bims-nurfan 2023-12-17 papers

bims-nurfan

Biomed News

on NRF2 and Neurological Diseases

Issue of 2023–12–17
34 papers selected by
Arif Kamil Salihoğlu, Karadeniz Technical University

Shank3 ameliorates neuronal injury after cerebral ischemia/reperfusion via inhibiting oxidative stress and inflammation.
Emerging trends and hotspots of Nuclear factor erythroid 2-related factor 2 in nervous system diseases.
Local production of reactive oxygen species drives vincristine-induced axon degeneration.
The interplay between neuroinflammatory pathways and Parkinson's disease.
Isoquercitrin attenuates the osteoclast-mediated bone loss in rheumatoid arthritis via the Nrf2/ROS/NF-κB pathway.
Proximity proteomic analysis of the NRF family reveals the Parkinson's disease protein ZNF746/PARIS as a co-complexed repressor of NRF2.
Involvement of Mitochondria in Parkinson's Disease.
Melatonin Protects Mouse Type A Spermatogonial Stem Cells against Oxidative Stress via The Mitochondrial Thioredoxin System.
Cepharanthine, a regulator of keap1-Nrf2, inhibits gastric cancer growth through oxidative stress and energy metabolism pathway.
Forsythiaside A Activates AMP-Activated Protein Kinase and Regulates Oxidative Stress via Nrf2 Signaling.
Xanthohumol attenuates collagen synthesis in scleroderma skin fibroblasts by ROS/Nrf2/TGFβ1/Smad3 pathway.
The Functional Significance of McMafF_G_K in Molluscs: Implications for Nrf2-Mediated Oxidative Stress Response.
Effect of esketamine pretreatment on acute sepsis-associated encephalopathy.
Dibromoacetonitrile induced autophagy by mediating the PERK signalling pathway and ROS interaction in HT22 cell.
The Pivotal Role of Nrf2 Signal Axis in Intervertebral Disc Degeneration.
Oxytocin mitigates peripheral nerve damage via Nrf2 and irisin pathway.
Taurine alleviates high-fat-high-glucose-induced pancreatic islet β-cell oxidative stress and apoptosis in rat.
Hexahydrocurcumin Attenuates Neuronal Injury and Modulates Synaptic Plasticity in Chronic Cerebral Hypoperfusion in Rats.
Age-induced aortic modifications are accompanied by alterations in the antioxidant defense system in female rats.
Neuroprotective Effects of N-methyl-(2S, 4R)-trans-4-hydroxy-L-proline (NMP) against Amyloid-β-Induced Alzheimer's Disease Mouse Model.
Chronic interleukin-6 mediated neuroinflammation decreases anxiety, and impaires spatial memory in aged female mice.
Parkin-mediated mitophagy is a potential treatment for oxaliplatin-induced peripheral neuropathy.
Chitosan/PLA-loaded Magnesium oxide nanocomposite to attenuate oxidative stress, neuroinflammation and neurotoxicity in rat models of Alzheimer's disease.
Autophagy and neuroprotection in astrocytes exposed to 6-hydroxydopamine is negatively regulated by NQO2: relevance to Parkinson's disease.
Syringic acid alleviates cisplatin-induced ovarian injury through modulating endoplasmic reticulum stress, inflammation and Nrf2 pathway.
Leptospiral lipopolysaccharide dampens inflammation through upregulation of autophagy adaptor p62 and NRF2 signaling in macrophages.
Butyrate ameliorated ferroptosis in ulcerative colitis through modulating Nrf2/GPX4 signal pathway and improving intestinal barrier.
Novel Antioxidant Peptides Derived from Feather Keratin Alleviate H2O2-Induced Oxidative Damage in HepG2 Cells via Keap1/Nrf2 Pathway.
Folic acid-functionalized chitosan nanoparticles with bioenzyme activity for the treatment of spinal cord injury.
Isoliquiritigenin inhibits apoptosis and ameliorates oxidative stress in rheumatoid arthritis chondrocytes through the Nrf2/HO-1-mediated pathway.
The possible role of nuclear factor erythroid-2-related factor 2 activators in the management of Covid-19.
Effects of antipsychotic drugs on energy metabolism.
Tetrabromobisphenol A induces neuronal cytotoxicity by inhibiting PINK1-Parkin-mediated mitophagy via upregulating ATF3 expression.
A review of pomegranate supplementation: A promising remedial avenue for Alzheimer's disease.

Redox Biol. 2023 Dec 05. pii: S2213-2317(23)00384-1. [Epub ahead of print]69 102983

Shank3 ameliorates neuronal injury after cerebral ischemia/reperfusion via inhibiting oxidative stress and inflammation.

Hongchen Zhang, Yuan Feng, Yanfang Si, Chuanhao Lu, Juan Wang, Shiquan Wang, Liang Li, Wenyu Xie, Zheming Yue, Jia Yong, Shuhui Dai, Lei Zhang, Xia Li.

  Shank3, a key molecule related to the development and deterioration of autism, has recently been found to downregulate in the murine brain after ischemia/reperfusion (I/R). Despite this discovery, however, its effects on neuronal injury and the mechanism underlying the effects remain to be clarified. To address this, in this study, based on genetically modified mice models, we revealed that the expression of Shank3 showed a time-dependent change in murine hippocampal neurons after I/R, and that conditional knockout (cko) of Shank3 in neurons resulted in aggravated neuronal injuries. The protective effects of Shank3 against oxidative stress and inflammation after I/R were achieved through direct binding STIM1 and subsequent proteasome-mediated degradation of STIM1. The STIM1 downregulation induced the phosphorylation of downstream Nrf2 Ser40, which subsequently translocated to the nucleus, and further increased the expression of antioxidant genes such as NQO1 and HO-1 in HT22 cells. In vivo, the study has further confirmed that double knockout of Shank3 and Stim1 alleviated oxidative stress and inflammation after I/R in Shank3cko mice. In conclusion, the present study has demonstrated that Shank3 interacts with STIM1 and inhibits post-I/R neuronal oxidative stress and inflammatory response via the Nrf2 pathway. This interaction can potentially contribute to the development of a promising method for I/R treatment.

Keywords:  Inflammation; Ischemia/reperfusion injury; Oxidative stress; STIM1; Shank3

DOI:  https://doi.org/10.1016/j.redox.2023.102983
World J Clin Cases. 2023 Nov 16. 11(32): 7833-7851

Emerging trends and hotspots of Nuclear factor erythroid 2-related factor 2 in nervous system diseases.

Xue-Qin Chang, Ling Xu, Yi-Xuan Zuo, Yi-Guo Liu, Jia Li, Hai-Tao Chi.

   BACKGROUND: The Nuclear factor erythroid 2-related factor 2 (NRF2) transcription factor has attracted much attention in the context of neurological diseases. However, none of the studies have systematically clarified this field's research hotspots and evolution rules.
AIM: To investigate the research hotspots, evolution patterns, and future research trends in this field in recent years.
METHODS: We conducted a comprehensive literature search in the Web of Science Core Collection database using the following methods: (((((TS=(NFE2 L2)) OR TS=(Nfe2 L2 protein, mouse)) OR TS=(NF-E2-Related Factor 2)) OR TS=(NRF2)) OR TS=(NFE2L2)) OR TS=(Nuclear factor erythroid2-related factor 2) AND (((((((TS=(neurological diseases)) OR TS=(neurological disorder)) OR TS=(brain disorder)) OR TS=(brain injury)) OR TS=(central nervous system disease)) OR TS=(CNS disease)) OR TS=(central nervous system disorder)) OR TS=(CNS disorder) AND Language = English from 2010 to 2022. There are just two forms of literature available: Articles and reviews. Data were processed with the software Cite-Space (version 6.1. R6).
RESULTS: We analyzed 1884 articles from 200 schools in 72 countries/regions. Since 2015, the number of publications in this field has increased rapidly. China has the largest number of publications, but the articles published in the United States have better centrality and H-index. Among the top ten authors with the most published papers, five of them are from China, and the author with the most published papers is Wang Handong. The institution with the most articles was Nanjing University. To their credit, three of the top 10 most cited articles were written by Chinese scholars. The keyword co-occurrence map showed that "oxidative stress", "NRF2", "activation", "expression" and "brain" were the five most frequently used keywords.
CONCLUSION: Research on the role of NRF2 in neurological diseases continues unabated. Researchers in developed countries published more influential papers, while Chinese scholars provided the largest number of articles. There have been numerous studies on the mechanism of NRF2 transcription factor in neurological diseases. NRF2 is also emerging as a potentially effective target for the treatment of neurological diseases. However, despite decades of research, our knowledge of NRF2 transcription factor in nervous system diseases is still limited. Further studies are needed in the future.

Keywords:  Activation; Brain; Expression; Ferroptosis; Nervous system diseases; Nuclear factor erythroid 2-related factor 2

DOI:  https://doi.org/10.12998/wjcc.v11.i32.7833
Cell Death Dis. 2023 Dec 08. 14(12): 807

Local production of reactive oxygen species drives vincristine-induced axon degeneration.

Jorge Gomez-Deza, Anastasia L Slavutsky, Matthew Nebiyou, Claire E Le Pichon.

Neurological side effects arising from chemotherapy, such as severe pain and cognitive impairment, are a major concern for cancer patients. These major side effects can lead to reduction or termination of chemotherapy medication in patients, negatively impacting their prognoses. With cancer survival rates improving dramatically, addressing side effects of cancer treatment has become pressing. Here, we use iPSC-derived human neurons to investigate the molecular mechanisms that lead to neurotoxicity induced by vincristine, a common chemotherapeutic used to treat solid tumors. Our results uncover a novel mechanism by which vincristine causes a local increase in mitochondrial proteins that produce reactive oxygen species (ROS) in the axon. Vincristine triggers a cascade of axon pathology, causing mitochondrial dysfunction that leads to elevated axonal ROS levels and SARM1-dependent axon degeneration. Importantly, we show that the neurotoxic effect of increased axonal ROS can be mitigated by the small molecule mitochondrial division inhibitor 1 (mdivi-1) and antioxidants glutathione and mitoquinone, identifying a novel therapeutic avenue to treat the neurological effects of chemotherapy.

DOI: https://doi.org/10.1038/s41419-023-06227-8
Exp Neurol. 2023 Dec 05. pii: S0014-4886(23)00329-1. [Epub ahead of print]372 114644

The interplay between neuroinflammatory pathways and Parkinson's disease.

Pinar Eser, Ersoy Kocabicak, Ahmet Bekar, Yasin Temel.

  Parkinson's disease, a progressive neurodegenerative disorder predominantly affecting elderly, is marked by the gradual degeneration of the nigrostriatal dopaminergic pathway, culminating in neuronal loss within the substantia nigra pars compacta (SNpc) and dopamine depletion. At the molecular level, neuronal loss in the SNpc has been attributed to factors including neuroinflammation, impaired protein homeostasis, as well as mitochondrial dysfunction and the resulting oxidative stress. This review focuses on the interplay between neuroinflammatory pathways and Parkinson's disease, drawing insights from current literature.

Keywords:  Mitochondria dysfunction; Neuroinflammation; Parkinson's disease

DOI:  https://doi.org/10.1016/j.expneurol.2023.114644
Biochim Biophys Acta Mol Basis Dis. 2023 Dec 06. pii: S0925-4439(23)00343-5. [Epub ahead of print] 166977

Isoquercitrin attenuates the osteoclast-mediated bone loss in rheumatoid arthritis via the Nrf2/ROS/NF-κB pathway.

Yan Liu, Tian-Qi Li, Jin Bai, Wei-Li Liu, Zi-Rou Wang, Chong Feng, Ling-Ling Pu, Xin-Xing Wang, Hui Liu.

  An excess of osteoclastogenesis significantly contributes to the development of rheumatoid arthritis (RA). Activation of the nuclear factor erythroid-2 related factor 2 (Nrf2) and nuclear factor kappa B (NF-κB) ligand (RANKL)-induced reactive oxygen species (ROS)-to-NF-κB signaling cascade are important mechanisms regulating osteoclastogenesis; however, whether Nrf2 is involved in RANKL-induced NF-κB activation is controversial. Isoquercitrin, a natural flavonoid compound, has been shown to have Nrf2-dependent antioxidant effects inprevious studies. We sought to verify whether isoquercitrin could modulate RANKL-induced NF-κB activation by activating Nrf2, thereby affecting osteoclastogenesis. Tartrate-resistant acid phosphatase staining, F-actin ring staining and resorption pit assay suggested that isoquercitrin significantly inhibited osteoclastogenesis and osteolytic function. Mitosox staining showed that RANKL-induced ROS generation was significantly inhibited by isoquercitrin from day 3 of the osteoclast differentiation cycle. Quantitative real-time PCR, Western blot, and immunofluorescence indicated that isoquercitrin activated the Nrf2 signaling pathway and inhibited NF-κB expression. And when we used the Nrf2-specific inhibitor ML385, the inhibition of NF-κB by isoquercitrin disappeared. Moreover, we found that Nrf2 is not uninvolved in RANKL-induced NF-κB activation and may be related to the timing of ROS regulation. When we limited isoquercitrin administration to 2 days, Nrf2 remained activated and the inhibition of NF-κB disappeared. In vivo experiments suggested that isoquercitrin attenuated RA modeling-induced bone loss. Overall, isoquercitrin-activated Nrf2 blocked the RANKL-induced ROS-to-NF-κB signaling cascade response, thereby inhibiting osteoclastogenesis and bone loss. These findings provide new ideas for the treatment of RA.

Keywords:  Antioxidant; NF-κB; Nrf2; Osteoclast; Rheumatoid arthritis

DOI:  https://doi.org/10.1016/j.bbadis.2023.166977
Sci Signal. 2023 Dec 12. 16(815): eadi9018

Proximity proteomic analysis of the NRF family reveals the Parkinson's disease protein ZNF746/PARIS as a co-complexed repressor of NRF2.

Kyle M LaPak, Soma Saeidi, Ilah Bok, Nathan T Wamsley, Isaac B Plutzer, Dhaval P Bhatt, Jingqin Luo, Ghazaleh Ashrafi, M Ben Major.

The nuclear factor erythroid 2-related factor 2 (NRF2) transcription factor activates cytoprotective and metabolic gene expression in response to various electrophilic stressors. Constitutive NRF2 activity promotes cancer progression, whereas decreased NRF2 function contributes to neurodegenerative diseases. We used proximity proteomic analysis to define protein networks for NRF2 and its family members NRF1, NRF3, and the NRF2 heterodimer MAFG. A functional screen of co-complexed proteins revealed previously uncharacterized regulators of NRF2 transcriptional activity. We found that ZNF746 (also known as PARIS), a zinc finger transcription factor implicated in Parkinson's disease, physically associated with NRF2 and MAFG, resulting in suppression of NRF2-driven transcription. ZNF746 overexpression increased oxidative stress and apoptosis in a neuronal cell model of Parkinson's disease, phenotypes that were reversed by chemical and genetic hyperactivation of NRF2. This study presents a functionally annotated proximity network for NRF2 and suggests a link between ZNF746 overexpression in Parkinson's disease and inhibition of NRF2-driven neuroprotection.

DOI: https://doi.org/10.1126/scisignal.adi9018
Int J Mol Sci. 2023 Dec 01. pii: 17027. [Epub ahead of print]24(23):

Involvement of Mitochondria in Parkinson's Disease.

Chi-Jing Choong, Hideki Mochizuki.

  Mitochondrial dysregulation, such as mitochondrial complex I deficiency, increased oxidative stress, perturbation of mitochondrial dynamics and mitophagy, has long been implicated in the pathogenesis of PD. Initiating from the observation that mitochondrial toxins cause PD-like symptoms and mitochondrial DNA mutations are associated with increased risk of PD, many mutated genes linked to familial forms of PD, including PRKN, PINK1, DJ-1 and SNCA, have also been found to affect the mitochondrial features. Recent research has uncovered a much more complex involvement of mitochondria in PD. Disruption of mitochondrial quality control coupled with abnormal secretion of mitochondrial contents to dispose damaged organelles may play a role in the pathogenesis of PD. Furthermore, due to its bacterial ancestry, circulating mitochondrial DNAs can function as damage-associated molecular patterns eliciting inflammatory response. In this review, we summarize and discuss the connection between mitochondrial dysfunction and PD, highlighting the molecular triggers of the disease process, the intra- and extracellular roles of mitochondria in PD as well as the therapeutic potential of mitochondrial transplantation.

Keywords:  PINK1; Parkin; Parkinson’s disease; extracellular mitochondria; mitochondria; mitochondria transplantation

DOI:  https://doi.org/10.3390/ijms242317027
Cell J. 2023 Nov 28. pii: 706601. [Epub ahead of print]25(11): 741-752

Melatonin Protects Mouse Type A Spermatogonial Stem Cells against Oxidative Stress via The Mitochondrial Thioredoxin System.

Somayeh Heidarizadi, Zahra Rashidi, Cyrus Jalili, Kamran Mansouri, Iraj Rashidi, Behzad Mahaki, Mohammadreza Gholami.

   OBJECTIVE: Mitochondrial oxidative stress is an important factor in infertility. The mitochondrial thioredoxin system plays an important role in this condition. N-acetyl-5-methoxy tryptamine (melatonin) plays a role in reducing oxidative stress and apoptosis in spermatogonial stem cells (SSCs). In this study, we explore the probable protective effects of melatonin on the mitochondrial thioredoxin system [thioredoxin 2 (Trx2)/Txnip] in SSCs under oxidative stress.
MATERIALS AND METHODS: In this experimental study, SSCs were co-cultured two-dimensionally (2D) with Sertoli cells in DMEM culture medium that contained 10% fetal bovine serum (FBS), 1% antibiotics, and 10 ng/ml glial cell-derived neurotrophic factor (GDNF) for 30 days. The cultured cells were subsequently divided into four groups: control; melatonin (250 μM, 24 hours); melatonin (250 μM, 24 hours)+hydrogen peroxide (H2O2, 50 μM, 24 hours); and H2O2 (50 μM, 24 hours). Intracellular reactive oxygen species (ROS) production was determined by flow cytometry. Malondialdehyde (MDA) levels were measured by Fluorometry. The expressions of apoptotic and antioxidant genes and nuclear factor erythroid 2-related factor 2 (Nrf2), Trx2, and nicotinamide nucleotide transhydrogenase (NNT) proteins were determined by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot. Adenosine triphosphate (ATP) levels were measured by fluorometry.
RESULTS: Melatonin reduced H2O2-induced ROS levels and apoptosis in the SSCs. Melatonin also increased mRNA expression of Nrf2, Trx2, NNT, Sirtuin 3 (Sirt3), and decreased mRNA expression of Txnip, and increased protein expressions of Nrf2, Trx2, NNT thereby increasing activity of the mitochondrial thioredoxin system. In addition, melatonin increased ATP levels.
CONCLUSION: Melatonin increased Trx2 expression through the Nrf2 pathway. This study suggests that melatonin may protect SSCs from oxidative stress in diseases related to infertility.

Keywords:  Melatonin; Oxidative Stress; SPERMATOGONIA

DOI:  https://doi.org/10.22074/cellj.2023.2003766.1316
Cell Death Discov. 2023 Dec 12. 9(1): 450

Cepharanthine, a regulator of keap1-Nrf2, inhibits gastric cancer growth through oxidative stress and energy metabolism pathway.

Yang-Yang Lu, Chun-Yang Zhu, Yi-Xin Ding, Bing Wang, Shu-Fen Zhao, Jing Lv, Shu-Ming Chen, Sha-Sha Wang, Yan Wang, Rui Wang, Wen-Sheng Qiu, Wei-Wei Qi.

Cepharanthine (CEP), a bioactive compound derived from Stephania Cephalantha Hayata, is cytotoxic to various malignancies. However, the underlying mechanism of gastric cancer is unknown. CEP inhibited the cellular activity of gastric cancer AGS, HGC27 and MFC cell lines in this study. CEP-induced apoptosis reduced Bcl-2 expression and increased cleaved caspase 3, cleaved caspase 9, Bax, and Bad expression. CEP caused a G2 cell cycle arrest and reduced cyclin D1 and cyclin-dependent kinases 2 (CDK2) expression. Meanwhile, it increased oxidative stress, decreased mitochondrial membrane potential, and enhanced reactive oxygen species (ROS) accumulation in gastric cancer cell lines. Mechanistically, CEP inhibited Kelch-like ECH-associated protein (Keap1) expression while activating NF-E2 related factor 2 (Nrf2) nuclear translocations, increasing transcription of Nrf2 target genes quinone oxidoreductase 1 (NQO1), heme oxygenase 1 (HMOX1), and glutamate-cysteine ligase modifier subunit (GCLM). Furthermore, a combined analysis of targeted energy metabolism and RNA sequencing revealed that CEP could alter the levels of metabolic substances such as D (+) - Glucose, D-Fructose 6-phosphate, citric acid, succinic acid, and pyruvic acid, thereby altering energy metabolism in AGS cells. In addition, CEP significantly inhibited tumor growth in MFC BALB/c nude mice in vivo, consistent with the in vitro findings. Overall, CEP can induce oxidative stress by regulating Nrf2/Keap1 and alter energy metabolism, resulting in anti-gastric cancer effects. Our findings suggest a potential application of CEP in gastric cancer treatment.

DOI: https://doi.org/10.1038/s41420-023-01752-z
Int J Mol Sci. 2023 Dec 01. pii: 17033. [Epub ahead of print]24(23):

Forsythiaside A Activates AMP-Activated Protein Kinase and Regulates Oxidative Stress via Nrf2 Signaling.

Young Eun Kim, Seon-Been Bak, Min-Jin Kim, Su-Jin Bae, Won-Yung Lee, Young Woo Kim.

  Forsythiaside A (FA) is an active constituent isolated from Forsythia suspensa, a beneficial herb used in traditional medicine known for its antioxidant and anti-inflammatory properties. Although various studies have suggested that FA has the protective effects, its impacts on arachidonic acid (AA) plus iron in vitro models and carbon tetrachloride (CCl₄)-induced mouse liver damage in vivo have not been explored. In this study, HepG2 cells were subjected to AA + iron treatment to induce apoptosis and mitochondrial impairment and determine the molecular mechanisms. FA exhibited protective effects by inhibiting cell damage and reactive oxygen species (ROS) production induced by AA + iron, as assessed via immunoblot and flow cytometry analyses. Further molecular investigations revealed that FA resulted in the activation of extracellular-signal-related protein kinase (ERK), which subsequently triggered the activation of AMP-activated protein kinase (AMPK), a critical regulator of cellular oxidative stress. Additionally, FA modulated the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway, which is a significant antioxidant transcription factor regulated by the AMPK pathway. For in vivo studies, mice were orally administered FA and then subjected to induction of CCl₄-based hepatotoxicity. The protective effect of FA was confirmed via blood biochemistry and immunohistochemical analyses. In conclusion, our findings demonstrated the protective effects of FA against oxidative stress both in vitro and in vivo, thus indicating that FA is a potential candidate for liver protection. Our study sheds light on the mechanistic pathways involved in the antioxidant effects of FA, highlighting the hepatoprotective potential of naturally occurring compounds in traditional herbs, such as FA.

Keywords:  AMPK; HO-1; Nrf2; forsythiaside A; liver injury

DOI:  https://doi.org/10.3390/ijms242317033
Eur J Pharmacol. 2023 Dec 08. pii: S0014-2999(23)00741-0. [Epub ahead of print]963 176227

Xanthohumol attenuates collagen synthesis in scleroderma skin fibroblasts by ROS/Nrf2/TGFβ1/Smad3 pathway.

Yu Xiao, Zhongzhou Huang, Yingyu Wang, Yan Wang, Ling Yu, Ji Yang, Hejian Zou, Weiguo Wan, Xue Yang.

  Skin fibrosis, the most obvious clinical manifestation of systemic sclerosis (SSc), has a high unmet need for treatment. Xanthohumol (Xn) has been shown to have beneficial effects on fibrotic diseases, but its efficacy in SSc remains unreported. This study aims to elucidate the effects and mechanisms of Xn on collagen synthesis in SSc skin fibroblasts (SScF). We found increased collagen production in SScF cultured in vitro, accompanied by dysregulated levels of oxidative stress. Cell experiments showed that Xn inhibited cell proliferation and promoted apoptosis. In addition, Xn was shown for the first time to upregulate reactive oxygen species (ROS) and nuclear factor erythroid 2-related factor 2 (Nrf2)levels in SScF, and when combined with the ROS scavenger N-acetylcysteine (NAC), Nrf2 expression was decreased. Importantly, we demonstrated that Xn significantly attenuated collagen synthesis by blocking the fibrotic classical transforming growth factor beta 1 (TGFβ1)/Smad3 pathway, which interestingly was upregulated when combined with the Nrf2 inhibitor 385. Taken together, Xn suppressed the TGFβ1/Smad3 pathway to ameliorate collagen overproduction by promoting ROS-induced oxidative stress damage and activating Nrf2, suggesting that Xn administration may be an emerging therapeutic strategy for skin fibrosis in SSc.

Keywords:  Fibrosis; Oxidative stress; Systemic sclerosis; Xanthohumol

DOI:  https://doi.org/10.1016/j.ejphar.2023.176227
Int J Mol Sci. 2023 Nov 27. pii: 16800. [Epub ahead of print]24(23):

The Functional Significance of McMafF_G_K in Molluscs: Implications for Nrf2-Mediated Oxidative Stress Response.

Ronghui Yao, Longmei Qiu, Li Zhu, Xinglu Chen, Jiaying Zhai, Weifeng Wang, Pengzhi Qi, Zhi Liao, Isabella Buttino, Xiaojun Yan, Baoying Guo.

  The nuclear factor erythroid 2-related factor 2 (Nrf2) is a pivotal regulator of antioxidant gene expression in mammals, forming heterodimer complexes with small Maf proteins through its BZip domain. However, the underlying mechanism of Nrf2 action in molluscs remains poorly understood. The thick shell mussel, Mytilus coruscus, represents a model organism for the marine environment and molluscs interaction research. In this study, we used in silico cloning to obtain a small Maf homologue called McMafF_G_K from M. coruscus. McMafF_G_K possesses a typical BZip domain, suggesting its affiliation with the traditional small Maf family and its potential involvement in the Nrf2 signaling pathway. Transcriptional analysis revealed that McMafF_G_K exhibited a robust response to benzo[a]pyrene (Bap) in the digestive glands. However, this response was down-regulated upon interference with McMafF_G_K-siRNA. Interestingly, the expression levels of Nrf2, NAD(P)H: quinone oxidoreductase (NQO-1), and Glutathione Peroxidase (GPx), which are key players in oxidative stress response, showed a positive correlation with McMafF_G_K in digested adenocytes of M. coruscus. Furthermore, in vitro analysis of antioxidant capacity in digestive gland cells demonstrated that Bap exposure led to an increase in reactive oxygen species (ROS) levels, accompanied by an elevation in total antioxidant capacity (T-AOC), potentially counterbalancing the excessive ROS. Strikingly, transfection of McMafF_G_K siRNA resulted in a significant rise in ROS level and a down-regulation of T-AOC level. To validate the functional relevance of McMafF_G_K, a glutathione S-transferase (GST) pull-down assay confirmed its interaction with McNrf2, providing compelling evidence of their protein interaction. This study significantly contributes to our understanding of the functional role of McMafF_G_K in the Nrf2 signaling pathway and sheds light on its potential as a target for further research in oxidative stress response.

Keywords:  Mytilus coruscus; nuclear factor erythroid 2-related factor 2; protein interaction; small Maf proteins

DOI:  https://doi.org/10.3390/ijms242316800
Exp Neurol. 2023 Dec 07. pii: S0014-4886(23)00331-X. [Epub ahead of print] 114646

Effect of esketamine pretreatment on acute sepsis-associated encephalopathy.

Cong-Mei Wang, Yan Zhang, Yu-Shen Yang, Shu Lin, He-Fan He.

   PURPOSE: Esketamine, the S(+) enantiomer of ketamine, exhibits good anesthetic efficacy and controllability; however, its potential clinical applications, particularly in sepsis-associated encephalopathy (SAE), remain underexplored. SAE involves the development of diffuse brain dysfunction after sepsis, leading to markedly increased sepsis-related disability and mortality. In this study, we investigated the effects of esketamine pretreatment on acute SAE.
METHODS: Mice were randomly divided into four groups: control (C, n = 22), acute SAE (L, n = 22), esketamine pretreatment + acute SAE (EL, n = 22), and nuclear factor erythroid 2-related factor 2 (Nrf2) inhibitor (ML385) + esketamine pretreatment + acute SAE (N + EL, n = 22). Acute SAE was established using intraperitoneal (i.p.) injection of lipopolysaccharide (LPS; 10 mg/kg), while controls received equal amounts of saline. The EL group received daily i.p. injections of esketamine (10 mg/kg) for 5 consecutive days, followed by LPS on day 6. The N + EL group received i.p. injections of ML385 (30 mg/kg) 1 h before esketamine pretreatment. The remainder of treatment followed the same protocol as the EL group. Behavioral tests were performed 24 h post-LPS injection, and whole blood and brain tissues were collected for further analysis.
RESULTS: Esketamine improved sepsis symptoms, 7-day survival, and spatial cognitive impairment, without altering locomotor activity. Moreover, esketamine reversed the LPS-induced increase in serum S100 calcium-binding protein β and neuron-specific enolase levels and reduced hippocampal neuroinflammation, oxidative stress, and neuronal apoptosis in the EL group. However, these neuroprotective effects of esketamine were reversed by ML385.
CONCLUSION: The results of our study suggest that esketamine pretreatment mitigates acute SAE, highlighting the involvement of the Nrf2/heme oxygenase-1 pathway in mediating its neuroprotective effects.

Keywords:  Aepsis-associated encephalopathy; Anesthesia; Apoptosis; Esketamine; Lipopolysaccharide; Neuroinflammation; Nuclear factor erythroid 2-related factor 2; Oxidative stress

DOI:  https://doi.org/10.1016/j.expneurol.2023.114646
Toxicology. 2023 Dec 06. pii: S0300-483X(23)00285-8. [Epub ahead of print] 153698

Dibromoacetonitrile induced autophagy by mediating the PERK signalling pathway and ROS interaction in HT22 cell.

Fang Li, Xueyu Zhu, Xinwei Xu, Jie Zhou, Rongzhu Lu, Suhua Wang, Guangwei Xing, Yang Ye.

  Dibromoacetonitrile (DBAN) is a high-risk haloacetonitrile (HAN) generated as a byproduct of chloramine disinfection in drinking water. DBAN-induced neurotoxicity in mouse hippocampal neuronal cells (HT22) and mammals was observed to be related to reactive oxygen species (ROS). ROS, endoplasmic reticulum stress (ERS) and autophagy play crucial roles in regulating a variety of cellular processes. However, whether ERS and autophagy are associated with HAN-responsive apoptosis remains unclear. This study indicated that DBAN (10μM, 24h) activated the ERS protein kinase like endoplasmic reticulum kinase (PERK) signaling pathway. The ERS inhibitor 4-phenylbutyric acid (4-PBA) reversed DBAN-inhibited cell viability and alleviated DBAN-induced apoptosis in HT22 cell, indicating that activation of the ERS PERK pathway mediates DBAN induced cytotoxicity. Moreover, DBAN activated autophagy. The autophagy inhibitor 3-methyladenine(3-MA) reversed DBAN-inhibited cell viability and alleviated DBAN-induced apoptosis in HT22 cell, suggesting that autophagy activation mediates DBAN-induced cell toxicity. Notably, the results showed that 4-PBA inhibited DBAN-activated autophagy, demonstrating that ERS-PERK promotes DBAN-induced cellular autophagy. Pretreatment with antioxidant N-acetylcysteine (NAC) inhibited the increase in ROS production and the activation of ERS, and protected cells from toxicity. Furthermore, 4-PBA pretreatment reduced the increase in ROS production, indicating that the ROS and PERK promote each other and form a positive feedback loop. ROS also promoted DBAN-induced autophagy. In summary, our findings indicate that DBAN induced autophagy by mediating the PERK signalling pathway and ROS interaction, leading to HT22 cell damage. Accordingly, targeting these pathogenic mechanisms may provide a potential target and theoretical basis for preventing and improving HAN-induced neurotoxicity.

Keywords:  Autophagy; Dibromoacetonitrile; Disinfection byproduct; Neurotoxicity; Oxidative stress; PERK signaling pathway

DOI:  https://doi.org/10.1016/j.tox.2023.153698
J Inflamm Res. 2023 ;16 5819-5833

The Pivotal Role of Nrf2 Signal Axis in Intervertebral Disc Degeneration.

Chunran Pan, Wenjie Hou, Xiaofeng Deng, Jiawei Liu, Ruimin Chi, Xingru Shang, Tao Xu, Xiaoxia Hao.

  Intervertebral disc degeneration (IDD) is considered as a dominant contributor to low back pain (LBP), causing severe pain, limited range of lumbar motion, physical dysfunction, and restriction of social activity. However, the specific pathological mechanisms underlying IDD remain elusive, and effective strategies to delay the pathogenesis of IDD are still unclear and limited. In recent years, some studies have found that nuclear factor erythroid 2-related factor 2 (Nrf2), an important antioxidant transcription factor, may play crucial roles in the pathogenesis and progression of age-related diseases including IDD. Nrf2 can maintain redox homeostasis and protecting nucleus pulposus (NP) cells against oxidative stress, inflammatory response, extracellular matrix (ECM) catabolism, cell senescence and cell death involving in the progression of IDD. In this review, we aim to systematically describe the vital roles and pathological mechanism of Nrf2 signaling axis in the pathogenesis of IDD, which may put forward potential therapeutic strategies for the prevention and treatment of IDD by targeting Nrf2.

Keywords:  Nrf2; intervertebral disc degeneration; nucleus pulposus cells; oxidative stress

DOI:  https://doi.org/10.2147/JIR.S432575
Eur Rev Med Pharmacol Sci. 2023 Dec;pii: 34573. [Epub ahead of print]27(23): 11340-11350

Oxytocin mitigates peripheral nerve damage via Nrf2 and irisin pathway.

H K Tosyalı, E S Bora, O S Çınaroğlu, O Erbaş.

OBJECTIVE: Peripheral nerve injuries present challenges in achieving full functional restoration, necessitating effective therapeutic strategies. Oxytocin, known for its neuroprotective and anti-inflammatory properties, has shown potential in nerve recovery. This study aims to elucidate the role of oxytocin in nerve recovery via the nuclear factor erythroid 2-related factor 2 (Nrf2) and irisin pathways.
MATERIALS AND METHODS: Adult male Wistar rats (n=30) were subjected to surgical dissection of sciatic nerves and divided into Control, Surgery and Saline Group, and Surgery and Oxytocin (OT) group. Electromyographic (EMG) recordings, inclined plane tests, and histological assessments were conducted to evaluate nerve function, and Nerve growth factor (NGF) immunoexpression and axonal parameters were measured. Plasma irisin levels, nerve NGF, and Nrf2 levels were quantified.
RESULTS: The Surgery and Saline Group exhibited impaired EMG latency, amplitude, and inclined plane score compared to Controls, while the Surgery and OT Group demonstrated improved outcomes. Histomorphometric analysis revealed increased NGF immunoexpression, axon number, diameter, and reduced fibrosis in the Surgery and OT Group. Plasma irisin levels were higher following oxytocin administration. Additionally, nerve NGF and Nrf2 levels were elevated in the Surgery and OT Group.
CONCLUSIONS: OT administration mitigated nerve injury effects, promoting functional and histological improvements. Elevated NGF and Nrf2 levels, along with increased irisin, indicated the potential interplay of these pathways in enhancing nerve recovery. The results align with OT's neuroprotective and anti-inflammatory roles, suggesting its potential as a therapeutic intervention for nerve injuries. OT's positive impact on nerve recovery is associated with its modulation of Nrf2 and irisin pathways, which collectively enhance antioxidant defense and neurotrophic support and mitigate inflammation. These findings underline OT's potential as a therapeutic agent to enhance nerve regeneration and recovery. Further research is needed to elucidate the intricate molecular mechanisms and potential clinical applications of OT in nerve injury management.

DOI: https://doi.org/10.26355/eurrev_202312_34573
Heliyon. 2023 Dec;9(12): e21879

Taurine alleviates high-fat-high-glucose-induced pancreatic islet β-cell oxidative stress and apoptosis in rat.

Dongdong Zhao, Deqi Yin, Xinxin Wang, Yanxi Li, Miao He, Jianmin Hu, Lin Shumei, Jiancheng Yang.

The effect of taurine (TAU) as a specific regulatory mediator on pancreatic function in obese rats induced by a high-fat-high-glucose (HFHG) diet was investigated. We fed male Sprague-Dawley rats under different conditions, namely the control, HFHG, TAU, and HFHG + TAU treatment groups for 4 months. Compared with the HFHG group, TAU supplementation significantly reduced malondialdehyde levels and increased superoxide dismutase, total antioxidant capacity, and glutathione levels in the rat pancreas. In addition, TAU significantly decreased the level of reactive oxygen species, and markedly increased the activity of heme oxygenase 1 (HO-1), Kelch-like ECH-associated protein 1 (KEAP-1), and nuclear factor erythrocyte-2-related factor 2 (Nrf2) in the rat pancreas. Notably, HFHG diet could induce pancreatic injury in the rats through the Nrf2/HO-1 signaling pathway and activate the mitochondrial channel-mediated apoptotic signaling pathway. The addition of TAU significantly improved the pancreatic tissue injury induced by the HFHG diet in the rats and reduced the protein expression of Caspase-3, Cleaved-caspase-3, Caspase-9 and Bcl-2 associated protein X (BAX), and increased the protein expression of B-cell lymphoma-2 (Bcl-2). In conclusion, this experiment confirmed that TAU could alleviate the oxidative stress and apoptosis induced by the HFHG diet in rat pancreatic β-cells.

DOI: https://doi.org/10.1016/j.heliyon.2023.e21879
Mol Neurobiol. 2023 Dec 12.

Hexahydrocurcumin Attenuates Neuronal Injury and Modulates Synaptic Plasticity in Chronic Cerebral Hypoperfusion in Rats.

Pranglada Jearjaroen, Phakkawat Thangwong, Chainarong Tocharus, Anusorn Lungkaphin, Waraluck Chaichompoo, Jaranwit Srijun, Apichart Suksamrarn, Jiraporn Tocharus.

  Dementia is the most common age-related problem due predominantly to Alzheimer's disease (AD) and vascular dementia (VaD). It has been shown that these contributors are associated with a high amount of oxidative stress that leads to changes in neurological function and cognitive impairment. The aim of study was to explore the mechanism by which hexahydrocurcumin (HHC) attenuates oxidative stress, amyloidogenesis, phosphorylated Tau (pTau) expression, neuron synaptic function, and cognitive impairment and also the potential mechanisms involved in induced permanent occlusion of bilateral common carotid arteries occlusion (BCCAO) or 2-vessel occlusion (2VO) in rats. After surgery, rats were treated with HHC (40 mg/kg) or piracetam (600 mg/kg) by oral gavage daily for 4 weeks. The results showed that HHC or piracetam attenuated oxidative stress by promoting nuclear factor erythroid 2-related factor 2 (Nrf2) activity, and alleviated expression of synaptic proteins (pre- and post-synaptic proteins) mediated by the Wingless/Integrated (Wnt)/β-catenin signaling pathway. Moreover, HHC or piracetam also improved synaptic plasticity via the brain-derived neurotrophic factor (BDNF)/Tyrosine receptor kinase B (TrkB)/cAMP responsive element binding protein (CREB) signaling pathway. In addition, HHC reduced amyloid beta (Aβ) production and pTau expression and improved memory impairment as evidenced by the Morris water maze. In conclusion, HHC exerted remarkable improvement in cognitive function in the 2VO rats possibly via the attenuation of oxidative stress, improvement in synaptic function, attenuation of amyloidogenesis, pTau, and neuronal injury, thereby improving cognitive performance.

Keywords:  2VO; Cognitive impairment; Hexahydrocurcumin; Vascular dementia

DOI:  https://doi.org/10.1007/s12035-023-03821-x
Front Med (Lausanne). 2023 ;10 1283302

Age-induced aortic modifications are accompanied by alterations in the antioxidant defense system in female rats.

Sabahat Binte Asad, Xin Qian, Jiao Wang, Wajeeha Asad, Qiang Gao, Yang Cao, Yujia Huang, Yousef A Bin Jardan, Tawaf Ali Shah, Gezahign Fentahun Wondmie, Mohammed Bourhia, Chunmei Lu, Hui Zhu.

   Introduction: Aging leads to significant structural and functional changes in blood vessels, which disrupt their normal function and impact cardiovascular health. Current research is actively exploring the NRF2 antioxidative pathway, recognizing its role in protecting cells by preserving their antioxidant defenses against damage. However, there has been limited exploration into the role of the NRF2 pathway in vascular aging. The primary objective of this study was to determine whether age-related changes in the aorta are associated with variations in the baseline levels of antioxidant enzymes, with a particular emphasis on how the NRF2 pathway operates in the aortic wall.
Methods: A group of healthy aging female SD rats was compared with their younger counterparts. Various assessments were conducted, including measuring blood pressure, analyzing serum lipid profiles, examining aortic tissue, and assessing the expression of antioxidant enzymes.
Results: The results revealed significant differences in both blood pressure and serum lipid levels between the aged and younger rats. The examination of the aorta in older rats showed structural alterations, increased apoptosis, and the accumulation of fatty deposits. In the older rats, levels of SOD-1 (superoxide dismutase) and GSS (glutathione synthetase) were lower, whereas NRF2, KEAP-1 (Kelch-like ECH-associated protein 1), and HO-1 (Heme oxygenase 1) were higher.
Discussion: This study advances our understanding of how aging affects the antioxidant system in blood vessels, particularly in relation to the regulation of the NRF2/HO-1 pathway in the aorta. These findings suggest that targeting the NRF2/HO-1 pathway could present anovel therapeutic approach for addressing age-related vascular issues.

Keywords:  NRF2 pathway; NRF2/HO-1 pathway; aging; antioxidant defense system; aorta; blood pressure

DOI:  https://doi.org/10.3389/fmed.2023.1283302
Nutrients. 2023 Dec 01. pii: 4986. [Epub ahead of print]15(23):

Neuroprotective Effects of N-methyl-(2S, 4R)-trans-4-hydroxy-L-proline (NMP) against Amyloid-β-Induced Alzheimer's Disease Mouse Model.

Jawad Ali, Amjad Khan, Jun Sung Park, Muhammad Tahir, Waqas Ahmad, Kyonghwan Choe, Myeong Ok Kim.

  Alzheimer's disease (AD), is a progressive neurodegenerative disorder that involves the deposition of β-amyloid plaques and the clinical symptoms of confusion, memory loss, and cognitive dysfunction. Despite enormous progress in the field, no curative treatment is available. Therefore, the current study was designed to determine the neuroprotective effects of N-methyl-(2S, 4R)-Trans-4-hydroxy-L-proline (NMP) obtained from Sideroxylon obtusifolium, a Brazilian folk medicine with anti-inflammatory and anti-oxidative properties. Here, for the first time, we explored the neuroprotective role of NMP in the Aβ1-42-injected mouse model of AD. After acclimatization, a single intracerebroventricular injection of Aβ1-42 (5 µL/5 min/mouse) in C57BL/6N mice induced significant amyloidogenesis, reactive gliosis, oxidative stress, neuroinflammation, and synaptic and memory deficits. However, an intraperitoneal injection of NMP at a dose of (50 mg/kg/day) for three consecutive weeks remarkably decreased beta secretase1 (BACE-1) and Aβ, activated the astrocyte and microglia expression level as well as downstream inflammatory mediators such as pNF-ĸB, TNF-α, and IL-1β. NPM also strongly attenuated oxidative stress, as evaluated by the expression level of NRF2/HO-1, and synaptic failure, by improving the level of both the presynaptic (SNAP-25 and SYN) and postsynaptic (PSD-95 and SNAP-23) regions of the synapses in the cortexes and hippocampi of the Aβ1-42-injected mice, contributing to cognitive improvement in AD and improving the behavioral deficits displayed in the Morris water maze and Y-maze. Overall, our data suggest that NMP provides potent multifactorial effects, including the inhibition of amyloid plaques, oxidative stress, neuroinflammation, and cognitive deficits.

Keywords:  Alzheimer’s disease; N-methyl-(2S, 4R)-Trans-4-hydroxy-L-proline (NMP); amyloid beta (Aβ1–42); neuroinflammation; neuroprotection; oxidative stress

DOI:  https://doi.org/10.3390/nu15234986
Front Neurosci. 2023 ;17 1267818

Chronic interleukin-6 mediated neuroinflammation decreases anxiety, and impaires spatial memory in aged female mice.

Ingrid Marguerite Wagnon, Lillian Jocelyn Jabur, Garry Niedermayer, Gerald Münch, Tim Karl, Rose Chesworth, Erika Gyengesi.

   Introduction: Neuroinflammation is a common feature of many psychiatric disorders as well as a common underlying mechanism of neurodegenerative diseases. Sex has been shown to strongly influence the development as well as the clinical expression of these pathologies. However, there is still a neglect regarding the consideration of sex effects in rodent experiments, and a substantial underrepresentation of females in studies. This work set out to expand our knowledge of neuroinflammatory mechanisms in female mice, at both a behavioral and molecular level.
Methods: This study used GFAP-IL6 mice, a model of chronic neuroinflammation, in which interleukin-6 (IL6) is overexpressed in the central nervous system under the control of the glial fibrillary acidic protein (GFAP) promoter. We evaluated aged (11-15-month-old) wild type-like (WT) and GFAP-IL6 female mice in behavioral tests assessing anxiety (elevated plus-maze, EPM, Light/dark box), and spatial learning and memory (Y-maze, YM and Barnes Maze, BM) and associative learning (fear conditioning, FC). We also examined gene expression of markers linked to neuroinflammation, neurodegeneration and neurotransmission via RT-qPCR in brain regions involved in motor control, anxiety, learning and memory.
Results: Female GFAP-IL6 mice exhibited reduced anxiety-like behavior in the EPM, and hypolocomotion in the light-dark test and EPM. Short-term memory impairment was evident in the YM but associative learning in FC was intact in GFAP-IL6 mice, suggesting domain-specific cognitive deficits in female GFAP-IL6 mice. In the BM, all mice showed intact learning and memory, but GFAP-IL6 mice exhibited higher latencies to enter the escape hole than WT mice. We analyzed the search strategy and found differences in the way GFAP-IL6 mice searched for the escape hole compared to WTs. RT-qPCR showed increased mRNA levels for molecules involved in pro-inflammatory pathways in the cerebellum, motor cortex, hippocampus, and amygdala in GFAP-IL6 mice. Of the regions examined, the cerebellum and the hippocampus showed upregulation of neuroinflammatory makers as well as dysregulation of glutamatergic and GABAergic neurotransmission gene expression in GFAP-IL6 mice compared to WTs.
Conclusion: In conclusion, we showed that chronic neuroinflammation via IL6 overexpression in aged female mice led to a less anxious-like phenotype, hypolocomotion and impaired intermediate-term spatial learning and memory in the YM.

Keywords:  Barnes maze; RT-qPCR; anxiety; behavioral phenotyping; chronic neuroinflammation; interleukin-6; learning and memory; mRNA

DOI:  https://doi.org/10.3389/fnins.2023.1267818
Am J Physiol Cell Physiol. 2023 Dec 11.

Parkin-mediated mitophagy is a potential treatment for oxaliplatin-induced peripheral neuropathy.

Guoqing Zhao, Te Zhang, Jiannan Li, Longyun Li, Peng Chen, Chunlu Zhang, Kai Li, Cancan Cui.

  Oxaliplatin-induced peripheral nerve pain (OIPNP) is a common chemotherapy-related complication, but the mechanism is complex. Mitochondria are vital for cellular homeostasis and regulating oxidative stress. Parkin-mediated mitophagy is a cellular process that removes damaged mitochondria, exhibiting a protective effect in various diseases; however, its role in OIPNP remains unclear. In this study, we found that Parkin-mediated mitophagy was decreased, and reactive oxygen species (ROS) was upregulated in OIPNP rat dorsal root ganglion (DRG) in vivo and in PC12 cells stimulated with oxaliplatin (OXA) in vitro. Overexpression of Parkin indicated that OXA might cause mitochondrial and cell damage by inhibiting mitophagy. We also showed that salidroside (SAL) upregulated Parkin-mediated mitophagy to eliminate damaged mitochondria and promote PC12 cell survival. Knockdown of Parkin indicated that mitophagy is crucial for apoptosis and mitochondrial homeostasis in PC12 cells. In vivo study also demonstrated that SAL enhances Parkin-mediated mitophagy in the DRG and alleviates peripheral nerve injury and pain. These results suggest that Parkin-mediated mitophagy is involved in the pathogenesis of OIPNP and may be a potential therapeutic target for OIPNP.

Keywords:  Parkin; mitophagy; oxaliplatin; peripheral nerve pain; salidroside

DOI:  https://doi.org/10.1152/ajpcell.00276.2023
Metab Brain Dis. 2023 Dec 12.

Chitosan/PLA-loaded Magnesium oxide nanocomposite to attenuate oxidative stress, neuroinflammation and neurotoxicity in rat models of Alzheimer's disease.

Manickam Rajkumar, Prabha Govindaraj, Karuppaiya Vimala, Ramasundaram Thangaraj, Soundarapandian Kannan.

  Alzheimer's disease (AD) is a neurodegenerative disease characterized by amyloid-beta (Aβ) aggregation, neuroinflammation, oxidative stress, and dysfunction in the mitochondria and cholinergic system. In this study, the synthesis of chitosan-polylactic acid-loaded magnesium oxide nanocomposite (CH/PLA/MgONCs) was examined using the green precipitation method. The synthesized CH/PLA/MgONCs were confirmed by using the UV-Vis spectrum, FT-IR, SEM-EDAX, and physical properties. The experiments were carried out using male Wistar rats by injecting streptozotocin (STZ) bilaterally into the brain's ventricles through the intracerebroventricular (ICV) route at a dose of 3 mg/kg. We also evaluated the effects of CH/PLA/MgONCs at doses of 10 mg/kg. To assess the cognitive dysfunction induced by ICV-STZ, we performed behavioral, biochemical, and histopathological analyses. In our study results, UV-Vis spectrum analysis of CH/PLA/MgONCs showed 285 nm, FT-IR analyses confirmed that the various functional groups were present, and SEM-EDAX analysis confirmed that a cauliflower-like spherical shape, Mg and O were present. Treatment with CH/PLA/MgONCs (10 mg/kg) showed a significant improvement in spatial and non-spatial memory functions. This was further supported by biochemical analysis showing improved antioxidant enzyme (GSH, SOD, CAT, and GPx activity) activities that significantly attenuated cholinergic activity and oxidative stress. In the CH/PLA/MgONCs-treated group, significant improvement was observed in the mitochondrial complex activity. ICV-STZ-induced neuroinflammation, as indicated by increased levels of TNF-α, IL-6, and CRP, was significantly reduced by CH/PLA/MgONCs treatment. Additionally, CH/PLA/MgONCs treated histological results showed improved healthy neuronal cells in the brain. Furthermore, in silico studies confirm that these molecules have good binding affinity and inhibit Aβ aggregation. In conclusion, CH/PLA/MgONCs treatment reversed AD pathology by improving memory and reducing oxidative stress, neuroinflammation, and mitochondrial dysfunction. These findings recommend that CH/PLA/MgONCs are possible therapeutic agents to treat AD.

Keywords:  Amyloid-β aggregation; Magnesium oxide; Neuroinflammation; Oxidative stress

DOI:  https://doi.org/10.1007/s11011-023-01336-x
Sci Rep. 2023 Dec 07. 13(1): 21624

Autophagy and neuroprotection in astrocytes exposed to 6-hydroxydopamine is negatively regulated by NQO2: relevance to Parkinson's disease.

Elzbieta Janda, Maddalena Parafati, Concetta Martino, Francesco Crupi, Jonahunnatha Nesson George William, Karine Reybier, Mariamena Arbitrio, Vincenzo Mollace, Jean A Boutin.

Dopaminergic degeneration is a central feature of Parkinson's disease (PD), but glial dysfunction may accelerate or trigger neuronal death. In fact, astrocytes play a key role in the maintenance of the blood-brain barrier and detoxification. 6-hydroxydopamine (6OHDA) is used to induce PD in rodent models due to its specific toxicity to dopaminergic neurons, but its effect on astrocytes has been poorly investigated. Here, we show that 6OHDA dose-dependently impairs autophagy in human U373 cells and primary murine astrocytes in the absence of cell death. LC3II downregulation was observed 6 to 48 h after treatment. Interestingly, 6OHDA enhanced NRH:quinone oxidoreductase 2 (NQO2) expression and activity in U373 cells, even if 6OHDA turned out not to be its substrate. Autophagic flux was restored by inhibition of NQO2 with S29434, which correlated with a partial reduction in oxidative stress in response to 6OHDA in human and murine astrocytes. NQO2 inhibition also increased the neuroprotective capability of U373 cells, since S29434 protected dopaminergic SHSY5Y cells from 6OHDA-induced cell death when cocultured with astrocytes. The toxic effects of 6OHDA on autophagy were attenuated by silencing NQO2 in human cells and primary astrocytes from NQO2-/- mice. Finally, the analysis of Gene Expression Omnibus datasets showed elevated NQO2 gene expression in the blood cells of early-stage PD patients. These data support a toxifying function of NQO2 in dopaminergic degeneration via negative regulation of autophagy and neuroprotection in astrocytes, suggesting a potential pharmacological target in PD.

DOI: https://doi.org/10.1038/s41598-023-44666-7
J Trace Elem Med Biol. 2023 Dec 07. pii: S0946-672X(23)00232-8. [Epub ahead of print]82 127356

Syringic acid alleviates cisplatin-induced ovarian injury through modulating endoplasmic reticulum stress, inflammation and Nrf2 pathway.

Elif Ayazoglu Demir.

   BACKGROUND: Reproductive toxicity is one of the most important side effects of cisplatin (CIS) and leading to discontinuation of treatment. Syringic acid (SA) is a phenolic acid whose industrial use has increased in recent years due to its antioxidant properties. Recent reports highlight the importance of the supressed Nrf2 pathway in the molecular pathogenesis of CIS toxicity. Therefore, this study aimed to evaluate the therapeutic effect of SA on CIS-induced ovotoxicity through the Nrf2 pathway for the first time.
MATERIAL AND METHODS: Thirty female rats were divided into 5 groups: control, CIS, CIS+SA (5 and 10 mg/kg) and only SA (per se, 10 mg/kg). CIS was administered intraperitoneally at a dose of 5 mg/kg on the 1st day, injections of SA followed by three consecutive days in the rats. Serum anti-mullerian hormone (AMH) levels and ovarian oxidative stress (OS), inflammation, endoplasmic reticulum stress (ERS), apoptosis and Nrf2 pathway markers were determined colorimetrically. Histopathological examinations of the ovaries with hematoxylin and eosin staining were also used to evaluate CIS-induced ovotoxicity.
RESULTS: The CIS treatment depleted serum AMH levels, caused histopathological findings and increased OS, inflammation, ERS and apoptosis levels in ovarian tissue. However, treatments with SA significantly ameliorated CIS-induced biochemical and histopathological changes by activating Nrf2 pathway.
CONCLUSION: The promising adjuvant potential of SA to alleviate CIS-related ovarian damage should be supported by more comprehensive studies.

Keywords:  Cisplatin; Endoplasmic reticulum stress; Inflammation; Nrf2; Ovotoxicity; Oxidative stress; Syringic acid

DOI:  https://doi.org/10.1016/j.jtemb.2023.127356
Microbes Infect. 2023 Dec 09. pii: S1286-4579(23)00184-3. [Epub ahead of print] 105274

Leptospiral lipopolysaccharide dampens inflammation through upregulation of autophagy adaptor p62 and NRF2 signaling in macrophages.

Delphine Bonhomme, Ignacio Santecchia, Pedro Escoll, Stylianos Papadopoulos, Frédérique Vernel-Pauillac, Ivo G Boneca, Catherine Werts.

  Leptospira interrogans are pathogenic bacteria responsible for leptospirosis, a worldwide zoonosis. All vertebrates can be infected, and some species like humans are susceptible to the disease whereas rodents such as mice are resistant and become asymptomatic renal carriers. Leptospires are stealth bacteria that are known to escape several immune recognition pathways and resist killing mechanisms. We recently published that leptospires may survive intracellularly in and exit macrophages, avoiding xenophagy, a pathogen-targeting form of autophagy. Interestingly, the latter is one of the antimicrobial mechanisms often highjacked by bacteria to evade the host immune response. In this study we explored whether leptospires subvert the key molecular players of autophagy to facilitate infection. We showed in macrophages that leptospires triggered a specific accumulation of autophagy-adaptor p62 in puncta-like structures, without altering autophagic flux. We demonstrated that Leptospira-induced p62 accumulation is a passive mechanism depending on the leptospiral virulence factor LPS signaling via TLR4/TLR2. p62 is a central pleiotropic protein, also mediating cell stress and death, via the translocation of transcription factors. We demonstrated that Leptospira-driven accumulation of p62 induced the translocation of transcription factor NRF2, a key player in the anti-oxidant response. However, NRF2 translocation upon Leptospira infection did not result as expected in antioxydant response, but dampened the production of inflammatory mediators such as iNOS/NO, TNF and IL6. Overall, these findings highlight a novel passive bacterial mechanism linked to LPS and p62/NRF2 signaling that decreases inflammation and contributes to the stealthiness of leptospires.

Keywords:  Autophagy adapter p62; LPS; Leptospira; NRF2; TLRs

DOI:  https://doi.org/10.1016/j.micinf.2023.105274
Biochim Biophys Acta Mol Basis Dis. 2023 Dec 06. pii: S0925-4439(23)00350-2. [Epub ahead of print]1870(2): 166984

Butyrate ameliorated ferroptosis in ulcerative colitis through modulating Nrf2/GPX4 signal pathway and improving intestinal barrier.

Hangping Chen, Yifan Qian, Chensheng Jiang, Leilei Tang, Jiawen Yu, Lingdi Zhang, Yiyang Dai, Guojun Jiang.

  Oxidative stress and intestinal inflammation are main pathological features of ulcerative colitis (UC). Ferroptosis, characterized by iron accumulation and lipid peroxidation, is closely related to the pathologic process of UC. 16S rRNA sequencing for intestinal microbiota analysis and gas chromatography-mass spectrometry (GC-MS) for short-chain fatty acid (SCFA) contents clearly demonstrated lower amounts of butyrate-producing bacteria and butyrate in colitis mice. However, the precise mechanisms of sodium butyrate (NaB) in treating UC remain largely unclear. We found that ferroptosis occurred in colitis models, as evidenced by the inflammatory response, intracellular iron level, mitochondria ultrastructural observations and associated protein expression. NaB inhibited ferroptosis in colitis, significantly rescued weight loss and colon shortening in mice and reduced inflammatory lesions and mitochondrial damage. Furthermore, NaB improved intestinal barrier integrity and markedly suppressed the expression of pro-ferroptosis proteins. Conversely, the protein expression of anti-ferroptosis markers including nuclear factor erythroid-related Factor 2 (Nrf2) and glutathione peroxidase 4 (GPX4), was significantly upregulated with NaB treatment. Moreover, the knockdown of Nrf2 reversed the anti-colitis effect of NaB. Taken together, NaB exhibited a protective effect by ameliorating ferroptosis in experimental colitis through Nrf2/GPX4 signaling and improving intestinal barrier integrity, which provides a novel mechanism for NaB prevention of UC.

Keywords:  Ferroptosis; Gut microbiota; Intestinal barrier integrity; Nrf2/GPX4 signaling; Sodium butyrate; Ulcerative colitis

DOI:  https://doi.org/10.1016/j.bbadis.2023.166984
J Agric Food Chem. 2023 Dec 11.

Novel Antioxidant Peptides Derived from Feather Keratin Alleviate H2O2-Induced Oxidative Damage in HepG2 Cells via Keap1/Nrf2 Pathway.

Xiao-Dong Pei, Yi-Ning He, Qing-Ling Wu, Yan-Mei Zhang, Fan Li, Dao-Quan Jiao, Xiao-Ling Liu, Cheng-Hua Wang.

  Reactive oxygen species (ROS) are crucial for signal transduction and the maintenance of cellular homeostasis. However, superfluous ROS may engender chronic pathologies. Feather keratin is a promising new source of antioxidant peptides that can eliminate excess ROS and potentially treat oxidative stress-related diseases, but the underlying mechanisms have remained elusive. This study investigated the antioxidant effects and mechanisms against H2O2-induced oxidative damage in HepG2 cells of the two latest discovered antioxidant peptides, CRPCGPTP (CP-8) and ANSCNEPCVR (AR-10), first decrypted from feather keratin. The results revealed that CP-8 and AR-10 did not exhibit cytotoxicity to HepG2 cells while reducing intracellular ROS accumulation. Simultaneously, they enhanced the activities of catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px), thus alleviating H2O2-induced cell apoptosis. Molecular docking analysis demonstrated that CP-8, AR-10 interacted well with the key amino acids in the Kelch domain of Keap1, thereby directly disrupting the Keap1-Nrf2 interaction. The peptides' biosafety and antioxidant activity via Keap1/Nrf2 signaling lay the groundwork for further animal studies and applications as functional food additives.

Keywords:  Keap1/Nrf2 pathway; antioxidant peptide; feather keratin; oxidative damage

DOI:  https://doi.org/10.1021/acs.jafc.3c05088
Eur J Pharm Sci. 2023 Dec 06. pii: S0928-0987(23)00295-6. [Epub ahead of print]192 106667

Folic acid-functionalized chitosan nanoparticles with bioenzyme activity for the treatment of spinal cord injury.

Yingqiao Li, Zhiru Zou, Jinyu An, Xiaoyao Liu, Qian Wu, Junpeng Sun, Xiaobang Liu, Jiaqun Du, Ying Xiong, Chao Wu, Xifan Mei, He Tian.

  Spinal cord injury (SCI) is a central system disease with a high rate of disability. Pathological changes such as ischemia and hypoxia of local tissues, oxidative stress and apoptosis could lead to limb pain, paralysis and even life-threatening. It was reported that catalase (CAT) was the main antioxidant in organisms, which could remove reactive oxygen species (ROS) and release oxygen (O2). However, the efficacy of the drug is largely limited due to its poor stability, low bioavailability and inability to cross the blood spinal cord barrier (BSCB). Therefore, in this study, we prepared folic acid-functionalized chitosan nanoparticles to deliver CAT (FA-CSNCAT) for solving this problem. In vivo small animal imaging results showed that FA-CSN could carry CAT across the BSCB and target to the inflammatory site. In addition, Immunofluorescence, ROS assay and JC-1 probe were used to detect the therapeutic effect of FA-CSNCAT in vitro and in vivo. The results showed that FA-CSNCAT could alleviate the hypoxic environment at the injured site and remove ROS, thereby inhibiting oxidative stress and protecting neurons, which may provide a new idea for clinical medication of SCI.

Keywords:  Apoptosis; Hypoxia; Oxidative stress; Spinal cord injury

DOI:  https://doi.org/10.1016/j.ejps.2023.106667
Biomed Pharmacother. 2023 Dec 12. pii: S0753-3322(23)01804-8. [Epub ahead of print]170 116006

Isoliquiritigenin inhibits apoptosis and ameliorates oxidative stress in rheumatoid arthritis chondrocytes through the Nrf2/HO-1-mediated pathway.

Shih-Ya Hung, Jen-Lung Chen, Yuan-Kun Tu, Hsin-Yi Tsai, Pin-Hsuan Lu, I-Ming Jou, Lulekiwe Mbuyisa, Ming-Wei Lin.

  Rheumatoid arthritis (RA) is a chronic inflammatory condition known for its irreversible destructive impact on the joints. Chondrocytes play a pivotal role in the production and maintenance of the cartilage matrix. However, the presence of inflammatory cytokines can hinder chondrocyte proliferation and promote apoptosis. Isoliquiritigenin (ISL), a flavonoid, potentially exerts protective effects against various inflammatory diseases. However, its specific role in regulating the nuclear factor E2-associated factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway in chondrocytes in RA remains unclear. To investigate this, this study used human chondrocytes and Sprague-Dawley rats to construct in vitro and in vivo RA models, respectively. The study findings reveal that cytokines markedly induced oxidative stress, the activation of matrix metalloproteinases, and apoptosis both in vitro and in vivo. Notably, ISL treatment significantly mitigated these effects. Moreover, Nrf2 or HO-1 inhibitors reversed the protective effects of ISL, attenuated the expression of Nrf2/HO-1 and peroxisome proliferator-activated receptor gamma-coactivator-1α, and promoted chondrocyte apoptosis. This finding indicates that ISL primarily targets the Nrf2/HO-1 pathway in RA chondrocytes. Moreover, ISL treatment led to improved behavior scores, reduced paw thickness, and mitigated joint damage as well as ameliorated oxidative stress in skeletal muscles in an RA rat model. In conclusion, this study highlights the pivotal role of the Nrf2/HO-1 pathway in the protective effects of ISL and demonstrates the potential of ISL as a treatment option for RA.

Keywords:  Chondrocytes; HO-1; Isoliquiritigenin; Nrf2; Oxidative stress; Rheumatoid arthritis; Skeletal muscles

DOI:  https://doi.org/10.1016/j.biopha.2023.116006
J Biochem Mol Toxicol. 2023 Dec 09. e23605

The possible role of nuclear factor erythroid-2-related factor 2 activators in the management of Covid-19.

Hayder M Al-Kuraishy, Ali I Al-Gareeb, Omayma A Eldahshan, Yasmine M Abdelkhalek, Magdy El Dahshan, Eman A Ahmed, Jean-Marc Sabatier, Gaber E-S Batiha.

  COVID-19 is caused by a novel SARS-CoV-2 leading to pulmonary and extra-pulmonary manifestations due to oxidative stress (OS) development and hyperinflammation. COVID-19 is primarily asymptomatic though it may cause acute lung injury (ALI), acute respiratory distress syndrome (ARDS), systemic inflammation, and thrombotic events in severe cases. SARS-CoV-2-induced OS triggers the activation of different signaling pathways, which counterbalances this complication. One of these pathways is nuclear factor erythroid 2-related factor 2 (Nrf2), which induces a series of cellular interactions to mitigate SARS-CoV-2-mediated viral toxicity and OS-induced cellular injury. Nrf2 pathway inhibits the expression of pro-inflammatory cytokines and the development of cytokine storm in COVID-19. Therefore, Nrf2 activators may play an essential role in reducing SARS-CoV-2 infection-induced inflammation by suppressing NLRP3 inflammasome in COVID-19. Furthermore, Nrf2 activators can attenuate endothelial dysfunction (ED), renin-angiotensin system (RAS) dysregulation, immune thrombosis, and coagulopathy. Thus this mini-review tries to clarify the possible role of the Nrf2 activators in the management of COVID-19. Nrf2 activators could be an effective therapeutic strategy in the management of Covid-19. Preclinical and clinical studies are recommended in this regard.

Keywords:  Covid-19; SARS CoV-2; angiotensin-converting enzyme; nuclear factor erythroid 2-related factor 2; oxidative stress

DOI:  https://doi.org/10.1002/jbt.23605
Eur Arch Psychiatry Clin Neurosci. 2023 Dec 10.

Effects of antipsychotic drugs on energy metabolism.

Bruna Panizzutti, Chiara C Bortolasci, Briana Spolding, Srisaiyini Kidnapillai, Timothy Connor, Sheree D Martin, Trang T T Truong, Zoe S J Liu, Laura Gray, Greg M Kowalski, Sean L McGee, Jee Hyun Kim, Michael Berk, Ken Walder.

  Schizophrenia (SCZ) is a complex neuropsychiatric disorder associated with altered bioenergetic pathways and mitochondrial dysfunction. Antipsychotic medications, both first and second-generation, are commonly prescribed to manage SCZ symptoms, but their direct impact on mitochondrial function remains poorly understood. In this study, we investigated the effects of commonly prescribed antipsychotics on bioenergetic pathways in cultured neurons. We examined the impact of risperidone, aripiprazole, amisulpride, and clozapine on gene expression, mitochondrial bioenergetic profile, and targeted metabolomics after 24-h treatment, using RNA-seq, Seahorse XF24 Flux Analyser, and gas chromatography-mass spectrometry (GC-MS), respectively. Risperidone treatment reduced the expression of genes involved in oxidative phosphorylation, the tricarboxylic acid cycle, and glycolysis pathways, and it showed a tendency to decrease basal mitochondrial respiration. Aripiprazole led to dose-dependent reductions in various mitochondrial function parameters without significantly affecting gene expression. Aripiprazole, amisulpride and clozapine treatment showed an effect on the tricarboxylic acid cycle metabolism, leading to more abundant metabolite levels. Antipsychotic drug effects on mitochondrial function in SCZ are multifaceted. While some drugs have greater effects on gene expression, others appear to exert their effects through enzymatic post-translational or allosteric modification of enzymatic activity. Understanding these effects is crucial for optimising treatment strategies for SCZ. Novel therapeutic interventions targeting energy metabolism by post-transcriptional pathways might be more effective as these can more directly and efficiently regulate energy production.

Keywords:  Antipsychotics; Energy metabolism; Mental health; Mitochondria; Neurons; Neuroscience; Psychiatry; Schizophrenia

DOI:  https://doi.org/10.1007/s00406-023-01727-2
Sci Total Environ. 2023 Dec 06. pii: S0048-9697(23)07805-1. [Epub ahead of print]912 169175

Tetrabromobisphenol A induces neuronal cytotoxicity by inhibiting PINK1-Parkin-mediated mitophagy via upregulating ATF3 expression.

Xijuan Chao, Dezhi Yao, Chuxuan Chen, Zhiguo Sheng, Benzhan Zhu.

  Tetrabromobisphenol A (TBBPA), as a widely used brominated flame retardant, has been implicated as a potential neurotoxicant. However, the mechanism of TBBPA-induced neurotoxicity has not been fully elucidated yet. In this study, using mouse hippocampal neuron cell HT22 as the in vitro model, the neuronal cytotoxicity of TBBPA and the mechanism by focusing on mitophagy have been studied. We found that neuronal cytotoxic effects were indeed induced by TBBPA exposure at concentrations of >20 μM for 24 h, including decreased cell viability (to 92.38 % at 20 μM; 18.25 % at 80 μM), enhanced ROS (enhanced 53.26 % at IC50 of 60 μM, compared with that in the control group) and mitochondrial ROS (mtROS) levels (enhanced 24.12 % at 60 μM), reduced mitochondrial membrane potential (MMP) (decreased 33.60 % at 60 μM). As a protective mechanism in cells, autophagy was initiated; however, mitophagy was inhibited, where PINK1 (PINK1-Parkin activation is critical in the depolarized MMP-induced mitophagy) expression was found to be repressed and decreased, further leading to the failure of Parkin recruitment to the damaged mitochondria. Mitophagy activator, nicotinamide mononucleotide (β-NMN) that activates the PINK1-Parkin pathway, could alleviate TBBPA-induced mitophagy deficiency and further reduce the neuronal cytotoxicity, demonstrating that TBBPA-induced PINK1-Parkin-mediated mitophagy deficiency contributed to the neuronal cytotoxicity. Furthermore, we found TBBPA caused the upregulation of Atf3 (activating transcription factor 3) gene transcription and expression levels, alongside reduced Pink1 levels; whereas enhanced Pink1 transcript levels were observed after ATF3 depletion even under TBBPA treatment, demonstrating TBBPA-induced overexpression of ATF3 should be responsible for the reduced PINK1 expression. Therefore, for the first time, here we demonstrate that TBBPA can inhibit PINK1-Parkin-mediated mitophagy via upregulating ATF3 expression, which further contributes to its neuronal cytotoxicity. This study should be able to improve our understanding of the mechanism of TBBPA-induced neuronal cytotoxicity.

Keywords:  ATF3; Mitophagy deficiency; Neuronal cytotoxicity; PINK1/Parkin; TBBPA

DOI:  https://doi.org/10.1016/j.scitotenv.2023.169175
Heliyon. 2023 Nov;9(11): e22483

A review of pomegranate supplementation: A promising remedial avenue for Alzheimer's disease.

Aman Ullah, Asif Khan, Sagheer Ahmed, Hafiz Muhammad Irfan, Amin A Hafiz, Kainat Jabeen, Mubarak Alruwaili, Muteb Alotaibi, Waiel Al Naeem, Ajmal Khan, Ahmed Al-Harrasi.

  Neurodegenerative complications, like Alzheimer's disease (AD) exert adverse effects i.e. psychological and physiological in the central nervous system. The synthetic drugs used for these complications have negative effects on body health and therefore natural remedies are a good and targeted approach to counter such complications. Alternatively, fruits and a variety of biochemicals which are an important source of diet, can be used for remedial purposes. Due to the antioxidant properties of polyphenolic compounds, several companies utilize this property to advertise polyphenol-rich beverages. Pomegranate (Punica granatum L.), is one such fruit that is well known for its medical usage due to its antioxidant properties. In the cuurent study a literature search survey was performed on traditional uses, phytochemicals on pomegranate and their medical applications especaily in neurodegenerative deasese using electronic data bases like PubMed, Google Scholar, Scopus, Science Direct Wikipedia and Springer Nature. Based on previous preclinical and clinical studies, pomegranate juice, extracts, and its bioactive constituents have shown many mitigating properties, including suppression of inflammatory cell signaling, reduction in expression of genes associated with oxidative stress as well as pro-inflammatory cytokines in neurons, decreased production of inflammatory and oxidative stress biomarkers and increased expression of endothelial nitric oxide synthase. It also decreases the expression of soluble amyloid protein procurer β (sAPPβ), β-secretase and carboxyl terminal fragment β (CTFβ). Similarly, during an in-vivo study on APP/PS1 mice, pomegranate supplementation has been shown to impart cognitive aid by the protection of neurons and triggering neurogenesis through anti-inflammatory signaling pathway. In conclusion, pomegranate supplementation can be a promising source of protection against Alzheimer's disease.

Keywords:  Alzheimer disease; Antioxidant; Nerve disorder; Phytochemicals; Pomegranate

DOI:  https://doi.org/10.1016/j.heliyon.2023.e22483