebral ischemia-reperfusion injury in rats through Nrf2/HO-1 signaling pathway.
Protective effects of Hinokitiol on neuronal ferroptosis by activating the KEAP1/NRF-2/HO-1 pathway in traumatic brain injury.
Ginger (Zingiber Officinale Roscoe) ameliorates ethanol-induced cognitive impairment by modulating NMDA and GABA-A receptors in rat hippocampus.
Double Attack to Oxidative Stress in Neurodegenerative Disorders: MAO-B and Nrf2 as Elected Targets.
Considering the protective effect of exendin-4 against oxidative stress in spiral ganglion neurons.
Hepatoprotective effects of gentisic acid through its anti-oxidant properties in nicotinamide-streptozotocin induced diabetic mice.
Mitochondrial dysfunction in Parkinson's disease - a key disease hallmark with therapeutic potential.
Mitochondrial Complex I and β-Amyloid Peptide Interplay in Alzheimer's Disease: A Critical Review of New and Old Little Regarded Findings.
The mechanisms of action of mitochondrial targeting agents in cancer: inhibiting oxidative phosphorylation and inducing apoptosis.
NRF1 Alleviated Oxidative Stress of Glioblastoma Cells by Regulating NOR1.
Cellular and Molecular Mechanisms in Oxidative Stress-Related Diseases 2.0/3.0.
A Critical Review of the Neuropharmacological Effects of Kratom: An Insight from the Functional Array of Identified Natural Compounds.
Gardenin A improves cognitive and motor function in A53T-α-syn mice.
Oxygen metabolism abnormality and Alzheimer's disease: An update.

bioRxiv. 2023 Oct 27. pii: 2023.10.26.564194. [Epub ahead of print]

Regulation of NRF2 by Phosphoinositides and Small Heat Shock Proteins.

Changliang Chen, Mo Chen, Tianmu Wen, Richard A Anderson, Vincent L Cryns.

Reactive oxygen species (ROS) are generated by aerobic metabolism, and their deleterious effects are buffered by the cellular antioxidant response, which prevents oxidative stress. The nuclear factor erythroid 2-related factor 2 (NRF2) is a master transcriptional regulator of the antioxidant response. Basal levels of NRF2 are kept low by ubiquitin-dependent degradation of NRF2 by E3 ligases, including the Kelch-like ECH-associated protein 1 (KEAP1). Here, we show that the stability and function of NRF2 is regulated by the type I phosphatidylinositol phosphate kinase g (PIPKIg), which binds NRF2 and transfers its product phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P 2 ) to NRF2. PtdIns(4,5)P 2 binding recruits the small heat shock protein HSP27 to the complex. Silencing PIPKIg or HSP27 destabilizes NRF2, reduces expression of its target gene HO-1, and sensitizes cells to oxidative stress. These data demonstrate an unexpected role of phosphoinositides and HSP27 in regulating NRF2 and point to PIPKIg and HSP27 as drug targets to destabilize NRF2 in cancer.In brief: Phosphoinositides are coupled to NRF2 by PIPKIγ, and HSP27 is recruited and stabilizes NRF2, promoting stress-resistance.

DOI: https://doi.org/10.1101/2023.10.26.564194
Int J Mol Sci. 2023 Nov 01. pii: 15864. [Epub ahead of print]24(21):

Mild Oxidative Stress Induced by Sodium Arsenite Reduces Lipocalin-2 Expression Levels in Cortical Glial Cells.

Ye-Jin Cho, So-Hyun Park, Kwon-Yul Ryu.

  Astrocytes and microglia, the most abundant glial cells in the central nervous system, are involved in maintaining homeostasis in the brain microenvironment and in the progression of various neurological disorders. Lipocalin-2 (LCN2) is a small secretory protein that can be transcriptionally upregulated via nuclear factor kappa B (NF-κB) signaling. It is synthesized and secreted by glial cells, resulting in either the restoration of damaged neural tissues or the induction of neuronal apoptosis in a context-dependent manner. It has recently been reported that when glial cells are under lipopolysaccharide-induced inflammatory stress, either reduced production or accelerated degradation of LCN2 can alleviate neurotoxicity. However, the regulatory mechanisms of LCN2 in glial cells are not yet fully understood. In this study, we used primary astroglial-enriched cells which produce LCN2 and found that the production of LCN2 could be reduced by sodium arsenite treatment. Surprisingly, the reduced LCN2 production was not due to the suppression of NF-κB signaling. Mild oxidative stress induced by sodium arsenite treatment activated antioxidant responses and downregulated Lcn2 expression without reducing the viability of astroglial-enriched cells. Intriguingly, reduced LCN2 production could not be achieved by simple activation of the nuclear factor erythroid-2-related factor 2 (Nrf2)-Kelch-like ECH-associated protein 1 (Keap1) pathway in astroglial-enriched cells. Thus, it appears that mild oxidative stress, occurring in an Nrf2-independent manner, is required for the downregulation of Lcn2 expression. Taken together, our findings provide new insights into the regulatory mechanisms of LCN2 and suggest that mild oxidative stress may alter LCN2 homeostasis, even under neuroinflammatory conditions.

Keywords:  astrocyte; glial cells; lipocalin-2; oxidative stress; sodium arsenite

DOI:  https://doi.org/10.3390/ijms242115864
Environ Toxicol. 2023 Nov 13.

Demethylnobiletin ameliorates cerebral ischemia-reperfusion injury in rats through Nrf2/HO-1 signaling pathway.

Dan Huang, Ali Chyadmarzok Al Awad, Chuai Tang, Yunqiang Chen.

  BACKGROUND: Demethylnobiletin (DN), with a variety of biological activities, is a polymethoxy-flavanone (PMF) found in citrus. In the present study, we explored the biological activities and potential mechanism of DN to improve cerebral ischemia reperfusion injury (CIRI) in rats, and identified DN as a novel neuroprotective agent for patients with ischemic brain injury.METHODS: Rat CIRI models were established via middle cerebral artery occlusion (MCAO). Primary nerve cells were isolated and cultured in fetal rat cerebral cortex in vitro, and oxygen-glucose deprivation/reperfusion (OGD/R) models of primary nerve cells were induced. After intervention with DN with different concentrations in MCAO rats and OGD/R nerve cells, 2,3,5-triphenyltetrazolium chloride staining was used to quantify cerebral infarction size in CIRI rats. Modified neurological severity score was utilized to assess neurological performance. Histopathologic staining and live/dead cell-viability staining was used to observe apoptosis. Levels of glutathione (GSH), superoxide dismutase (SOD), reactive oxygen species (ROS) and malondialdehyde (MDA) in tissues and cells were detected using commercial kits. DN level in serum and cerebrospinal fluid of MCAO rats were measured by liquid chromatography tandem mass spectrometry. In addition, expression levels of proteins like Kelch like ECH associated protein 1 (Keap1), nuclear factor erythroid 2-related factor 2 (Nfr2) and heme oxygenase 1 (HO-1) in the Nrf2/HO-1 pathway, and apoptosis-related proteins like Cleaved caspase-3, BCL-2-associated X protein (Bax) and B-cell lymphoma-2 (Bcl-2) were determined by Western blot and immunofluorescence.
RESULTS: DN can significantly enhance neurological function recovery by reducing cerebral infarction size and weakening neurocytes apoptosis in MCAO rats. It was further found that DN could improve oxidative stress (OS) injury of nerve cells by bringing down MDA and ROS levels and increasing SOD and GSH levels. Notably, DN exerts its pharmacological influences through entering blood-brain barrier. Mechanically, DN can reduce Keap1 expression while activate Nrf2 and HO-1 expression in neurocytes.
CONCLUSIONS: The protective effect of DN on neurocytes have been demonstrated in both in vitro and in vivo circumstances. It deserves to be developed as a potential neuroprotective agent through regulating the Nrf2/HO-1 signaling pathway to ameliorate neurocytes impairment caused by OS.

Keywords:  Demethylnobiletin; Nrf2/HO-1 signaling pathway; cerebral ischemia

DOI:  https://doi.org/10.1002/tox.24036
J Neurotrauma. 2023 Nov 14.

Protective effects of Hinokitiol on neuronal ferroptosis by activating the KEAP1/NRF-2/HO-1 pathway in traumatic brain injury.

Hongxing Tang, Kejun He, Kun Zhao, Chen Zheng, Weichi Wu, Weilin Jin, Lixuan Yang, Baoshu Xie.

  Hinokitiol (β-thujaplicin, HIK) is a natural monoterpene small molecule compound showing various biological effects including antibacterial, anti- inflammatory and anti-tumor. Ferroptosis, a new form of iron-dependent cell death, has been demonstrated as one of the pathophysiological mechanisms of traumatic brain injury (TBI). However, the effect of hinokitiol on neuronal ferroptosis after traumatic brain injury has not been reported. Here, we show that hinokitiol alleviated excessive glutamate-induced intracellular reactive oxygen species (ROS), lipid peroxidation, and Fe2+ accumulation in HT-22. Moreover, hinokitiol upregulated heme oxygenase-1 (HO-1) expression, promoted nuclear factor-erythroid factor 2-related factor 2 (Nrf2) nuclear translocation, and inhibited the activation of microglia and astrocyte after TBI. Furthermore, hinokitiol remarkably reduced brain tissue lesions, mitigated neuron loss, iron deposition and attenuated neurologic impairment in the CCI-constructed TBI model in vivo. These results suggest that hinokitiol has neuroprotective effects on rescuing cells from TBI-induced neuronal ferroptosis. In summary, we reveal a novel role of hinokitiol in TBI, which has neuroprotective effects on rescuing cells from TBI-induced neuronal ferroptosis. Moreover, hinokitiol through activating the Nrf2/Keap1/HO-1 signaling pathway significantly reduces the neuronal damage, suggesting that it is a potential therapeutic candidate for TBI.

Keywords:  ANTIOXIDANTS; IN VITRO STUDIES; IN VIVO STUDIES; NEURONAL CELL DEATH

DOI:  https://doi.org/10.1089/neu.2023.0150
Metab Brain Dis. 2023 Nov 15.

Ginger (Zingiber Officinale Roscoe) ameliorates ethanol-induced cognitive impairment by modulating NMDA and GABA-A receptors in rat hippocampus.

Jiaojiao Wang, Abolfazl Akbari, Marjan Chardahcherik, Jun Wu.

  Brain damage caused by ethanol abuse may lead to permanent damage, including severe dementia. The aim of this study was to investigate the effects of ginger powder on ethanol-induced cognitive disorders by examining oxidative damage and inflammation status, and the gene expression of N-methyl-D-aspartate (NMDA) and γ-Aminobutyric acid (GABA)-A receptors in the hippocampus of male rats. 24 adult male Sprague-Dawley rats were allocated randomly to four groups as follows control, ethanol (4g/kg/day, by gavage), ginger (1g/kg/day, by gavage), and ginger-ethanol. At the end of the study, memory and learning were evaluated by the shuttle box test. Moreover, to explore mechanisms involved in ethanol-induced cognitive impairment and the protective effect of ginger, the expression of Nuclear factor kappa B (NF-κB), nuclear factor erythroid 2-related factor 2 (Nrf2), NMDA receptor, and GABA-A receptor was measured along with inflammatory and oxidative biomarkers in the hippocampus tissue. The results showed that ethanol could induce cognitive impairment in the ethanol group, while pretreatment with ginger could reverse it. The gene expression of the NF-κB/ Tumor necrosis factor (TNF)-α/Interleukin (IL)-1β pathway and NMDA and GABA-A receptors significantly increased in the ethanol group compared to the control group. While pretreatment with ginger could significantly improve ethanol-induced cognitive impairment through these pathways in the ginger-ethanol group compared to the ethanol group (P < 0.05). It can be concluded that ginger powder could ameliorate ethanol-induced cognitive impairment by modulating the expression of NMDA and GABA-A receptors and inhibiting oxidative damage and the NF-κB/TNF-α/IL-1β pathway in the rat hippocampus.

Keywords:  Cognitive Impairment; Ethanol; Ginger; Hippocampus; NMDA and GABA-A receptors

DOI:  https://doi.org/10.1007/s11011-023-01301-8
Molecules. 2023 Nov 04. pii: 7424. [Epub ahead of print]28(21):

Double Attack to Oxidative Stress in Neurodegenerative Disorders: MAO-B and Nrf2 as Elected Targets.

Filippo Basagni, Maria Luisa Di Paolo, Giorgio Cozza, Lisa Dalla Via, Francesca Fagiani, Cristina Lanni, Michela Rosini, Anna Minarini.

  Oxidative stress and neuroinflammation play a pivotal role in triggering the neurodegenerative pathological cascades which characterize neurodegenerative disorders, such as Alzheimer's and Parkinson's diseases. In search for potential efficient treatments for these pathologies, that are still considered unmet medical needs, we started from the promising properties of the antidiabetic drug pioglitazone, which has been repositioned as an MAO-B inhibitor, characterized by promising neuroprotective properties. Herein, with the aim to broaden its neuroprotective profile, we tried to enrich pioglitazone with direct and indirect antioxidant properties by hanging polyphenolic and electrophilic features that are able to trigger Nrf2 pathway and the resulting cytoprotective genes' transcription, as well as serve as radical scavengers. After a preliminary screening on MAO-B inhibitory properties, caffeic acid derivative 2 emerged as the best inhibitor for potency and selectivity over MAO-A, characterized by a reversible mechanism of inhibition. Furthermore, the same compound proved to activate Nrf2 pathway by potently increasing Nrf2 nuclear translocation and strongly reducing ROS content, both in physiological and stressed conditions. Although further biological investigations are required to fully clarify its neuroprotective properties, we were able to endow the pioglitazone scaffold with potent antioxidant properties, representing the starting point for potential future pioglitazone-based therapeutics for neurodegenerative disorders.

Keywords:  MAO-B; Nrf2; cinnamic acid; electrophile; oxidative stress; pioglitazone

DOI:  https://doi.org/10.3390/molecules28217424
Iran J Basic Med Sci. 2023 ;26(12): 1423-1430

Considering the protective effect of exendin-4 against oxidative stress in spiral ganglion neurons.

Hongxia Wu, Yangxi Ou, Siji Wang, Fenghui Yu, Xiaoxia Fan, Houyong Kang, Tao Chen.

  Objectives: The protection of spiral ganglion neurons (SGNs) is crucial for hearing loss. Exendin-4 has been shown to have neuroprotective effects in several neurological disorders. Therefore, this study aimed to investigate the effect of the glucagon-like protein-1 receptor (GLP-1R) agonist exendin-4 on kanamycin-induced injury in mouse SGNs in vitro.Materials and Methods: In this study, GLP-1R expression in SGNs was verified by immunofluorescence and immunohistochemical staining. In vitro-cultured SGNs and the organ of Corti were exposed to kanamycin with or without exendin-4 treatment. The cell survival rate was measured using the cell counting kit-8 assay, and the damage to auditory nerve fibers (ANF) projecting radially from the SGNs was evaluated using immunofluorescence staining. Reactive oxygen species (ROS) content was determined by flow cytometry, and glutathione peroxidase (GSH-Px) content, superoxide dismutase (SOD) activity, and malondialdehyde (MDA) content were determined by spectrophotometry. Protein expression of nuclear factor erythroid-2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) was detected using western blotting.
Results: GLP-1R was expressed in SGNs. Treatment with 1 mM kanamycin for 24 hr induced SGN damage. Exendin-4 (100 nM) had a protective effect against kanamycin-induced SGN cell injury, improved cell survival rate, reduced nerve fiber injury, increased SOD activity and GSH-Px level, and reduced MDA and ROS contents. The Nrf2/HO-1 pathway was activated.
Conclusion: Exendin-4 alleviates oxidative damage and exerts neuroprotective effects in kanamycin-induced SGN injury through the Nrf2/HO-1 signaling pathway. Exendin-4 has the potential to prevent or treat hearing loss due to SGN damage.

Keywords:  Exenatide; Hearing loss; Kanamycin; Mice; Oxidative damage; Spiral ganglio

DOI:  https://doi.org/10.22038/IJBMS.2023.69190.15076
Iran J Basic Med Sci. 2023 ;26(12): 1409-1415

Hepatoprotective effects of gentisic acid through its anti-oxidant properties in nicotinamide-streptozotocin induced diabetic mice.

Reza Noei Razliqi, Elnaz Harooni, Niloofar Neisi, Maryam Jafar Sameri, Akram Ahangarpour.

  Objectives: Type 2 diabetes mellitus (T2DM) is a common metabolic disorder that causes many complications. Liver failure is one of the complications of T2DM. Oxidative stress plays a major role in the development and progression of T2DM-induced liver injury. Gentisic acid (GA) is a metabolite of aspirin and also a phenolic compound found in natural sources that is a highly effective antioxidant and free radical scavenger. So, in this study, the potential preventive benefits of GA against liver damage induced by T2DM were explored.Materials and Methods: This study was conducted on 24 adult male mice. T2DM was induced by intraperitoneal injection of a single dose of streptozotocin (at a dose of 65 mg/kg), 15 min after the injection of nicotinamide (at a dose of 120 mg/kg). The grouping was as follows: 1) Normal Control Group; 2) Diabetic Control Group; 3) Positive Control Group: received metformin (150 mg/kg body weight daily) through gavage; 4) Treatment Group: received GA at the dose of 100 mg/kg body weight daily through gavage. Treatments continued for two weeks.
Results: Two weeks of GA treatment in diabetic mice reduced fasting blood glucose, improved plasma levels of hepatic enzymes, and increased liver tissue antioxidant capacity. Histopathological examination revealed that GA administration reduced diabetes-induced liver damage. Furthermore, GA treatment led to the down-regulation of Kelch-like ECH-associated protein 1 (Keap1) and up-regulation of nuclear factor E2-related factor 2 (Nrf2).
Conclusion: The results of this study showed that GA exerts hepatoprotective effects in STZ-induced T2DM mice.

Keywords:  Gentisic acid; Liver failure; Nuclear factor E2-related- factor 2; Oxidative stress; Type 2 diabetes mellitus

DOI:  https://doi.org/10.22038/IJBMS.2023.70659.15359
Mol Neurodegener. 2023 Nov 11. 18(1): 83

Mitochondrial dysfunction in Parkinson's disease - a key disease hallmark with therapeutic potential.

Martin T Henrich, Wolfgang H Oertel, D James Surmeier, Fanni F Geibl.

  Mitochondrial dysfunction is strongly implicated in the etiology of idiopathic and genetic Parkinson's disease (PD). However, strategies aimed at ameliorating mitochondrial dysfunction, including antioxidants, antidiabetic drugs, and iron chelators, have failed in disease-modification clinical trials. In this review, we summarize the cellular determinants of mitochondrial dysfunction, including impairment of electron transport chain complex 1, increased oxidative stress, disturbed mitochondrial quality control mechanisms, and cellular bioenergetic deficiency. In addition, we outline mitochondrial pathways to neurodegeneration in the current context of PD pathogenesis, and review past and current treatment strategies in an attempt to better understand why translational efforts thus far have been unsuccessful.

Keywords:  Antioxidants; Electron transport chain; MPTP; Mitochondria; Mitochondrial dysfunction; Neuroprotective therapies; Parkinson’s disease; Synuclein

DOI:  https://doi.org/10.1186/s13024-023-00676-7
Int J Mol Sci. 2023 Nov 03. pii: 15951. [Epub ahead of print]24(21):

Mitochondrial Complex I and β-Amyloid Peptide Interplay in Alzheimer's Disease: A Critical Review of New and Old Little Regarded Findings.

Anna Atlante, Daniela Valenti.

  Alzheimer's disease (AD) is the most common neurodegenerative disorder and the main cause of dementia which is characterized by a progressive cognitive decline that severely interferes with daily activities of personal life. At a pathological level, it is characterized by the accumulation of abnormal protein structures in the brain-β-amyloid (Aβ) plaques and Tau tangles-which interfere with communication between neurons and lead to their dysfunction and death. In recent years, research on AD has highlighted the critical involvement of mitochondria-the primary energy suppliers for our cells-in the onset and progression of the disease, since mitochondrial bioenergetic deficits precede the beginning of the disease and mitochondria are very sensitive to Aβ toxicity. On the other hand, if it is true that the accumulation of Aβ in the mitochondria leads to mitochondrial malfunctions, it is otherwise proven that mitochondrial dysfunction, through the generation of reactive oxygen species, causes an increase in Aβ production, by initiating a vicious cycle: there is therefore a bidirectional relationship between Aβ aggregation and mitochondrial dysfunction. Here, we focus on the latest news-but also on neglected evidence from the past-concerning the interplay between dysfunctional mitochondrial complex I, oxidative stress, and Aβ, in order to understand how their interplay is implicated in the pathogenesis of the disease.

Keywords:  Alzheimer’s disease; amyloid-β peptide; mitochondrial complex I; mitochondrial dysfunction; reactive oxygen species

DOI:  https://doi.org/10.3390/ijms242115951
Front Pharmacol. 2023 ;14 1243613

The mechanisms of action of mitochondrial targeting agents in cancer: inhibiting oxidative phosphorylation and inducing apoptosis.

Yi Yang, Yahui An, Mingli Ren, Haijiao Wang, Jing Bai, Wenli Du, Dezhi Kong.

  The tumor microenvironment affects the structure and metabolic function of mitochondria in tumor cells. This process involves changes in metabolic activity, an increase in the amount of reactive oxygen species (ROS) in tumor cells compared to normal cells, the production of more intracellular free radicals, and the activation of oxidative pathways. From a practical perspective, it is advantageous to develop drugs that target mitochondria for the treatment of malignant tumors. Such drugs can enhance the selectivity of treatments for specific cell groups, minimize toxic effects on normal tissues, and improve combinational treatments. Mitochondrial targeting agents typically rely on small molecule medications (such as synthetic small molecules agents, active ingredients of plants, mitochondrial inhibitors or autophagy inhibitors, and others), modified mitochondrial delivery system agents (such as lipophilic cation modification or combining other molecules to form targeted mitochondrial agents), and a few mitochondrial complex inhibitors. This article will review these compounds in three main areas: oxidative phosphorylation (OXPHOS), changes in ROS levels, and endogenous oxidative and apoptotic processes.

Keywords:  electron transport chain (ETC); mechanism; mitocans; mitochondria targeting drug; oxidative phoshorylation; reactive oxygen species

DOI:  https://doi.org/10.3389/fphar.2023.1243613
Folia Biol (Praha). 2023 ;69(1): 13-21

NRF1 Alleviated Oxidative Stress of Glioblastoma Cells by Regulating NOR1.

Jiali Wang, Shuai Chen, Wang Xiang, Qing Zhu, Nianjun Ren.

  Oxidored-nitro domain-containing protein 1 (NOR1) is a critical tumour suppressor gene, though its regulatory mechanism in oxidative stress of glioblastoma (GBM) remains unclear. Hence, further study is needed to unravel the function of NOR1 in the progression of oxidative stress in GBM. In this study, we evaluated the expression of NOR1 and nuclear respiratory factor 1 (NRF1) in GBM tissue and normal brain tissue (NBT) using quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot (WB), and investigated their relationship. We then induced oxidative stress in U251 cells through H2O2 treatment and conducted Cell Count-ing Kit-8, Transwell and wound healing assays to analyse cell proliferation, invasion and migration. Cell apoptosis was assessed by flow cytometry and TUNEL staining. We also measured the activities of superoxide dismutase and catalase, as well as the level of reactive oxygen species (ROS) using biochemical techniques. Via qRT-PCR and WB, the mRNA and protein expression levels of NOR1 and NRF1 were determined. Chromatin immunoprecipitation (ChIP) assays were applied to validate NRF1's interaction with NOR1. Our results showed that the expression of NOR1 and NRF1 was low in GBM, and their expression levels were positively correlated. H2O2-induced oxidative stress reduced NRF1 and NOR1 expression levels and increased the ROS level. The ChIP assay confirmed the binding of NRF1 to NOR1. Over-expression of NRF1 attenuated the inhibitory effect of oxidative stress on the proliferation, migration and invasion of U251 cells, which was reversed by knockdown of NOR1.

Keywords:  GBM; NOR1; NRF1; oxidative stress

DOI:  https://doi.org/10.14712/fb2023069010013
Int J Mol Sci. 2023 Nov 06. pii: 16018. [Epub ahead of print]24(21):

Cellular and Molecular Mechanisms in Oxidative Stress-Related Diseases 2.0/3.0.

Alessia Remigante, Rossana Morabito.

Oxidative stress is frequently described as the balance between the production of reactive species (including oxygen and nitrogen) in biological systems and the ability of the latter to defend itself through the sophisticated antioxidant machinery [...].

DOI: https://doi.org/10.3390/ijms242116018
Molecules. 2023 Oct 31. pii: 7372. [Epub ahead of print]28(21):

A Critical Review of the Neuropharmacological Effects of Kratom: An Insight from the Functional Array of Identified Natural Compounds.

Rahni Hossain, Abida Sultana, Manit Nuinoon, Kunwadee Noonong, Jitbanjong Tangpong, Kazi Helal Hossain, Md Atiar Rahman.

  Kratom (Mitragyna speciosa Korth. Havil) has been considered a narcotic drug for years, barred by the law in many parts of the world, while extensive research over the past few decades proves its several beneficial effects, some of which are still in ambiguity. In many countries, including Thailand, the indiscriminate use and abuse of kratom have led to the loss of life. Nonetheless, researchers have isolated almost fifty pure compounds from kratom, most of which are alkaloids. The most prevalent compounds, mitragynine and 7-hydroxy mitragynine, are reported to display agonist morphine-like effects on human μ-opioid receptors and antagonists at κ- and δ-opioid receptors with multimodal effects at other central receptors. Mitragynine is also credited to be one of the modulatory molecules for the Keap1-Nrf2 pathway and SOD, CAT, GST, and associated genes' upregulatory cascades, leading it to play a pivotal role in neuroprotective actions while evidently causing neuronal disorders at high doses. Additionally, its anti-inflammatory, antioxidative, antibacterial, and gastroprotective effects are well-cited. In this context, this review focuses on the research gap to resolve ambiguities about the neuronal effects of kratom and demonstrate its prospects as a therapeutic target for neurological disorders associated with other pharmacological effects.

Keywords:  7-Hydroxymitragynine; anti-inflammation; antioxidant; kratom; mitragynine; neurological effects

DOI:  https://doi.org/10.3390/molecules28217372
bioRxiv. 2023 Nov 01. pii: 2023.10.27.564401. [Epub ahead of print]

Gardenin A improves cognitive and motor function in A53T-α-syn mice.

Wyatt Hack, Noah Gladen-Kolarsky, Swarnali Chatterjee, Qiaoli Liang, Urmila Maitra, Lukasz Ciesla, Nora E Gray.

Oxidative stress and neuroinflammation are widespread in the Parkinson's disease (PD) brain and contribute to the synaptic degradation and dopaminergic cell loss that result in cognitive impairment and motor dysfunction. The polymethoxyflavone Gardenin A (GA) has been shown to activate the NRF2-regulated antioxidant pathway and inhibit the NFkB-dependent pro-inflammatory pathway in a Drosophila model of PD. Here, we evaluate the effects of GA on A53T alpha-synuclein overexpressing (A53TSyn) mice. A53TSyn mice were treated orally for 4 weeks with 0, 25, or 100 mg/kg GA. In the fourth week, mice underwent behavioral testing and tissue was harvested for immunohistochemical analysis of tyrosine hydroxylase (TH) and phosphorylated alpha synuclein (pSyn) expression, and quantification of synaptic, antioxidant and inflammatory gene expression. Results were compared to vehicle-treated C57BL6 mice. Treatment with 100 mg/kg GA improved associative memory and decreased abnormalities in mobility and gait in A53TSyn mice. GA treatment also reduced cortical and hippocampal levels of pSyn and attenuated the reduction in TH expression in the striatum. Additionally, GA increased cortical expression of NRF2-regulated antioxidant genes and decreased expression of NFkB-dependent pro-inflammatory genes. GA was readily detectable in the brains of treated mice and modulated the lipid profile in the deep gray brain tissue of those animals. While the beneficial effects of GA on cognitive deficits, motor dysfunction and PD pathology are promising, future studies are needed to further fully elucidate the mechanism of action of GA, optimizing dosing and confirm these effects in other PD models.Significance Statement: The polymethoxyflavone Gardenin A can improve cognitive and motor function and attenuate both increases in phosphorylated alpha synuclein and reductions in tyrosine hydroxylase expression in A53T alpha synuclein overexpressing mice. These effects may be related to activation of the NRF2-regulated antioxidant response and downregulation of NFkB-dependent inflammatory response by Gardenin A in treated animals. The study also showed excellent brain bioavailability of Gardenin A and modifications of the lipid profile, possibly through interactions between Gardenin A with the lipid bilayer, following oral administration. The study confirms neuroprotective activity of Gardenin A previously reported in toxin induced Drosophila model of Parkinson's disease.

DOI: https://doi.org/10.1101/2023.10.27.564401
Redox Biol. 2023 Nov 08. pii: S2213-2317(23)00356-7. [Epub ahead of print]68 102955

Oxygen metabolism abnormality and Alzheimer's disease: An update.

Guangdong Liu, Cui Yang, Xin Wang, Xi Chen, Yanjiang Wang, Weidong Le.

  Oxygen metabolism abnormality plays a crucial role in the pathogenesis of Alzheimer's disease (AD) via several mechanisms, including hypoxia, oxidative stress, and mitochondrial dysfunction. Hypoxia condition usually results from living in a high-altitude habitat, cardiovascular and cerebrovascular diseases, and chronic obstructive sleep apnea. Chronic hypoxia has been identified as a significant risk factor for AD, showing an aggravation of various pathological components of AD, such as amyloid β-protein (Aβ) metabolism, tau phosphorylation, mitochondrial dysfunction, and neuroinflammation. It is known that hypoxia and excessive hyperoxia can both result in oxidative stress and mitochondrial dysfunction. Oxidative stress and mitochondrial dysfunction can increase Aβ and tau phosphorylation, and Aβ and tau proteins can lead to redox imbalance, thus forming a vicious cycle and exacerbating AD pathology. Hyperbaric oxygen therapy (HBOT) is a non-invasive intervention known for its capacity to significantly enhance cerebral oxygenation levels, which can significantly attenuate Aβ aggregation, tau phosphorylation, and neuroinflammation. However, further investigation is imperative to determine the optimal oxygen pressure, duration of exposure, and frequency of HBOT sessions. In this review, we explore the prospects of oxygen metabolism in AD, with the aim of enhancing our understanding of the underlying molecular mechanisms in AD. Current research aimed at attenuating abnormalities in oxygen metabolism holds promise for providing novel therapeutic approaches for AD.

Keywords:  Alzheimer's disease; HIF-1; Hypoxia; Mitochondrial dysfunction; Oxidative stress; Oxygen metabolism

DOI:  https://doi.org/10.1016/j.redox.2023.102955