bims-nurfan 2023-12-31 papers

bims-nurfan

Biomed News

on NRF2 and Neurological Diseases

Issue of 2023‒12‒31
thirty papers selected by
Arif Kamil Salihoğlu, Karadeniz Technical University

Fangchinoline alleviates cognitive impairments through enhancing autophagy and mitigating oxidative stress in Alzheimer's disease models.
Sulforaphane protects from kidney damage during the release of unilateral ureteral obstruction (RUUO) by activating nuclear factor erythroid 2-related factor 2 (Nrf2): Role of antioxidant, anti-inflammatory, and antiapoptotic mechanisms.
Fisetin suppresses ferroptosis through Nrf2 and attenuates intervertebral disc degeneration in rats.
Omaveloxolone ameliorates isoproterenol-induced pathological cardiac hypertrophy in mice.
Icariside II suppresses ferroptosis to protect against MPP+-Induced Parkinson's disease through Keap1/Nrf2/GPX4 signaling.
Mangiferin alleviates 6-OHDA-induced Parkinson's disease by inhibiting AKR1C3 to activate Wnt signaling pathway.
The flower of Abelmoschus manihot (L.) Medik exerts antioxidant effects by regulating the Nrf2 signaling pathway in scald injury.
Sesamol: A Phenolic Compound of Health Benefits and Therapeutic Promise in Neurodegenerative Diseases.
Acupuncture alleviates CUMS-induced depression-like behaviors of rats by regulating oxidative stress, neuroinflammation and ferroptosis.
Potential involvement of ferroptosis in BPA-induced neurotoxicity: An in vitro study.
Acrolein suppresses anticancer drug-induced toxicity mediated by activating claudin-1 and Nrf2 axis in a spheroid model of human lung squamous cell carcinoma cells.
Mechanism by which HDAC3 regulates manganese induced H3K27ac in SH-SY5Y cells and intervention by curcumin.
Ophiopogonin D improves oxidative stress and mitochondrial dysfunction in pancreatic β cells induced by hydrogen peroxide through Keap1/Nrf2/ARE pathway in diabetes mellitus.
Protective Effect of Compound Tongluo Decoction on Brain Vascular Endothelial Cells after Ischemia-Reperfusion by Inhibition of Ferroptosis Through Regulating Nrf2/ARE/SLC7A11 Signaling Pathway.
Neuroprotective role of FOXA1 in Parkinson's disease: Involvements of NF1 transcription activation and MAPK signaling pathway inhibition.
Neuroprotective effects of nanogold-based Ayurveda medicine Suvarna Bhasma against rotenone-induced Parkinson's-like model.
Diosmetin alleviates neuropathic pain by regulating the Keap1/Nrf2/NF-κB signaling pathway.
Selenomethionine alleviates decabromodiphenyl ether-induced oxidative stress and ferroptosis via the NRF2/GPX4 pathway in the chicken brain.
Understanding the Therapeutic Approaches for Neuroprotection.
Does hazelnut consumption affect brain health and function against neurodegenerative diseases?
Rosmarinic Acid Inhibits Ultraviolet B-Mediated Oxidative Damage via the AKT/ERK-NRF2-GSH Pathway In Vitro and In Vivo.
Kaempferol improves Pb-induced cognitive impairments via inhibiting autophagy.
The Effect of Physical Exercise Pretreatment on Spatial Memory and Learning and Function of Mitochondria in the Brain in Type 2 Diabetic Rats.
Inhibition of USP30 Promotes Mitophagy by Regulating Ubiquitination of MFN2 by Parkin to Attenuate Early Brain Injury After SAH.
Evaluating the Protective Effects of Melatonin Against Chronic Iron Administration in Male Wistar Rats: a Comparative Analysis of Affective, Cognitive, and Oxidative Stress with EDTA Chelator.
Anethole via increase in the gene expression of PI3K/AKT/mTOR mitigates the autistic-like behaviors induced by maternal separation stress in mice.
The protective effects of hesperidin as an antioxidant against quinolinic acid-induced toxicity on oligodendroglia cells: An in vitro study.
TREM2-IGF1 Mediated Glucometabolic Enhancement Underlies Microglial Neuroprotective Properties During Ischemic Stroke.
The elderberry diet protection against intrahippocampal Aβ-induced memory dysfunction; the abrogated apoptosis and neuroinflammation.
Echinacea purpurea extract intervention for counteracting neurochemical and behavioral changes induced by bifenthrin.

Front Cell Dev Biol. 2023 ;11 1288506

Fangchinoline alleviates cognitive impairments through enhancing autophagy and mitigating oxidative stress in Alzheimer's disease models.

Lilin Yi, Man Luo, Maoju Wang, Zhifang Dong, Yehong Du.

  Introduction: Alzheimer's disease (AD) is a debilitating, progressive, neurodegenerative disorder characterized by the deposition of amyloid-β (Aβ) peptides and subsequent oxidative stress, resulting in a cascade of cytotoxic effects. Fangchinoline (Fan), a bisbenzylisoquinoline alkaloid isolated from traditional Chinese herb Stephania tetrandra S. Moorec, has been reported to possess multiple potent biological activities, including anti-inflammatory and antioxidant properties. However, the potential neuroprotective efficacy of Fan against AD remains unknown. Methods: N2AAPP cells, the mouse neuroblastoma N2A cells stably transfected with human Swedish mutant APP695, were served as an in vitro AD model. A mouse model of AD was constructed by microinjection of Aβ1-42 peptides into lateral ventricle of WT mice. The neuroprotective effects of Fan on AD were investigated through a combination of Western blot analysis, immunoprecipitation and behavioral assessments. Results and discussion: It was found that Fan effectively attenuated the amyloidogenic processing of APP by augmenting autophagy and subsequently fostering lysosomal degradation of BACE1 in N2AAPP cells, as reflected by the decrease in P62 levels, concomitant with the increase in Beclin-1 and LC3-II levels. More importantly, Fan significantly ameliorated cognitive impairment in an Aβ1-42-induced mouse model of AD via the induction of autophagy and the inhibition of oxidative stress, as evidenced by an increase in antioxidants including glutathione reductase (GR), total antioxidant capacity (T-AOC), nuclear factor erythroid-2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and superoxide dismutase-1 (SOD-1) and a decrease in pro-oxidants including hydrogen peroxide (H2O2) and inducible nitric oxide synthase (i-NOS), coupled with a reduction in apoptosis marker, cleaved caspase-3. Taken together, our study demonstrate that Fan ameliorates cognitive dysfunction through promoting autophagy and mitigating oxidative stress, making it a potential therapeutic agent for AD.

Keywords:  BACE1; alzheimer’s disease; amyloid-β; autophagy; cognition; oxidative stress

DOI:  https://doi.org/10.3389/fcell.2023.1288506
Free Radic Biol Med. 2023 Dec 21. pii: S0891-5849(23)01178-4. [Epub ahead of print]212 49-64

Sulforaphane protects from kidney damage during the release of unilateral ureteral obstruction (RUUO) by activating nuclear factor erythroid 2-related factor 2 (Nrf2): Role of antioxidant, anti-inflammatory, and antiapoptotic mechanisms.

Ana Karina Aranda-Rivera, Alfredo Cruz-Gregorio, Isabel Amador-Martínez, Omar Noel Medina-Campos, Misael Garcia-Garcia, Bismarck Bernabe-Yepes, Juan Carlos León-Contreras, Rogelio Hernández-Pando, Omar Emiliano Aparicio-Trejo, Laura Gabriela Sánchez-Lozada, Edilia Tapia, José Pedraza-Chaverri.

  Releasing unilateral ureteral obstruction (RUUO) is the gold standard for decreasing renal damage induced during unilateral ureteral obstruction (UUO); however, the complete recovery after RUUO depends on factors such as the time and severity of obstruction and kidney contralateral compensatory mechanisms. Interestingly, previous studies have shown that kidney damage markers such as oxidative stress, inflammation, and apoptosis are present and even increase after removal obstruction. To date, previous therapeutic strategies have been used to potentiate the recovery of renal function after RUUO; however, the mechanisms involving renal damage reduction are poorly described and sometimes focus on the recovery of renal functionality. Furthermore, using natural antioxidants has not been completely studied in the RUUO model. In this study, we selected sulforaphane (SFN) because it activates the nuclear factor erythroid 2-related factor 2 (Nrf2), a transcription factor that induces an antioxidant response, decreasing oxidative stress and inflammation, preventing apoptosis. Thus, we pre-administrated SFN on the second day after UUO until day five, where we released the obstruction on the three days after UUO. Then, we assessed oxidative stress, inflammation, and apoptosis markers. Interestingly, we found that SFN administration in the RUUO model activated Nrf2, inducing its translocation to the nucleus to activate its target proteins. Thus, the Nrf2 activation upregulated glutathione (GSH) content and the antioxidant enzymes catalase, glutathione peroxidase (GPx), and glutathione reductase (GR), which reduced the oxidative stress markers. Moreover, the improvement of antioxidant response by SFN restored S-glutathionylation in the mitochondrial fraction. Activated Nrf2 also reduced inflammation by lessening the nucleotide-binding domain-like receptor family pyrin domain containing 3 and interleukin 1β (IL-1β) production. Reducing oxidative stress and inflammation prevented apoptosis by avoiding caspase 3 cleavage and increasing B-cell lymphoma 2 (Bcl2) levels. Taken together, the obtained results in our study showed that the upregulation of Nrf2 by SFN decreases oxidative stress, preventing inflammation and apoptosis cell death during the release of UUO.

Keywords:  Apoptosis; Inflammation; Nuclear factor erythroid 2-related factor 2 (Nrf2); Oxidative damage markers; Oxidative stress; Releasing unilateral ureteral obstruction (RUUO); Sulforaphane (SFN)

DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.12.022
Eur J Pharmacol. 2023 Dec 23. pii: S0014-2999(23)00812-9. [Epub ahead of print]964 176298

Fisetin suppresses ferroptosis through Nrf2 and attenuates intervertebral disc degeneration in rats.

Chenchao Li, Yekai Zhang, Yuxin Deng, Yu Chen, Chenyu Wu, Xiaoying Zhao, Ximiao Chen, Xiangyang Wang, Yifei Zhou, Xiaolei Zhang, Naifeng Tian.

  Low back pain, primarily caused by intervertebral disc degeneration (IVDD), lacks effective pharmacological treatments. Oxidative stress has been identified as a significant contributor to IVDD. This study aims to establish an in vitro model of IVDD induced by oxidative stress and identify potential therapeutic agents and their underlying mechanisms. By screening the natural product library, fisetin emerged as the most promising compound in suppressing cell death induced by oxidative stress in nucleus pulposus cells (NPCs). Furthermore, our investigation revealed that the cell death induced by oxidative stress was predominantly associated with ferroptosis, and fisetin demonstrated the ability to inhibit ferroptosis in NPCs. Mechanistic exploration suggested that the impact of fisetin on ferroptosis may be mediated through the Nrf2/HO-1 (Nuclear factor erythroid 2-related factor 2/heme oxygenase-1) axis. Notably, the in vivo study demonstrated that fisetin could alleviate IVDD in rats. These findings highlight fisetin as a potential therapeutic option for IVDD and implicate the involvement of the Nrf2/HO-1 pathway in its mechanism of action.

Keywords:  Fisetin; IVDD; Nrf2; Oxidative stress

DOI:  https://doi.org/10.1016/j.ejphar.2023.176298
Free Radic Res. 2023 Dec 25. 1-29

Omaveloxolone ameliorates isoproterenol-induced pathological cardiac hypertrophy in mice.

Li Xianchao, Yang Wu, Yunzhao Yang, Yaohua Wu, Xi Yu, Wenjuan Hu.

  Nuclear factor erythroid 2-related factor 2 (Nrf2) is an important transcriptional regulator that plays a protective role against various cardiovascular diseases, including atherosclerosis, myocardial infarction, cardiac hypertrophy and heart failure. Omaveloxolone is a newly discovered potent activator of Nrf2 that has a variety of cytoprotective functions. However, the potential prophylactic role and mechanisms of omaveloxolone in the process of pathological cardiac hypertrophy and heart failure are still unknown. In this study, an isoproterenol (ISO)-induced pathological cardiac hypertrophy model was established to investigate the protective effect of omaveloxolone in vivo and in vitro. Our study first confirmed that omaveloxolone administration improved ISO-induced pathological cardiac hypertrophy in mice and neonatal cardiomyocytes. Omaveloxolone administration also diminished ISO-induced cardiac oxidative stress, inflammation and cardiomyocyte apoptosis. In addition, omaveloxolone administration activated the Nrf2 signaling pathway, and Nrf2 knockdown almost completely abolished the cardioprotective effect of omaveloxolone, indicated that the cardioprotective effect of omaveloxolone was directly related to the activation of the Nrf2 signaling. In summary, our study identified that omaveloxolone may be a promising therapeutic agent to mitigate pathological cardiac hypertrophy in the future.

Keywords:  Cardiac remodeling; Isoproterenol; Nuclear factor erythroid 2-related factor 2; Omaveloxolone

DOI:  https://doi.org/10.1080/10715762.2023.2299359
Chin J Physiol. 2023 Nov-Dec;66(6):66(6): 437-445

Icariside II suppresses ferroptosis to protect against MPP+-Induced Parkinson's disease through Keap1/Nrf2/GPX4 signaling.

Wenbo Fan, Jianwu Zhou.

  Parkinson's disease (PD) is recognized as a degenerative and debilitating neurodegenerative disorder. The novel protective role of icariside II (ICS II) as a plant-derived flavonoid compound in neurodegenerative diseases has aroused much attention. Herein, the definite impacts of ICS II on the process of PD and the relevant action mechanism were studied. Human neuroblastoma SK-N-SH cells were challenged with 1-methyl-4-phenylpyridinium ion (MPP+) to construct the PD cell model. MTT assay and flow cytometry analysis, respectively, appraised cell viability and apoptosis. Caspase 3 Activity Assay examined caspase 3 activity. Corresponding kits examined oxidative stress levels. BODIPY 581/591 C11 assay evaluated lipid reactive oxygen species. Iron Assay Kit assessed iron content. Western blot tested the expression of apoptosis-, ferroptosis- and Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2)/glutathione peroxidase 4 (GPX4) signaling-associated proteins. Molecular docking verified the binding of ICS II with Keap1. The existing experimental results unveiled that ICS II elevated the viability whereas reduced the apoptosis, oxidative stress, and ferroptosis in MPP+-treated SK-N-SH cells in a concentration-dependent manner. Furthermore, ICS II declined Keap1 expression while raised Nrf2, heme oxygenase 1, and GPX4 expression. In addition, ICS II had a strong binding with Keap1 and Nrf2 inhibitor ML385 partially abolished the suppressive role of ICS II in MPP+-triggered apoptosis, oxidative stress, and ferroptosis in SK-N-SH cells. To summarize, ICS II might inhibit apoptosis, oxidative stress, and ferroptosis in the MPP+-stimulated PD cell model, which might be due to the activation of Keap1/Nrf2/GPX4 signaling.

Keywords:  Ferroptosis; Keap1/Nrf2/GPX4 signaling; Parkinson's disease; icariside II; oxidative stress

DOI:  https://doi.org/10.4103/cjop.CJOP-D-23-00107
Neurosci Lett. 2023 Dec 22. pii: S0304-3940(23)00567-0. [Epub ahead of print] 137608

Mangiferin alleviates 6-OHDA-induced Parkinson's disease by inhibiting AKR1C3 to activate Wnt signaling pathway.

Wanran Huang, Yanni Wang, Wei Huang.

  Parkinson's disease (PD) is a neurodegenerative disorder with a lack of effective treatment options. mangiferin, a bioactive compound derived from mango, has been shown to possess strong neuroprotective properties. In this study, we investigated the neuroprotective effects of mangiferin on PD and its underlying mechanisms using both in vitro and in vivo models of 6-OHDA-induced PD. Additionally, we conducted molecular docking experiments to evaluate the interaction between mangiferin and AKR1C3 and β-catenin. Our results demonstrated that treatment with mangiferin significantly attenuated 6-OHDA-induced cell damage in PC12 cells, reducing intracellular oxidative stress, improving mitochondrial membrane potential, and restoring the expression of tyrosine hydroxylase (TH), a characteristic protein of dopaminergic neurons. Furthermore, mangiferin reduced the accumulation of α-synuclein and inhibited the expression of AKR1C3, thereby activating the Wnt/β-catenin signaling pathway. In vivo studies revealed that mangiferin improved motor dysfunction in 6-OHDA-induced PD mice. Molecular docking analysis confirmed the interaction between mangiferin and AKR1C3 and β-catenin. These findings indicate that mangiferin exerts significant neuroprotective effects in 6-OHDA-induced PD by inhibiting AKR1C3 and activating the Wnt/β-catenin signaling pathway. Therefore, mangiferin may emerge as an innovative therapeutic strategy in the comprehensive treatment regimen of PD patients, providing them with better clinical outcomes and quality of life.

Keywords:  AKR1C3; Mangiferin; Parkinson's disease; Wnt/β-catenin signaling pathway

DOI:  https://doi.org/10.1016/j.neulet.2023.137608
Wound Repair Regen. 2023 Dec 27.

The flower of Abelmoschus manihot (L.) Medik exerts antioxidant effects by regulating the Nrf2 signaling pathway in scald injury.

Ying Song, Zailin Fu, Xinyi Zhu, Jun Zhang, Wenwen Bai, Biwei Song.

  Scald is a common skin injury in daily life. It is well known that skin burns are associated with inflammation and oxidative stress. In our previous study, we found that Abelmoschus Manihot (L.) medik had excellent therapeutic effects on scald-induced inflammation, but its effect on scald-induced oxidative stress was not reported. In this study, a deep second-degree scald model in mice was established, and the wound healing rate, healing time, MDA (malondialdehyde) and T-SOD (total superoxide dismutase) levels, and nuclear factor erythroid 2-related Factor 2 (Nrf2) expression in wound tissue were measured to evaluate the scald wound healing performance of extraction from Abelmoschus manihot (L.) medik(EAM). Scalding activity in mice was examined in vivo by hot-water induced finger swelling. The treatment scald activities were also examined in vivo by subjecting mice to thermal water-induced digit swelling. Additionally, the antioxidant effect of EAM on fibroblasts was also used to determine the mechanism in vitro. The results showed that EAM not only decreased the wound healing time but also effectively regulated the levels of oxidizing, MDA, and T-SOD in wound tissue. Concurrently, EAM suppressed digit swelling and hyperalgesia. Furthermore, EAM had a significant protective effect on NIH-3T3 cells after H2 O2 injury by regulating the Nrf2 signaling pathway against oxidative injury. Therefore, EAM is a promising drug for the treatment of scald-induced inflammation. This article is protected by copyright. All rights reserved.

Keywords:  Abelmoschus Manihot (L.) medik; NIH-3T3 cells; Nrf2 pathway; antioxidant; scald injury

DOI:  https://doi.org/10.1111/wrr.13146
Curr Top Med Chem. 2023 Dec 20.

Sesamol: A Phenolic Compound of Health Benefits and Therapeutic Promise in Neurodegenerative Diseases.

Hayate Javed, Mohamed Fizur Nagoor Meeran, Niraj Kumar Jha, Ghulam Md Ashraf, Shreesh Ojha.

  Sesamol, one of the key bioactive ingredients of sesame seeds (sesamum indicum L.), is responsible for many of its possible nutritional benefits. Both the Chinese and Indian medical systems have recognized the therapeutic potential of sesame seeds. It has been shown to have significant therapeutic potential against oxidative stress, inflammatory diseases, metabolic syndrome, neurodegeneration, and mental disorders. Sesamol is a benign molecule that inhibits the expression of inflammatory indicators like numerous enzymes responsible for inducing inflammation, protein kinases, cytokines, and redox status. This review summarises the potential beneficial effects of sesamol against neurological diseases including Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). Recently, sesamol has been shown to reduce amyloid peptide accumulation and attenuate cognitive deficits in AD models. Sesamol has also been demonstrated to reduce the severity of PD and HD in animal models by decreasing oxidative stress and inflammatory pathways. The mechanism of sesamol's pharmacological activities against neurodegenerative diseases will also be discussed in this review.

Keywords:  Alzheimer’s disease; Antioxidant; Huntington’s disease; Parkinson’s disease; Sesame seeds; Sesamol

DOI:  https://doi.org/10.2174/0115680266273944231213070916
Brain Res. 2023 Dec 22. pii: S0006-8993(23)00486-9. [Epub ahead of print] 148715

Acupuncture alleviates CUMS-induced depression-like behaviors of rats by regulating oxidative stress, neuroinflammation and ferroptosis.

Junliang Shen, Chongyao Hao, Siyu Liu, Wenjie Chen, Tao Tong, Yiping Chen, Muhammad Shahzad Aslam, Simin Yan, Jianguo Li, Jingyu Zeng, Yiwen Chen, Yanqin Jiang, Peng Li, Xianjun Meng.

  BACKGROUND: The treatment of depression with acupuncture has been documented. The mechanism behind acupuncture's curative and preventative effects is still unknown.METHODS: The current study examined the effects of acupuncture on depression-like behaviors in a rat model of chronic unpredictable mild stress (CUMS), while also exploring its potential mechanisms. A total of six groups of rats were randomly assigned: control, CUMS, acupuncture, fluoxetine, acupoint catgut embedding and sham acupoint catgut embedding. Fluoxetine (2.1 mg/kg) and acupoint catgut embedding were used for comparative research to acupuncture. The modelling evaluation is measured by body weight and behavior tests. Western blotting and reverse transcription-polymerase chain reaction were used to detect the proteins and mRNA expression of Silent information regulator 1 (Sirt1)/ nuclear factor-erythroid 2-related factor 2 (Nrf2)/ heme oxygenase-1 (HO-1)/ Glutathione peroxidase 4 (GPX4) pathway in the hippocampus. The expression of oxidative stress (OS)-related proteins and inflammatory cytokines in the serum was detected with ELISA. Immunofluorescence showed microglia and astrocytes activity in the hippocampus.
RESULTS: Acupuncture and fluoxetine could alleviate CUMS-induced depression-like behaviors. Acupuncture was also found to effectively reverse the levels of MDA, SOD, GSH, GSH-PX and T-AOC, IL-1β, IL-6 and TNF-α in the serum of CUMS-induced rats. Rats with CUMS showed decreased levels of Sirt1, Nrf2, HO-1 and GPX4 in the hippocampus, while acupuncture treatment could partly reverse the diminished effects. In addition, acupuncture treatment significantly reduced the activation of hippocampal microglia and astrocytes in CUMS-induced rats.
CONCLUSION: The study's findings indicate that acupuncture has the potential to mitigate depression-like behaviors in rats induced with CUMS by mitigating OS and reducing neuroinflammation.

Keywords:  Acupuncture; Depression; Ferroptosis; Hippocampus; Neuroinflammation; Oxidative stress

DOI:  https://doi.org/10.1016/j.brainres.2023.148715
Environ Toxicol Pharmacol. 2023 Dec 26. pii: S1382-6689(23)00297-1. [Epub ahead of print] 104355

Potential involvement of ferroptosis in BPA-induced neurotoxicity: An in vitro study.

Nita Jangid, Ankita Sharma, Nidhi Srivastava.

  BACKGROUND: Ferroptosis is a newly recognized cell death pathway having distinct characteristics compared to traditional cell death pathways such as apoptosis, necroptosis, or autophagy. However, the potential involvement of ferroptosis in bisphenol A (BPA)-induced neurotoxicity has not been well explored so far. In present study, we analyzed the relationship between ferroptosis and BPA-induced neurotoxicity.METHODS: In this study, a human neuroblastoma cell line, SH-SY5Y, was treated with BPA, ferrostatin-1 (FS-1, ferroptosis inhibitor) and RSL-3 (ferroptosis inducer). The cell viability was measured using MTT assay. Additionally, the levels of lipid peroxidation, total iron content, reactive oxygen species (ROS) generation, and nitrite content were measured to evaluate the key markers of ferroptosis. To further confirm the involvement of ferroptosis in BPA-induced neurotoxicity, other ferroptosis markers such as glutathione peroxidase (GPx) activity, total glutathione contents and antioxidant parameters were also evaluated.
RESULTS: The cell viability of SH-SY5Y cells was down-regulated by BPA treatment in a concentration-dependent manner, the cell viability at 0.1µM concentration was 97.63% whereas at highest BPA concentration i.e. 10µM, the cell viability was 86.05% (p < 0.0001). Also the antioxidant parameters including catalase and superoxide dismutase activity of neuronal cells were down-regulated upon BPA exposure. However, the levels of lipid peroxidation, total iron, reactive oxygen species, and nitrite contents were increased in a concentration-dependent manner which could be rescued by FS-1 and exacerbated by RSL-3. The total iron in SH-SY5Y cells at 0.1µM concentration was found to be 1.2 fold (p < 0.05) of control and at highest BPA concentration total iron was about 1.41 fold (p < 0.001) of control.
CONCLUSIONS: The present study indicated that, ferroptosis plays an important role in the progression of BPA-induced neurotoxicity, and ferroptosis may become a novel target in the treatment of various neurological disorders.

Keywords:  Bisphenol-A; Ferroptosis; Ferrostatin-1; Neurotoxicity; RSL-3

DOI:  https://doi.org/10.1016/j.etap.2023.104355
Toxicol Lett. 2023 Dec 21. pii: S0378-4274(23)01119-0. [Epub ahead of print]

Acrolein suppresses anticancer drug-induced toxicity mediated by activating claudin-1 and Nrf2 axis in a spheroid model of human lung squamous cell carcinoma cells.

Hiroaki Eguchi, Yaqing Yu, Toshiyuki Matsunaga, Yuta Yoshino, Akira Ikari.

  Tobacco smoke contains various carcinogenic ingredients such as nicotine, acrolein, and benzopyrene; however, their effects on cancer treatment are not fully understood. Claudin-1 (CLDN1), a component of tight junctions, is involved in the increased resistance to anticancer drugs. In this study, we found that acrolein increases the mRNA and protein levels of CLDN1 in RERF-LC-AI cells derived from human lung squamous cell carcinoma (SCC). Acrolein increased the p-extracellular signal-regulated kinase (ERK) 1/2 levels without affecting the p-Akt level. The acrolein-induced elevation of CLDN1 expression was attenuated by U0126, a mitogen-activated protein kinase kinas (MEK) inhibitor. These results indicate that the activation of MEK/ERK pathway is involved in the acrolein-induced elevation of CLDN1 expression. In a spheroid model, acrolein suppressed the accumulation and toxicity of doxorubicin (DXR), which were rescued by CLDN1 silencing. The acrolein-induced effects were also observed in lung SCC-derived EBC-1 and LK-2 cells. Acrolein also increased the expression level of nuclear factor erythroid 2-related factor 2 (Nrf2), a transcription factor that regulates antioxidant and detoxifying genes, which were inhibited by CLDN1 silencing. In spheroid cells, the levels of reactive oxygen species were enhanced by acrolein, which was inhibited by CLDN1 silencing. Taken together, acrolein may reduce the anticancer drug-induced toxicity in human lung SCC cells mediated by high CLDN1 expression followed by the upregulation of Nrf2 signaling pathway.

Keywords:  acrolein; claudin-1, chemoresistance; lung squamous cell carcinoma

DOI:  https://doi.org/10.1016/j.toxlet.2023.12.012
Arch Biochem Biophys. 2023 Dec 25. pii: S0003-9861(23)00377-6. [Epub ahead of print] 109878

Mechanism by which HDAC3 regulates manganese induced H3K27ac in SH-SY5Y cells and intervention by curcumin.

Ying Liu, Hua Zhao, Yue Yang, Yan Liu, Chun-Yan Ao, Jia-Min Zeng, Jia-Qi Ban, Jun Li.

  Long-term excessive exposure to manganese can impair neuronal function in the brain, but the underlying pathological mechanism remains unclear. Oxidative stress plays a central role in manganese-induced neurotoxicity. Numerous studies have established a strong link between abnormal histone acetylation levels and the onset of various diseases. Histone deacetylase inhibitors and activators, such as TSA and ITSA-1, are often used to investigate the intricate mechanisms of histone acetylation in disease. In addition, recent experiments have provided substantial evidence demonstrating that curcumin (Cur) can act as an epigenetic regulator. Given these findings, this study aims to investigate the mechanisms underlying oxidative damage in SH-SY5Y cells exposed to MnCl2·4H2O, with a particular focus on histone acetylation, and to assess the potential therapeutic efficacy of Cur. In this study, SH-SY5Y cells were exposed to manganese for 24 h, were treated with TSA or ITSA-1, and were treated with or without Cur. The results suggested that manganese exposure, which leads to increased expression of HDAC3, induced H3K27 hypoacetylation, inhibited the transcription of antioxidant genes, decreased antioxidant enzyme activities, and induced oxidative damage in cells. Pretreatment with an HDAC3 inhibitor (TSA) increased the acetylation of H3K27 and the transcription of antioxidant genes and thus slowed manganese exposure-induced cellular oxidative damage. In contrast, an HDAC3 activator (ITSA-1) partially increased manganese-induced cellular oxidative damage, while Cur prevented manganese-induced oxidative damage. In summary, these findings suggest that inhibiting H3K27ac is a possible mechanism for ameliorating manganese-induced damage to dopaminergic neurons and that Cur exerts a certain protective effect against manganese-induced damage to dopaminergic neurons.

Keywords:  Curcumin; Cytotoxicity; H3K27 acetylation; HDAC3; MnCl(2)·4H(2)O; SH-SY5Y cells

DOI:  https://doi.org/10.1016/j.abb.2023.109878
Chin J Physiol. 2023 Nov-Dec;66(6):66(6): 494-502

Ophiopogonin D improves oxidative stress and mitochondrial dysfunction in pancreatic β cells induced by hydrogen peroxide through Keap1/Nrf2/ARE pathway in diabetes mellitus.

Hongyan Zhang, Xuezhi Kang, Jun Ruan, Li Ma, Wenbo Peng, Haonan Shang, Bing Wang, Yongning Sun.

  Diabetes mellitus (DM) is a metabolic disease characterized by high blood sugar. Due to its complex pathogenesis, no effective drugs have been found so far. Ophiopogonin D (OP-D) has anti-inflammatory, antioxidant, and anticancer activities, but its role in DM has not been studied so far. Hydrogen peroxide (H2O2) was used to induce INS-1 cells. INS-1 cells induced by H2O2 were treated with OP-D, and cell apoptosis, oxidative stress damage, and related indexes of mitochondrial function were respectively detected by cell counting kit-8, flow cytometry, western blot, enzyme-linked immunosorbent assay, real-time quantitative polymerase chain reaction, JC-1 fluorescent probe, and related kits. Subsequently, molecular docking techniques were used to investigate the relationship between OP-D and Keap1 and to explore the regulation mechanism of OP-D on H2O2-induced oxidative stress and mitochondrial function in INS-1 cells. OP-D inhibited the apoptosis and oxidative stress level of H2O2-induced INS-1 cells, thereby inhibiting cell damage. Moreover, OP-D inhibited mitochondrial dysfunction in H2O2-induced INS-1 cells. At last, we found that Keap1/Nrf2 specific signaling pathway inhibitor ML385 was able to reverse the inhibitory effect of OP-D on H2O2-induced oxidative stress and mitochondrial dysfunction in INS-1 cells. In conclusion, OP-D improves oxidative stress and mitochondrial dysfunction in pancreatic β cells induced by H2O2 through activating Keap1/Nrf2/ARE pathway in DM.

Keywords:  Diabetes mellitus; Keap1/Nrf2/ARE pathway; mitochondrial dysfunction; ophiopogonin D; oxidative stress

DOI:  https://doi.org/10.4103/cjop.CJOP-D-23-00069
Adv Biol (Weinh). 2023 Dec 24. e2300416

Protective Effect of Compound Tongluo Decoction on Brain Vascular Endothelial Cells after Ischemia-Reperfusion by Inhibition of Ferroptosis Through Regulating Nrf2/ARE/SLC7A11 Signaling Pathway.

Peiyi Li, Zhongda Wang, Tong Zhao, Xiaolan Cheng, Zhennian Zhang, Jingqing Wang, Sulei Wang, Ruiou Huang, Zhen Hui.

  Cerebral infarction is one of the most common diseases for aged people. Compound Tongluo Decoction (CTLD), a classic traditional Chinese Medicine prescription, has been widely used in the treatment of ischemic cerebral infarction. Transient middle cerebral artery occlusion (tMCAO) rat model is established for the animal experiment and oxygen-glucose deprivation and reperfusion (OGD/R) human umbilical vein endothelial cells (HUVECs) model are established for the cell experiment. This also use Nrf2-/- rats to detect the role of nuclear factor erythroid 2-related factor 2 (Nrf2). Longa score, Evans blue staining, brain water content measurement, and histological observation are done. The levels of reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD), and other ferroptosis-related components are detected respectively. In the vivo experiment, CTLD relieved ischemia-reperfusion (IR) injury symptoms and attenuated IR injury in brain tissues of tMCAO rats by relieving peroxidation injury in brain tissues and inhibiting ferroptosis in tMCAO rats. Moreover, CTLD reversed OGD/R-induced oxidative damage of endothelial cells via suppressing ferroptosis. After knocking out the Nrf2 gene, the protective effect of CTLD is sharply reduced. This study put forward that CTLD can inhibit ferroptosis in I/R-injured vascular endothelium by regulating Nrf2/ARE/SLC7A11 signaling to improve the relative symptoms of rats after cerebral I/R injury, thus providing a viable treatment option for cerebrovascular disease.

Keywords:  Compound Tongluo Decoction (CTLD); Nrf2; SLC7A11; ferroptosis; ischemia-reperfusion (IR)

DOI:  https://doi.org/10.1002/adbi.202300416
Brain Res Bull. 2023 Dec 22. pii: S0361-9230(23)00285-X. [Epub ahead of print]206 110860

Neuroprotective role of FOXA1 in Parkinson's disease: Involvements of NF1 transcription activation and MAPK signaling pathway inhibition.

Yu Fan, Meili Zhao, Fei Hao, Ruyi Sun, Jinyu Chen, Jiahui Liu.

  Forkhead box A1 (FOXA1), a member of the forkhead family of transcription factors, plays a crucial role in the development of various organ systems and exhibits neuroprotective properties. This study aims to investigate the effect of FOXA1 on Parkinson's disease (PD) and unravel the underlying mechanism. Transcriptome analysis of PD was conducted using three GEO datasets to identify aberrantly expressed genes. A mouse model of PD was generated by injecting neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP), resulting in reduced FOXA1 expression. FOXA1 decline was also observed in 1-methyl-4-phenylpyridinium-treated SH-SY5Y cells. Artificial upregulation of FOXA1 improved motor abilities of mice according to rotarod and pole tests, and it mitigated tissue damage, cell loss, and neuronal damage in the mouse substantia nigra or in vitro. FOXA1 was found to bind to the neurofibromin 1 (NF1) promoter, thereby inducing its transcription and inactivating the mitogen-activated protein kinase (MAPK) signaling pathway. Further experimentation revealed that silencing NF1 in mice or SH-SY5Y cells counteracted the neuroprotective effects of FOXA1. In conclusion, this research suggests that FOXA1 activates NF1 transcription and inactivates the MAPK signaling pathway, ultimately ameliorating neuronal damage and motor disability in PD. The findings may offer novel ideas in the field of PD management.

Keywords:  Forkhead box A1; MAPK signaling pathway; Neurofibromin 1; Neuroprotection; Parkinson's disease

DOI:  https://doi.org/10.1016/j.brainresbull.2023.110860
J Ayurveda Integr Med. 2023 Dec 24. pii: S0975-9476(23)00171-7. [Epub ahead of print]15(1): 100854

Neuroprotective effects of nanogold-based Ayurveda medicine Suvarna Bhasma against rotenone-induced Parkinson's-like model.

Snehasis Biswas, Mukesh Chawda, Ramacharya Gudi, Jayesh Bellare.

  BACKGROUND: Neurodegenerative diseases have been one of the major concerns for human health. Genetic and environmental factors are believed to be responsible for neuronal diseases such as Parkinson's disease, Alzheimer's disease, and Huntington's disease. It is difficult to restore normal nervous function after neurodegeneration; hence, prevention could be the best strategy against these diseases. Ayurved medicines such as Suvarna Bhasma (SB) have enormous potential to treat these neurological diseases.AIM: The aim of this study is to examine the protective effect of SB against rotenone-induced Parkinson's-like model in zebrafish.
MATERIALS AND METHODS: In this study, we induced Parkinson's-like disease model in zebrafish by inducing it with rotenone (7 μg/L). We examined the behavioural, proteomics and dopamine alterations of rotenone induced zebrafish of SB pre-treated group as compared to the control group.
RESULTS: The behavioural experiments showed that due to rotenone exposure, Parkinson's-like behavioural abnormality was induced in zebrafish. However, because of SB treatment, this behavioural abnormality was reduced. The proteomics study of zebrafish brains clearly showed that the SB-treated group was not significantly affected due to rotenone exposure. However, in the SB non-treated group, expression of nine proteins that are linked to Parkinson's disease (gene name: sncgb, ywhae1, ywhah, uchl1, ywhaba, psma6a, ywhabl, ywhaqb, and ywhabb) were differentially expressed after rotenone exposure. Finally, prevention of dopamine alteration in SB-treated fish brains confirmed the protective action of SB against rotenone-induced Parkinson's-like model in zebrafish.
CONCLUSIONS: This study finds that Suvarna Bhasma has neuroprotective effects against Parkinson's-like disease model.

Keywords:  Dopamine; Neuroprotection; Parkinson's; Rotenone; Suvarna bhasma

DOI:  https://doi.org/10.1016/j.jaim.2023.100854
Biomed Pharmacother. 2023 Dec 26. pii: S0753-3322(23)01865-6. [Epub ahead of print]170 116067

Diosmetin alleviates neuropathic pain by regulating the Keap1/Nrf2/NF-κB signaling pathway.

Lin Zhao, Xueshu Tao, Qian Wang, Xue Yu, Daosong Dong.

  BACKGROUND: Neuropathic pain, a chronic condition with a high incidence, imposes psychological burdens on both patients and society. It is urgent to improve pain management and develop new analgesic drugs. Traditional Chinese medicine has gained popularity as a method for pain relief. Diosmetin (Dio) is mainly found in Chinese herbal medicines with effective antioxidant, anti-cancer, and anti-inflammatory properties. There are few known mechanisms underlying the effectiveness of Dio in treating neuropathic pain. However, the complete understanding of its therapeutic effect is missing.PURPOSE: This study aimed to evaluate Dio's therapeutic effects on neuropathic pain models and determine its possible mechanism of action. We hypothesized that Dio may activate antioxidants and reduce inflammation, inhibit the activation of Kelch-like epichlorohydrin-associated protein 1 (Keap1) and nuclear factor-k-gene binding (NF-κB), promote the metastasis of nuclear factor erythroid 2-related factor 2 (Nrf2) and the expression of heme oxygenase 1 (HO-1), thus alleviating the neuropathic pain caused by spinal nerve ligation.
METHODS: Chronic nociceptive pain mouse models were established in vivo by L4 spinal nerve ligation (SNL). Different dosages of Dio (10, 50, 100 mg/kg) were intragastrically administered daily from the third day after the establishment of the SNL model. Allodynia, caused by mechanical stimuli, and hyperalgesia, caused by heat, were assessed using the paw withdrawal response frequency (PWF) and paw withdrawal latency (PWL), respectively. Cold allodynia were assessd by acetone test. RT-PCR was used to detect the content of interleukin-(IL)- 1β, IL-6 and tumor necrosis factor (TNF)-a. Immunofluorescence and western blotting were employed to assess the expression levels of Glial fibrillary acidic protein (GFAP), ionized calcium-binding adapter molecule (Iba1), Keap1, Nrf2, HO-1, and NF-κB p-p65 protein.
RESULTS: Dio administration relieved SNL-induced transient mechanical and thermal allodynia in mice. The protective effect of Dio in the SNL model was associated with its anti-inflammatory and anti-glial responses in the spinal cord. Dio inhibited both inflammatory factors and macrophage activation in the DRG. Furthermore, Dio regulated the Keap1/Nrf2/NF-κB signaling pathway. HO-1 and Nrf2 were upregulated following Dio administration, which also decreased the levels of Keap1 and NF-κB p65 protein.
CONCLUSION: Mice with SNL-induced neuropathic pain were therapeutically treated with Dio. Dio may protect against pain by inhibiting inflammatory responses and improved Keap1/Nrf2/NF-κB pathway. These results highlight the potential therapeutic effect of Dio for the development of new analgesic drugs.

Keywords:  Diosmetin; Keap1; NF-κB; Neuropathic pain; Nrf2

DOI:  https://doi.org/10.1016/j.biopha.2023.116067
J Hazard Mater. 2023 Dec 22. pii: S0304-3894(23)02591-8. [Epub ahead of print]465 133307

Selenomethionine alleviates decabromodiphenyl ether-induced oxidative stress and ferroptosis via the NRF2/GPX4 pathway in the chicken brain.

Bowen Dong, Yangyang Jiang, Bendong Shi, Zhuoqi Zhang, Ziwei Zhang.

  Decabromodiphenyl ether (BDE209) is a toxic environmental pollutant that can cause neurotoxicity, behavioral abnormalities, and cognitive impairment in animals. However, the specific mechanisms of BDE209-induced neurological injury and effective preventative and therapeutic interventions are lacking. Even though selenomethionine (Se-Met) has a significant detoxification effect and protects the nervous system, it remains unclear whether Se-Met can counteract the toxic effects of BDE209. For the in vivo test, we randomly divided 60 1-week-old hy-line white variety chicks into the Con, BDE209, Se-Met, and BDE209 +Se-Met groups. In vitro experiments were performed, exposing chick embryo brain neurons to BDE209, Se-Met, N-Acetylcysteine (NAC, a ROS inhibitor), and RSL3 (a GPX4 inhibitor). We demonstrated that BDE209 induced oxidative stress and ferroptosis in the chicken brain, which mainly manifested as mitochondrial atrophy, cristae breakage, increased Fe2+ and MDA content, decreased antioxidant enzyme activity, and the inhibition of the NRF2/GPX4 signaling pathway in the brain neurons. However, Se-Met supplementation reversed these changes by activating the NRF2/GPX4 pathway, reducing mitochondrial damage, enhancing antioxidant enzyme activity, and alleviating ferroptosis. This study provides insight into the mechanism of BDE209-related neurotoxicity and suggests Se-Met as an effective preventative and control measure against BDE209 poisoning.

Keywords:  Chicken brain; Decabromodiphenyl ether; Ferroptosis; NRF2/GPX4; Oxidative stress; Selenomethionine

DOI:  https://doi.org/10.1016/j.jhazmat.2023.133307
Curr Pharm Des. 2023 Dec 26.

Understanding the Therapeutic Approaches for Neuroprotection.

Nazrana Payal, Lalit Sharma, Aditi Sharma, Yahya Hosan Hobanii, Mashael Ahmed Hakami, Nemat Ali, Summya Rashid, Monika Sachdeva, Monica Gulati, Shivam Yadav, Sridevi Chigurupati, Abhiav Singh, Haroon Khan, Tapan Behl.

  The term "neurodegenerative disorders" refers to a group of illnesses in which deterioration of nerve structure and function is a prominent feature. Cognitive capacities such as memory and decision-making deteriorate as a result of neuronal damage. The primary difficulty that remains is safeguarding neurons since they do not proliferate or regenerate spontaneously and are therefore not substituted by the body after they have been damaged. Millions of individuals throughout the world suffer from neurodegenerative diseases. Various pathways lead to neurodegeneration, including endoplasmic reticulum stress, calcium ion overload, mitochondrial dysfunction, reactive oxygen species generation, and apoptosis. Although different treatments and therapies are available for neuroprotection after a brain injury or damage, the obstacles are inextricably connected. Several studies have revealed the pathogenic effects of hypothermia, different breathed gases, stem cell treatments, mitochondrial transplantation, multi-pharmacological therapy, and other therapies that have improved neurological recovery and survival outcomes after brain damage. The present review highlights the use of therapeutic approaches that can be targeted to develop and understand significant therapies for treating neurodegenerative diseases.

Keywords:  Neurodegenerative diseases; brain injury/damage; drug targeting; neurodegeneration; oxidative stress; therapeutics.

DOI:  https://doi.org/10.2174/0113816128275761231103102125
Nutr Neurosci. 2023 Dec 27. 1-17

Does hazelnut consumption affect brain health and function against neurodegenerative diseases?

Shadi Talebi, Fariba Khodagholi, Zahra Bahaeddin, Mitra Ansari Dezfouli, Arman Zeinaddini-Meymand, Samuel Berchi Kankam, Forough Foolad, Fatemeh Alijaniha, Fatemeh Fayazi Piranghar.

  INTRODUCTION: A healthy daily diet and consuming certain nutrients, such as polyphenols, vitamins, and unsaturated fatty acids, may help neuronal health maintenance. Polyphenolic chemicals, which have antioxidant and anti-inflammatory properties, are involved in the neuroprotective pathway. Because of their nutritional value, nuts have been shown in recent research to be helpful in neuroprotection.OBJECTIVE: Hazelnut is often consumed worldwide in various items, including processed foods, particularly in bakery, chocolate, and confectionery products. This nut is an excellent source of vitamins, amino acids, tocopherols, phytosterols, polyphenols, minerals, and unsaturated fatty acids. Consuming hazelnut may attenuate the risk of neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, and Huntington's disease due to its anti-inflammatory and anti-oxidant qualities.
RESULTS: Many documents introduce hazelnut as an excellent choice to provide neuroprotection against neurodegenerative disorders and there is some direct proof of its neuroprotective effects.
DISCUSSION: So hazelnut consumption in daily diet may reduce neurodegenerative disease risk and be advantageous in reducing the imposed costs of dealing with neurodegenerative diseases.

Keywords:  Alzheimer’s disease; Hazelnut; Huntington’s disease; Parkinson’s disease; amyotrophic lateral sclerosis; anti-inflammatory; multiple sclerosis; neuroprotection

DOI:  https://doi.org/10.1080/1028415X.2023.2296164
Biomol Ther (Seoul). 2024 Jan 01. 32(1): 84-93

Rosmarinic Acid Inhibits Ultraviolet B-Mediated Oxidative Damage via the AKT/ERK-NRF2-GSH Pathway In Vitro and In Vivo.

Mei Jing Piao, Pattage Madushan Dilhara Jayatissa Fernando, Kyoung Ah Kang, Pincha Devage Sameera Madushan Fernando, Herath Mudiyanselage Udari Lakmini Herath, Young Ree Kim, Jin Won Hyun.

  Rosmarinic acid (RA) is a phenolic ester that protects human keratinocytes against oxidative damage induced by ultraviolet B (UVB) exposure, however, the mechanisms underlying its effects remain unclear. This study aimed to elucidate the cell signaling mechanisms that regulate the antioxidant activity of RA and confirm its cyto-protective role. To explore the signaling mechanisms, we used the human keratinocyte cell line HaCaT and SKH1 hairless mouse skin. RA enhanced glutamate-cysteine ligase catalytic subunit (GCLC) and glutathione synthetase (GSS) expression in HaCaT cells in a dose- and time-dependent manner. Moreover, RA induced nuclear factor erythroid-2-related factor 2 (NRF2) nuclear translocation and activated the signaling kinases protein kinase B (AKT) and extracellular signal-regulated kinase (ERK). Treatment with the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002, the ERK inhibitor U0126, and small interfering RNA (siRNA) gene silencing suppressed RA-enhanced GCLC, GSS, and NRF2 expression, respectively. Cell viability tests showed that RA significantly prevented UVB-induced cell viability decrease, whereas the glutathione (GSH) inhibitors buthionine sulfoximine, LY294002, and U0126 significantly reduced this effect. Moreover, RA protected against DNA damage and protein carbonylation, lipid peroxidation, and apoptosis caused by UVB-induced oxidative stress in a concentration-dependent manner in SKH1 hairless mouse skin tissues. These results suggest that RA protects against UVB-induced oxidative damage by activating AKT and ERK signaling to regulate NRF2 signaling and enhance GSH biosynthesis. Thus, RA treatment may be a promising approach to protect the skin from UVB-induced oxidative damage.

Keywords:  Glutathione; NRF2; Oxidative damage; Rosmarinic acid (RA)

DOI:  https://doi.org/10.4062/biomolther.2023.179
J Nutr Biochem. 2023 Dec 25. pii: S0955-2863(23)00289-9. [Epub ahead of print] 109556

Kaempferol improves Pb-induced cognitive impairments via inhibiting autophagy.

Mengmeng Wang, Yanzhou Xia, Shu Ai, Xiaozhen Gu, Hui-Li Wang.

  Kaempferol (Kam) is a flavonoid antioxidant found in fruits and vegetables, which were discovered as neuroprotective antioxidants. Lead (Pb), an environmental pollution, could induce learning and memory deficits. Nevertheless, little is known about the mechanisms underlying Kam actions in Pb-induced learning and memory deficits. In this study, we investigated the effects of Kam on Pb-induced cognitive deficits. Pb-exposed rats were treated with 50 mg/kg Kam from postnatal day (PND) 30 to PND 60. Then, Y-maze and morris water maze have been used to detect the spatial memory in all groups of rats. Hematoxylin and eosin (HE) staining and nissl staining were used to analyze the neuronal structure damages. The results found Kam treatment improved the learning and memory ability and alleviated hippocampal neuronal pathological damages. Besides, Kam could significantly reverse the synaptic transmission related protein expression including PSD95 and NMDAR2B. Further research found that Kam downregulated autophagy markers, P62, ATG5, Beclin1, and LC3-II. Furthermore, 3-MA, autophagy inhibitor, increased the levels of NMDAR2B and PSD95 in Pb-induced PC12 cells, indicating Kam alleviated Pb-induced neurotoxicity through inhibiting autophagy activation. Our results showed that Kam could ameliorate Pb-induced cognitive impairments and neuronal damages by decreasing Pb-induced excess autophagy accumulation.

Keywords:  Kaempferol; Pb; autophagy, cognitive impairments

DOI:  https://doi.org/10.1016/j.jnutbio.2023.109556
Iran J Pharm Res. 2023 Jan-Dec;22(1):22(1): e135315

The Effect of Physical Exercise Pretreatment on Spatial Memory and Learning and Function of Mitochondria in the Brain in Type 2 Diabetic Rats.

Homayoon Behmadi, Fatemeh Samiei, Marzieh Noruzi, Zahra Halvaei Khankahdani, Shokoufeh Hassani, Maryam Mehdizadeh, Jalal Pourahmad, Ghorban Taghizadeh, Mohammad Sharifzadeh.

  Background: The prevalence of type 2 diabetes mellitus (T2DM) is increasing worldwide, and this issue is one of the major concerns in the pending years. T2DM causes numerous complications, including cognition, learning, and memory impairments. The positive effect of physical exercise as a popular approach has been shown in many chronic diseases. Further, the improvement effects of exercise on cognition and memory impairment have been noticed.Objectives: This study examines the possible preventative effects of physical exercise on spatial memory attenuation and brain mitochondrial dysfunction caused by T2DM.
Methods: Male Wistar rats received treadmill exercise (30 min per day, five days per week for two or four weeks). Then, T2DM was induced by a high-fat diet and an injection of streptozotocin (30 mg/kg). Spatial learning and memory were assessed by the Morris water maze test. Further, brain mitochondrial function, including reactive oxygen species (ROS) generation, mitochondrial membrane potential (MMP), mitochondrial swelling, outer membrane damage, cytochrome c release, and ADP/ATP ratio, were measured.
Results: Impaired spatial memory in T2DM rats was observed. Furthermore, brain mitochondrial dysfunction was demonstrated proved by increased ROS generation, MMP collapse, mitochondrial swelling, outer membrane damage, cytochrome c release, and ADP/ATP ratio. Conversely, physical exercise, before diabetes onset, significantly ameliorated spatial memory impairment and brain mitochondrial dysfunction.
Conclusions: This study reveals that physical exercise could prevent diabetes-induced spatial memory impairment. Moreover, it could ameliorate brain mitochondrial dysfunction as one of the possible underlying mechanisms of spatial memory impairment in T2DM.

Keywords:  Exercise; Mitochondria; Spatial Memory; Streptozotocin; Type 2 Diabetes

DOI:  https://doi.org/10.5812/ijpr-135315
Transl Stroke Res. 2023 Dec 26.

Inhibition of USP30 Promotes Mitophagy by Regulating Ubiquitination of MFN2 by Parkin to Attenuate Early Brain Injury After SAH.

Yang Liu, Chenbei Yao, Bin Sheng, Simin Zhi, Xiangxin Chen, Pengfei Ding, Jiatong Zhang, Zhennan Tao, Wei Li, Zong Zhuang, Jiannan Mao, Zheng Peng, Huiying Yan, Wei Jin.

  Subarachnoid hemorrhage (SAH) is a type of stroke with a high disability and mortality rate. Apoptosis caused by massive damage to mitochondria in neuron cells and inflammatory responses caused by high extracellular ATP lead to poor outcomes. USP30 is a deubiquitinating enzyme that inhibits mitophagy, resulting in a failure to remove damaged mitochondria in a timely manner after SAH; nevertheless, the pathway through which USP30 inhibits mitophagy is unknown. This study evaluated the neuroprotective role and possible molecular basis by which inhibiting USP30 to attenuate SAH-induced EBI by promoting neuronal mitophagy. We used an in vitro model of hemoglobin exposure and an in vivo model of intravascular perforation. Increased expression of USP30 was found after SAH in vivo and in vitro, and USP30 inhibition expression in SAH mice treated with MF094 resulted in significant improvement of neurological injury and inflammatory response and mediated good outcomes, suggesting a neuroprotective effect of USP30 inhibition. In cultured neurons, inhibition of USP30 promoted ubiquitination modification of mitochondrial fusion protein 2 (MFN2) by E3 ubiquitin ligase (Parkin), separating damaged mitochondria from the healthy mitochondrial network and prompting mitophagy, causing early clearance of damaged intracellular mitochondria, and reducing the onset of apoptosis. The high extracellular ATP environment was meliorated, reversing the conversion of microglia to a pro-inflammatory phenotype and reducing inflammatory injury. USP30 inhibition had no autophagy-promoting effect on structurally and functionally sound mitochondria and did not inhibit normal intracellular ATP production. The findings suggest that USP30 inhibition has a neuroprotective effect after SAH by promoting early mitophagy after SAH to clear damaged mitochondria.

Keywords:  MF094; Mitochondrial fusion protein 2 (MFN2); Mitophagy; Subarachnoid hemorrhage (SAH); Ubiquitin-specific protease 30 (USP30); Ubiquitination

DOI:  https://doi.org/10.1007/s12975-023-01228-3
Biol Trace Elem Res. 2023 Dec 26.

Evaluating the Protective Effects of Melatonin Against Chronic Iron Administration in Male Wistar Rats: a Comparative Analysis of Affective, Cognitive, and Oxidative Stress with EDTA Chelator.

Ayoub Rezqaoui, Soufiane Boumlah, Aboubaker El Hessni, Mohamed Yassine El Brouzi, Abdelghafour El Hamzaoui, Laila Ibouzine-Dine, Samir Benkirane, Manal Adnani, Abdelhalem Mesfioui.

  Iron is the dominant metal in the brain and is distributed widely. However, it can lead to various neuropathological and neurobehavioral abnormalities as well as oxidative stress. On the other hand, melatonin, a pineal hormone, is known for its neuroprotective properties, as well as its ability to act as a natural chelator against oxidative stress. It has also been used as an antidepressant and anxiolytic. The study investigated the potential of melatonin and EDTA treatment to prevent anxiety, depressive behavior, and memory impairment in male rats induced by chronic iron administration, and its connection to oxidative stress regulation in the hippocampus and prefrontal cortex. The rats were divided into six groups and intraperitoneally injected for 8 weeks with NaCl solution (control), iron sulfate (1 mg/kg), melatonin (4 mg/kg), EDTA (4 mg/kg), 1 mg/kg of iron + 4 mg/kg of melatonin, or 1 mg/kg of iron + 4 mg/kg of EDTA. In this study, we performed a neurobehavioral assessment and biochemical determinations of oxidative stress levels in the hippocampus and prefrontal cortex of each animal. The results indicate that chronic exposure to iron sulfate induced anxiety-like depressive behavior, and cognitive impairment also increased the levels of lipid peroxidation and nitric oxide, and reduced the activity of catalase in the hippocampus and prefrontal cortex in male Wistar rats, suggesting the induction of oxidative stress. In contrast, these alterations were reversed by melatonin better than EDTA. The results of this study show that melatonin protects against the neurobehavioral changes caused by iron, which may be associated with decreasing oxidative stress in the hippocampus and prefrontal cortex.

Keywords:  Anxiety-like; Depression-like; Iron; Melatonin; Memory; Oxidative stress

DOI:  https://doi.org/10.1007/s12011-023-04006-2
IBRO Neurosci Rep. 2024 Jun;16 1-7

Anethole via increase in the gene expression of PI3K/AKT/mTOR mitigates the autistic-like behaviors induced by maternal separation stress in mice.

Yasaman Yadollahi-Farsani, Vahid Reisi Vanani, Zahra Lorigooini, Anahita Farahzad, Hossein Amini-Khoei.

  Autism spectrum disorder (ASD) is a neurodegenerative disease with increasing incidence in the world. The maternal separation (MS) stress at early life with its own neuroendocrine and neurostructural changes can provide the basis for development of ASD. Previously it has been reported neuroprotective characteristics for anethole. The PI3K/AKT/mTOR signaling pathway has pivotal role in the function of central nervous system (CNS). This study aimed to evaluate the possible effects of anethole on the autistic-like behaviors in the maternally separated (MS) mice focusing on the potential role of the PI3K/AKT/mTOR pathway. Forty male Naval Medical Research Institute (NMRI) mice were assigned to five groups (n = 8) comprising a control group (treated with normal saline) and four groups subjected to MS and treated with normal saline and or anethole at doses of 31.25, 62.5 and 125 mg/kg, respectively. All gents were administrated via intraperitoneal (i.p.) route for 14 constant days. Behavioral tests were conducted, including the three-chamber test, shuttle box and resident-intruder test. The gene expression of the PI3K, AKT and mTOR assessed in the hippocampus by qRT-PCR. Findings indicated that MS is associated with autistic-like behaviors. Anethole increased the sociability and social preference indexes in the three-chamber test, increased duration of secondary latency in the shuttle box test and decreased aggressive behaviors in the resident-intruder test. Also, anethole increased the gene expression of PI3K, AKT and mTOR in the hippocampus of MS mice. We concluded that anethole through increase in the gene expression of PI3K/ AKT/mTOR mitigated autistic-like behaviors induced by MS in mice.

Keywords:  Anethole; Autism; Maternal separation; PI3K/ AKT/mTOR

DOI:  https://doi.org/10.1016/j.ibneur.2023.11.009
Mult Scler Relat Disord. 2023 Dec 22. pii: S2211-0348(23)00900-8. [Epub ahead of print]82 105401

The protective effects of hesperidin as an antioxidant against quinolinic acid-induced toxicity on oligodendroglia cells: An in vitro study.

Hamed Amiri, Hossein Javid, Seyedeh Fatemeh Hashemi, Amirali Reihani, Ali Esparham, Seyed Isaac Hashemy.

  INTRODUCTION: Multiple sclerosis (MS) is a complex central nervous system disorder, marked by neurodegenerative and inflammatory processes, where overproduction of reactive oxygen species (ROS) is a key factor in demyelination and neurodegeneration. The current study aims to investigate the effect of hesperidin and Quinolinic acid (QA) on ROS and antioxidant levels, and cell viability of OLN-93 cells.METHODS: OLN-93 cell lines were treated with hesperidin and QA. OLN-93 cells were cultured in Dulbecco's modified Eagle's medium under controlled conditions. Cell viability assays were performed using resazurin to assess the toxicity of hesperidin and QA. Additionally, ROS levels were measured using DCFDA, and malondialdehyde (MDA) levels were determined to evaluate oxidative stress. Superoxide dismutase (SOD) activity and cell viability were assessed by trypan blue staining after exposure to hesperidin and QA.
RESULTS: The results of the current study showed that co-administration of 8 mM QA with 50, 100, and 200 μM hesperidin significantly reduced both ROS and MDA levels, demonstrating a substantial attenuation in comparison to the elevated ROS and MDA levels induced by 8 mM QA (p-value < 0.01). Furthermore, 8 mM QA + 50, 100, and 200 μM hesperidin significantly increased SOD levels compared with QA alone (p-value < 0.01). In addition, treatment of OLN cells with 8 mM QA + 50, 100, and 200 μM hesperidin led to higher cell viability compared to QA alone (p value <0.0001).
CONCLUSION: The current study demonstrated the antioxidant effect of hesperidin on OLN-93 cells suggesting new insights into the clinical application of hesperidin as an effective treatment for patients with MS. Future in vivo studies, focusing on cellular mechanisms are recommended.

Keywords:  Antioxidant; Hesperidin; Multiple sclerosis; OLN-93

DOI:  https://doi.org/10.1016/j.msard.2023.105401
Adv Sci (Weinh). 2023 Dec 27. e2305614

TREM2-IGF1 Mediated Glucometabolic Enhancement Underlies Microglial Neuroprotective Properties During Ischemic Stroke.

Sheng Yang, Chuan Qin, Man Chen, Yun-Hui Chu, Yue Tang, Luo-Qi Zhou, Hang Zhang, Ming-Hao Dong, Xiao-Wei Pang, Lian Chen, Long-Jun Wu, Dai-Shi Tian, Wei Wang.

  Microglia, the major resident immune cells in the central nervous system, serve as the frontline soldiers against cerebral ischemic injuries, possibly along with metabolic alterations. However, signaling pathways involved in the regulation of microglial immunometabolism in ischemic stroke remain to be further elucidated. In this study, using single-nuclei RNA sequencing, a microglial subcluster up-regulated in ischemic brain tissues is identified, with high expression of Igf1 and Trem2, neuroprotective transcriptional signature and enhanced oxidative phosphorylation. Microglial depletion by PLX3397 exacerbates ischemic brain damage, which is reversed by repopulating the microglia with high Igf1 and Trem2 phenotype. Mechanistically, Igf1 serves as one of the major down-stream molecules of Trem2, and Trem2-Igf1 signaling axis regulates microglial functional and metabolic profiles, exerting neuroprotective effects on ischemic stroke. Overexpression of Igf1 and supplementation of cyclocreatine restore microglial glucometabolic levels and cellular functions even in the absence of Trem2. These findings suggest that Trem2-Igf1 signaling axis reprograms microglial immunometabolic profiles and shifts microglia toward a neuroprotective phenotype, which has promising therapeutic potential in treating ischemic stroke.

Keywords:  Trem2-Igf1 signaling pathway; ischemic stroke; microglia; oxidative phosphorylation

DOI:  https://doi.org/10.1002/advs.202305614
Toxicol Res (Camb). 2023 Dec;12(6): 1063-1076

The elderberry diet protection against intrahippocampal Aβ-induced memory dysfunction; the abrogated apoptosis and neuroinflammation.

Hadiseh Jahanbakhshi, Meysam Hassani Moghaddam, Mojtaba Sani, Siavash Parvardeh, Mahdi Eskandarian Boroujeni, Kimia Vakili, Mobina Fathi, Helia Azimi, Maryam Mehranpour, Mohammad-Amin Abdollahifar, Shiva Ghafghazi, Maryam Sadidi, Abbas Aliaghaei, Amir-Hossein Bayat, Ali Asghar Peyvandi.

  This study evaluates whether elderberry (EB) effectively decreases the inflammation and oxidative stress in the brain cells to reduce Aβ toxicity. In the Aβ + EB group, EB powder was added to rats' routine diet for eight consecutive weeks. Then, spatial memory, working memory, and long-term memory, were measured using the Morris water maze, T-maze, and passive avoidance test. Also, in this investigation immunohistopathology, distribution of hippocampal cells, and gene expression was carried out. Voronoi tessellation method was used to estimate the spatial distribution of the cells in the hippocampus. In addition to improving the memory functions of rats with Aβ toxicity, a reduction in astrogliosis and astrocytes process length and the number of branches and intersections distal to the soma was observed in their hippocampus compared to the control group. Further analysis indicated that the EB diet decreased the caspase-3 expression in the hippocampus of rats with Aβ toxicity. Also, EB protected hippocampal pyramidal neurons against Aβ toxicity and improved the spatial distribution of the hippocampal neurons. Moreover, EB decreased the expression of inflammatory and apoptotic genes. Overall, our study suggest that EB can be considered a potent modifier of astrocytes' reactivation and inflammatory responses.

Keywords:  apoptosis; astrocyte; hippocampus; inflammation; oxidative stress; pyramidal neurons

DOI:  https://doi.org/10.1093/toxres/tfad097
Metab Brain Dis. 2023 Dec 27.

Echinacea purpurea extract intervention for counteracting neurochemical and behavioral changes induced by bifenthrin.

Khaled G Abdel-Wahhab, Rehab S Sayed, Doaa G El-Sahra, Laila K Hassan, Ghada M Elqattan, Fathia A Mannaa.

  This study was conducted to elucidate the possible protective efficiency of Echinacea purpurea hydroethanolic extract (EchEE) against bifenthrin (BIF)-induced neuro-chemical and behavioral changes in rats. Total phenolics content, reducing power and radical scavenging activity of EchEE were estimated. Four groups of adult male albino rats were used (10 rats each) as follows: 1) Control healthy rats ingested with placebo, 2) Healthy rats orally received EchEE (465 mg/kg/day), 3) Rats intoxicated with BIF (7mg/kg/day) dissolved in olive oil, and 4) Rats co-treated with EchEE (465 mg/kg/day) besides to BIF (7mg/kg/day) intoxication. After 30 days, some neuro-chemical and behavioral tests were assessed. The behavioral tests revealed that rats received BIF exhibited exploratory behavior and spatial learning impairments, memory and locomotion dysfunction, and enhanced anxiety level. Biochemical findings revealed that BIF induced-oxidative stress in the cortex and hippocampus; this was appeared from the significant rise in malondialdehyde (MDA) and nitric oxide (NO) levels, coupled with decreased catalase (CAT), superoxide dismutase (SOD), paraoxonase-1 (PON-1) activities, and reduced glutathione (GSH) level in both brain areas. Also, BIF induced a significant increase caspas-3, tumor necrosis factor alpha (TNF), and interleukin-1beta (IL-1ß) in both areas; dopamine and serotonin levels, and ACh-ase activity were markedly decreased in both areas. Interestingly, treatment of rats with EchEE in combination with BIF resulted in a significant decrease in oxidative stress damage, and modulation of the apoptotic and pro-inflammatory markers. Also, EchEE markedly improved behavioral activities and neurotransmitters level that were impaired by BIF. In conclusion, the present study clearly indicated that EchEE can attenuate brain dysfunction induced by pesticides exposure through preventing the oxidative stress. This may be attributed to its high antioxidant component.

Keywords:  Behavior; Brain; Herbal extract; Neurotoxicity; Oxidative stress; Rats

DOI:  https://doi.org/10.1007/s11011-023-01303-6