bims-nurfan 2023-11-26 papers

bims-nurfan

Biomed News

on NRF2 and Neurological Diseases

Issue of 2023‒11‒26
twenty-two papers selected by
Arif Kamil Salihoğlu, Karadeniz Technical University

Demethylcalabaxanthone from Garcinia mangostana Exerts Antioxidant Effects through the Activation of the Nrf2 Pathway as Assessed via Molecular Docking and Biological Evaluation.
Sedanolide Activates KEAP1-NRF2 Pathway and Ameliorates Hydrogen Peroxide-Induced Apoptotic Cell Death.
Parthenolide alleviates cognitive dysfunction and neurotoxicity via regulation of AMPK/GSK3β(Ser9)/Nrf2 signaling pathway.
Tetramethylpyrazine nitrone exerts neuroprotection via activation of PGC-1α/Nrf2 pathway in Parkinson's disease models.
Astrocytic Nrf2 Mediates the Neuroprotective and Anti-Inflammatory Effects of Nootkatone in an MPTP-Induced Parkinson's Disease Mouse Model.
The MT1 receptor as the target of ramelteon neuroprotection in ischemic stroke.
Metal profiling in coronary ischemia-reperfusion injury: Implications for KEAP1/NRF2 regulated redox signaling.
Histone deacetylase 3 inhibition alleviates 2,4-dinitrochlorobenzene-induced atopic dermatitis via epigenetically upregulating Nrf2/HO-1 signaling pathway.
Unleashing the Potential of Nrf2: A Novel Therapeutic Target for Pulmonary Vascular Remodeling.
Anticarcinogenic Potency of EF24: An Overview of Its Pharmacokinetics, Efficacy, Mechanism of Action, and Nanoformulation for Drug Delivery.
Adaptive changes in tumor cells in response to reductive stress.
Melatonin alleviates particulate matter-induced liver fibrosis by inhibiting ROS-mediated mitophagy and inflammation via Nrf2 activation.
Oxyberberine an Oxoderivative of Berberine Confers Neuroprotective Effects in Controlled-Cortical Impact Mouse Model of Traumatic Brain Injury.
Thiosulfate sulfurtransferase deficiency promotes oxidative distress and aberrant NRF2 function in the brain.
Current advancement in the preclinical models used for the assessment of diabetic neuropathy.
Celastrol Alleviates Mitochondrial Oxidative Stress and Brain Injury after Intracerebral Hemorrhage by Promoting OPA1-Dependent Mitochondrial Fusion.
Icaritin greatly attenuates β-amyloid-induced toxicity in vivo.
Reactive Oxygen Species Mediate Transcriptional Responses to Dopamine and Cocaine in Human Cerebral Organoids.
Knockdown of Smox protects the integrity of the blood-brain barrier through antioxidant effect and Nrf2 pathway activation in stroke.
Nrf2 attenuates oxidative stress to mediate the protective effect of ciprofol against cerebral ischemia-reperfusion injury.
Glucose Transport and Utilization in the Hippocampus: From Neurophysiology to Diabetes-Related Development of Dementia.
Antioxidant and Hypoglycemic Potential of Essential Oils in Diabetes Mellitus and Its Complications.

Antioxidants (Basel). 2023 Nov 07. pii: 1980. [Epub ahead of print]12(11):

Demethylcalabaxanthone from Garcinia mangostana Exerts Antioxidant Effects through the Activation of the Nrf2 Pathway as Assessed via Molecular Docking and Biological Evaluation.

Simona De Vita, Milena Masullo, Sabrina Grambone, Paloma Bermejo Bescós, Sonia Piacente, Giuseppe Bifulco.

  Nuclear factor erythroid 2-related factor 2 (Nrf2) pathway activation promotes the expression of antioxidant enzymes in response to rising oxidative stress, resulting in reactive oxygen species (ROS) detoxification and playing a central role in the maintenance of intracellular redox homeostasis and regulation of inflammation. Moreover, the biological effects of Nrf2 pathway activation contribute to reducing apoptosis and enhancing cell survival. The activity of Nrf2 is negatively regulated by Kelch-like ECH-associated protein 1 (Keap1). Prompted by the recent results reporting the impact of xanthone metabolites on oxidative stress, cancer, and inflammation, the antioxidant properties of xanthones isolated from Garcinia mangostana (γ-mangostin, α-mangostin, 8-deoxygartanin, demethylcalabaxanthone, garcinone D) were assessed. In particular, the capability of these natural products to disrupt the interaction between Kelch-like ECH-associated protein 1 (Keap1) and nuclear factor erythroid 2-related factor 2 (Nrf2), triggering the activation of the Nrf2-mediated pathway, was evaluated using molecular docking experiments and in vitro tests. The modulation of some key Nrf2-related mediators like glutathione (GSH) and lactate dehydrogenase (LDH) to highlight a possible direct antioxidant effect was investigated. Among the tested compounds, demethylcalabaxanthone showed an indirect antioxidant effect, as corroborated by a Western blot assay, displaying a significant increase in the translocated protein upon its administration.

Keywords:  Garcinia mangostana; Xanthones; antioxidant activity; molecular docking

DOI:  https://doi.org/10.3390/antiox12111980
Int J Mol Sci. 2023 Nov 20. pii: 16532. [Epub ahead of print]24(22):

Sedanolide Activates KEAP1-NRF2 Pathway and Ameliorates Hydrogen Peroxide-Induced Apoptotic Cell Death.

Yosuke Tabei, Hiroko Abe, Shingo Suzuki, Nobuaki Takeda, Jun-Ichiro Arai, Yoshihiro Nakajima.

  Sedanolide is a bioactive compound with anti-inflammatory and antitumor activities. Although it has been recently suggested that sedanolide activates the nuclear factor E2-related factor 2 (NRF2) pathway, there is little research on its effects on cellular resistance to oxidative stress. The objective of the present study was to investigate the function of sedanolide in suppressing hydrogen peroxide (H2O2)-induced oxidative damage and the underlying molecular mechanisms in human hepatoblastoma cell line HepG2 cells. We found that sedanolide activated the antioxidant response element (ARE)-dependent transcription mediated by the nuclear translocation of NRF2. Pathway enrichment analysis of RNA sequencing data revealed that sedanolide upregulated the transcription of antioxidant enzymes involved in the NRF2 pathway and glutathione metabolism. Then, we further investigated whether sedanolide exerts cytoprotective effects against H2O2-induced cell death. We showed that sedanolide significantly attenuated cytosolic and mitochondrial reactive oxygen species (ROS) generation induced by exposure to H2O2. Furthermore, we demonstrated that pretreatment with sedanolide conferred a significant cytoprotective effect against H2O2-induced cell death probably due to preventing the decrease in the mitochondrial membrane potential and the increase in caspase-3/7 activity. Our study demonstrated that sedanolide enhanced cellular resistance to oxidative damage via the activation of the Kelch-like ECH-associated protein 1 (KEAP1)-NRF2 pathway.

Keywords:  ARE; NRF2; apoptosis; oxidative stress; sedanolide

DOI:  https://doi.org/10.3390/ijms242216532
Biomed Pharmacother. 2023 Nov 21. pii: S0753-3322(23)01707-9. [Epub ahead of print]169 115909

Parthenolide alleviates cognitive dysfunction and neurotoxicity via regulation of AMPK/GSK3β(Ser9)/Nrf2 signaling pathway.

Jinfeng Sun, Liwei Li, Li Xiong, Fan Chen, Lingyu She, Hao Tang, Yuqing Zeng, Ying Duan, Luyao Li, Wei Wang, Gao Li, Xia Zhao, Guang Liang.

  Alzheimer's disease (AD) stands as the predominant age-related neurodegenerative disorder, for which efficacious treatment remains elusive. An auspicious avenue for this disease lies in natural compounds sourced from tranditional medicine and plant origins. Parthenolide (PTN) is a natural product with multiple biological functionsand. Recent investigations have illuminated PTN's protective properties against neurological maladies; however, its potential therapeutic role against AD remains uncharted. This study aims to explore the role of PTN in treating AD. Our in vitro findings underscore PTN's bioactivity, as evidenced by its capacity to curtail apoptosis, reduce reactive oxygen species (ROS) production, and restore mitochondrial membrane potential in PC12 cells. Moreover, PTN treatment demonstrates a capacity to ameliorate deficits in spatial learning and memory in the 3 ×Tg-AD murine model. Notably, PTN's therapeutic efficacy surpasses that of a clinical agent, donepezil. Mechanistically, PTN's neuroprotective effects stem from its adept regulation of the AMPK/GSK3β(ser9)/Nrf2 signaling pathway and protection on neuronal cells from ROS-related apoptosis. Although the molecular target and the pre-clinical evaluations of PTN need to be further explored, this study indicates PTN as a potential agent or lead compound for the drug development against AD.

Keywords:  AMPK; Alzheimer’s disease; Cell apoptosis; Cognitive deficits; Parthenolide

DOI:  https://doi.org/10.1016/j.biopha.2023.115909
J Adv Res. 2023 Nov 19. pii: S2090-1232(23)00360-0. [Epub ahead of print]

Tetramethylpyrazine nitrone exerts neuroprotection via activation of PGC-1α/Nrf2 pathway in Parkinson's disease models.

Baojian Guo, Chengyou Zheng, Jie Cao, Fangcheng Luo, Haitao Li, Shengquan Hu, Simon Mingyuan Lee, Xifei Yang, Gaoxiao Zhang, Zaijun Zhang, Yewei Sun, Yuqiang Wang.

  INTRODUCTION: Parkinson's disease (PD) is common neurodegenerative disease where oxidative stress and mitochondrial dysfunction play important roles in its progression. Tetramethylpyrazine nitrone (TBN), a potent free radical scavenger, has shown protective effects in various neurological conditions. However, the neuroprotective mechanisms of TBN in PD models remain unclear.OBJECTIVES: We aimed to investigate TBN's neuroprotective effects and mechanisms in PD models.
METHODS: TBN's neuroprotection was initially measured in MPP+/MPTP-induced PD models. Subsequently, a luciferase reporter assay was used to detect peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α) promoter activity. Effects of TBN on antioxidant damage and the PGC-1α/Nuclear factor erythroid-2-related factor 2 (Nrf2) pathway were thoroughly investigated.
RESULTS: In MPP+-induced cell model, TBN (30 to 300 μM) increased cell survival by 9.95% (P < 0.05), 16.63% (P < 0.001), and 24.09% (P < 0.001), respectively. TBN enhanced oxidative phosphorylation (P < 0.05) and restored PGC-1α transcriptional activity suppressed by MPP+ (84.30% vs 59.03%, P < 0.01). In MPTP-treated mice, TBN (30 mg/kg) ameliorated motor impairment, increased striatal dopamine levels (16.75%, P < 0.001), dopaminergic neurons survival (27.12%, P < 0.001), and tyrosine hydroxylase expression (28.07%, P < 0.01). Selegiline, a positive control, increased dopamine levels (15.35%, P < 0.001) and dopaminergic neurons survival (25.34%, P < 0.001). Additionally, TBN reduced oxidative products and activated the PGC-1α/Nrf2 pathway. PGC-1α knockdown diminished TBN's neuroprotective effects, decreasing cell viability from 73.65% to 56.87% (P < 0.001).
CONCLUSION: TBN has demonstrated consistent effectiveness in MPP+-induced midbrain neurons and MPTP-induced mice. Notably, the therapeutic effect of TBN in mitigating motor deficits and neurodegeneration is superior to selegiline. The neuroprotective mechanisms of TBN are associated with activation of the PGC-1α/Nrf2 pathway, thereby reducing oxidative stress and maintaining mitochondrial function. These findings suggest that TBN may be a promising therapeutic candidate for PD, warranting further development and investigation.

Keywords:  Nuclear factor erythroid-2-related factor 2; Parkinson’s disease; Peroxisome proliferator-activated receptor γ co-activator 1α; Tetramethylpyrazine nitrone

DOI:  https://doi.org/10.1016/j.jare.2023.11.021
Antioxidants (Basel). 2023 Nov 13. pii: 1999. [Epub ahead of print]12(11):

Astrocytic Nrf2 Mediates the Neuroprotective and Anti-Inflammatory Effects of Nootkatone in an MPTP-Induced Parkinson's Disease Mouse Model.

Jung-Eun Park, Yea-Hyun Leem, Jin-Sun Park, Seong-Eun Kim, Hee-Sun Kim.

  This study aims to investigate the neuroprotective effects of nootkatone (NKT), a sesquiterpenoid compound isolated from grapefruit, in an MPTP-induced Parkinson's disease (PD) mouse model. NKT restored MPTP-induced motor impairment and dopaminergic neuronal loss and increased the expression of neurotrophic factors like BDNF, GDNF, and PGC-1α. In addition, NKT inhibited microglial and astrocyte activation and the expression of pro-inflammatory markers like iNOS, TNF-α, and IL-1β and oxidative stress markers like 4-HNE and 8-OHdG. NKT increased the expression of nuclear factor erythroid 2-related factor 2 (Nrf2)-driven antioxidant enzymes like HO-1 and NQO-1 in astrocytes, but not in neurons or microglia in MPTP-treated mice. To investigate whether Nrf2 mediates the anti-inflammatory, antioxidant, or neuroprotective effects of NKT, mice were pretreated with Nrf2-specific inhibitor brusatol (BT) prior to NKT treatment. BT attenuated the NKT-mediated inhibition of 4-HNE and 8-OHdG and the number of Nrf2+/HO-1+/NQO1+ cells co-localized with GFAP+ astrocytes in the substantia nigra of MPTP-treated mice. In addition, BT reversed the effects of NKT on dopaminergic neuronal cell death, neurotrophic factors, and pro-/anti-inflammatory cytokines in MPTP-treated mice. Collectively, these data suggest that astrocytic Nrf2 and its downstream antioxidant molecules play pivotal roles in mediating the neuroprotective and anti-inflammatory effects of NKT in an MPTP-induced PD mouse model.

Keywords:  Nrf2; Parkinson’s disease; anti-inflammation; astrocyte; neuroprotection; nootkatone

DOI:  https://doi.org/10.3390/antiox12111999
J Pineal Res. 2023 Nov 20. e12925

The MT1 receptor as the target of ramelteon neuroprotection in ischemic stroke.

Xinmu Zhang, Bin Peng, Shenqi Zhang, Jian Wang, Xiong Yuan, Sharon Peled, Wu Chen, Jinyin Ding, Wei Li, Andrew Zhang, Qiaofeng Wu, Irina G Stavrovskaya, Chengliang Luo, Bharati Sinha, Yanyang Tu, Xiaojing Yuan, Mingchang Li, Shuqing Liu, Jianfang Fu, Ali Aziz-Sultan, Bruce S Kristal, Gil Alterovitz, Rose Du, Shuanhu Zhou, Xin Wang.

  Stroke is the leading cause of death and disability worldwide. Novel and effective therapies for ischemic stroke are urgently needed. Here, we report that melatonin receptor 1A (MT1) agonist ramelteon is a neuroprotective drug candidate as demonstrated by comprehensive experimental models of ischemic stroke, including a middle cerebral artery occlusion (MCAO) mouse model of cerebral ischemia in vivo, organotypic hippocampal slice cultures ex vivo, and cultured neurons in vitro; the neuroprotective effects of ramelteon are diminished in MT1-knockout (KO) mice and MT1-KO cultured neurons. For the first time, we report that the MT1 receptor is significantly depleted in the brain of MCAO mice, and ramelteon treatment significantly recovers the brain MT1 losses in MCAO mice, which is further explained by the Connectivity Map L1000 bioinformatic analysis that shows gene-expression signatures of MCAO mice are negatively connected to melatonin receptor agonist like Ramelteon. We demonstrate that ramelteon improves the cerebral blood flow signals in ischemic stroke that is potentially mediated, at least, partly by mechanisms of activating endothelial nitric oxide synthase. Our results also show that the neuroprotection of ramelteon counteracts reactive oxygen species-induced oxidative stress and activates the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 pathway. Ramelteon inhibits the mitochondrial and autophagic death pathways in MCAO mice and cultured neurons, consistent with gene set enrichment analysis from a bioinformatics perspective angle. Our data suggest that Ramelteon is a potential neuroprotective drug candidate, and MT1 is the neuroprotective target for ischemic stroke, which provides new insights into stroke therapy. MT1-KO mice and cultured neurons may provide animal and cellular models of accelerated ischemic damage and neuronal cell death.

Keywords:  CBF; MRI; MT1 receptor; MT1−/− cultured neurons; MT1−/− mice; Nrf2/HO-1; ROS; Ramelteon; bioinformatics; ischemic stroke; mitochondrial and autophagic death pathways; p-eNOS/eNOS

DOI:  https://doi.org/10.1111/jpi.12925
Free Radic Biol Med. 2023 Nov 19. pii: S0891-5849(23)01114-0. [Epub ahead of print]

Metal profiling in coronary ischemia-reperfusion injury: Implications for KEAP1/NRF2 regulated redox signaling.

Fan Yang, Matthew J Smith.

  Coronary ischemia-reperfusion (IR) injury results from a blockage of blood supply to the heart followed by restoration of perfusion, leading to oxidative stress induced pathological processes. Nuclear factor erythroid 2-related factor 2 (NRF2), a master antioxidant transcription factor, plays a key role in regulating redox signaling. Over the past decades, the field of metallomics has provided novel insights into the mechanism of pro-oxidant and antioxidant pathological processes. Both redox-active (e.g. Fe and Cu) and redox-inert (e.g. Zn and Mg) metals play unique roles in establishing redox balance under IR injury. Notably, Zn protects against oxidative stress in coronary IR injury by serving as a cofactor of antioxidant enzymes such as superoxide dismutase [Cu-Zn] (SOD1) and proteins such as metallothionein (MT) and KEAP1/NRF2 mediated antioxidant defenses. An increase in labile Zn2+ inhibits proteasomal degradation and ubiquitination of NRF2 by modifying KEAP1 and glycogen synthase kinase 3β (GSK3β) conformations. Fe and Cu catalyse the formation of reactive oxygen species via the Fenton reaction and also serve as cofactors of antioxidant enzymes and can activate NRF2 antioxidant signaling. We review the evidence that Zn and redox-active metals Fe and Cu affect redox signaling in coronary cells during IR and the mechanisms by which oxidative stress influences cellular metal content. In view of the unique double-edged characteristics of metals, we aim to bridge the role of metals and NRF2 regulated redox signaling to antioxidant defenses in IR injury, with a long-term aim of informing the design and application of novel therapeutics.

Keywords:  Copper; Coronary artery; Hyperoxia; Hypoxia; Hypoxia-reoxygenation; Iron; Ischemia-reperfusion injury; Magnesium; Metal; NRF2; Oxidative stress; Oxygen; Physiological normoxia; Redox; Zinc

DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.11.013
Int Immunopharmacol. 2023 Nov 21. pii: S1567-5769(23)01433-9. [Epub ahead of print]126 111107

Histone deacetylase 3 inhibition alleviates 2,4-dinitrochlorobenzene-induced atopic dermatitis via epigenetically upregulating Nrf2/HO-1 signaling pathway.

Wei Zhou, Dan Zeng, Shunan Liu, Yunxia Huang, Fenglin Lv, Weikang Zhou.

  Atopic dermatitis (AD) is a frequent skin disorder that is associated with immune dysfunction and skin inflammation. Histone deacetylase 3 (HDAC3) possesses strong immune and inflammatory modulatory properties in multiple diseases. However, the role and mechanism of HDAC3 in AD remain unknown. Here, we reported that HDAC3 expression was aberrantly upregulated in 2,4-dinitrochlorobenzene (DNCB)-induced lesional AD skin in mice. Inhibition of HDAC3 by RGFP966 protected against DNCB-induced AD, indicated by improved histological damages, relieved inflammatory and immune dysfunction. Nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) signaling pathway activity in lesional AD skin was significantly decreased and RGFP966 attenuated the decrease. Inhibition of Nrf2/HO-1 signaling pathway via Nrf2 inhibitor ML385 blunted anti-AD effect of RGFP966 in DNCB-treated mice. Mechanistically, RGFP966 promoted Nrf2 expression and upregulated H3K27ac deposition on the promoter region of Nrf2. Collectively, HDAC3 inhibition protects against AD via epigenetically activating Nrf2 transcription to upregulate Nrf2/HO-1 signaling pathway activity. HDAC3 may act as a promising therapeutic target for the treatment of AD.

Keywords:  Atopic dermatitis; HDAC3; HO-1; Nrf2

DOI:  https://doi.org/10.1016/j.intimp.2023.111107
Antioxidants (Basel). 2023 Nov 07. pii: 1978. [Epub ahead of print]12(11):

Unleashing the Potential of Nrf2: A Novel Therapeutic Target for Pulmonary Vascular Remodeling.

Qin Fang, Yang Bai, Shuiqing Hu, Jie Ding, Lei Liu, Meiyan Dai, Jie Qiu, Lujin Wu, Xiaoquan Rao, Yan Wang.

  Pulmonary vascular remodeling, characterized by the thickening of all three layers of the blood vessel wall, plays a central role in the pathogenesis of pulmonary hypertension (PH). Despite the approval of several drugs for PH treatment, their long-term therapeutic effect remains unsatisfactory, as they mainly focus on vasodilation rather than addressing vascular remodeling. Therefore, there is an urgent need for novel therapeutic targets in the treatment of PH. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a vital transcription factor that regulates endogenous antioxidant defense and emerges as a novel regulator of pulmonary vascular remodeling. Growing evidence has suggested an involvement of Nrf2 and its downstream transcriptional target in the process of pulmonary vascular remodeling. Pharmacologically targeting Nrf2 has demonstrated beneficial effects in various diseases, and several Nrf2 inducers are currently undergoing clinical trials. However, the exact potential and mechanism of Nrf2 as a therapeutic target in PH remain unknown. Thus, this review article aims to comprehensively explore the role and mechanism of Nrf2 in pulmonary vascular remodeling associated with PH. Additionally, we provide a summary of Nrf2 inducers that have shown therapeutic potential in addressing the underlying vascular remodeling processes in PH. Although Nrf2-related therapies hold great promise, further research is necessary before their clinical implementation can be fully realized.

Keywords:  Nrf2; oxidative stress; pulmonary hypertension; pulmonary vascular remodeling

DOI:  https://doi.org/10.3390/antiox12111978
Cancers (Basel). 2023 Nov 20. pii: 5478. [Epub ahead of print]15(22):

Anticarcinogenic Potency of EF24: An Overview of Its Pharmacokinetics, Efficacy, Mechanism of Action, and Nanoformulation for Drug Delivery.

Iliyana Sazdova, Milena Keremidarska-Markova, Daniela Dimitrova, Vadim Mitrokhin, Andre Kamkin, Nikola Hadzi-Petrushev, Jane Bogdanov, Rudolf Schubert, Hristo Gagov, Dimiter Avtanski, Mitko Mladenov.

  EF24, a synthetic monocarbonyl analog of curcumin, shows significant potential as an anticancer agent with both chemopreventive and chemotherapeutic properties. It exhibits rapid absorption, extensive tissue distribution, and efficient metabolism, ensuring optimal bioavailability and sustained exposure of the target tissues. The ability of EF24 to penetrate biological barriers and accumulate at tumor sites makes it advantageous for effective cancer treatment. Studies have demonstrated EF24's remarkable efficacy against various cancers, including breast, lung, prostate, colon, and pancreatic cancer. The unique mechanism of action of EF24 involves modulation of the nuclear factor-kappa B (NF-κB) and nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathways, disrupting cancer-promoting inflammation and oxidative stress. EF24 inhibits tumor growth by inducing cell cycle arrest and apoptosis, mainly through inhibiting the NF-κB pathway and by regulating key genes by modulating microRNA (miRNA) expression or the proteasomal pathway. In summary, EF24 is a promising anticancer compound with a unique mechanism of action that makes it effective against various cancers. Its ability to enhance the effects of conventional therapies, coupled with improvements in drug delivery systems, could make it a valuable asset in cancer treatment. However, addressing its solubility and stability challenges will be crucial for its successful clinical application.

Keywords:  EF24; anticancer agent; curcumin; mechanism of action; nanoformulation; pharmacokinetics

DOI:  https://doi.org/10.3390/cancers15225478
Biochem Pharmacol. 2023 Nov 22. pii: S0006-2952(23)00522-1. [Epub ahead of print] 115929

Adaptive changes in tumor cells in response to reductive stress.

Leilei Zhang, Jie Zhang, Zhi-Wei Ye, Aslam Muhammad, Li Li, John W Culpepper, Danyelle M Townsend, Kenneth D Tew.

  Reductive stress is characterized by an excess of cellular electron donors and can be linked with various human pathologies including cancer. We developed melanoma cell lines resistant to reductive stress agents: rotenone (ROTR), n-acetyl-L-cysteine, (NACR), or dithiothreitol (DTTR). Resistant cells divided more rapidly and had intracellular homeostatic redox-couple ratios that were shifted towards the reduced state. Resistance caused alterations in general cell morphology, but only ROTR cells had significant changes in mitochondrial morphology with higher numbers that were more isolated, fragmented and swollen, with greater membrane depolarization and decreased numbers of networks. These changes were accompanied by lower basal oxygen consumption and maximal respiration rates. Whole cell flux analyses and mitochondrial function assays showed that NACR and DTTR preferentially utilized tricarboxylic acid (TCA) cycle intermediates, while ROTR used ketone body substrates such as D, L-β-hydroxybutyric acid. NACR and DTTR cells had constitutively decreased levels of reactive oxygen species (ROS), although this was accompanied by activation of nuclear factor erythroid 2-related factor 2 (Nrf2), with concomitant increased expression of the downstream gene products such as glutathione S-transferase P (GSTP). Further adaptations included enhanced expression of endoplasmic reticulum proteins controlling the unfolded protein response (UPR). Although expression patterns of these UPR proteins were distinct between the resistant cells, a trend implied that resistance to reductive stress is accompanied by a constitutively increased UPR phenotype in each line. Overall, tumor cells, although tolerant of oxidative stress, can adapt their energy and survival mechanisms in lethal reductive stress conditions.

Keywords:  Glycolysis; Melanoma cell lines; Mitochondrial morphology; Reactive oxygen species; Reductive stress; Unfolded protein response

DOI:  https://doi.org/10.1016/j.bcp.2023.115929
Ecotoxicol Environ Saf. 2023 Nov 21. pii: S0147-6513(23)01221-6. [Epub ahead of print]268 115717

Melatonin alleviates particulate matter-induced liver fibrosis by inhibiting ROS-mediated mitophagy and inflammation via Nrf2 activation.

Laiyu Zhu, Qi Zhang, Cong Hua, Xinxin Ci.

  OBJECTIVE: Fine particulate matter (PM2.5) is a source of pollution worldwide, that causes inflammation and liver fibrosis. Melatonin, as the predominant hormone secreted by the pineal gland, can inhibit PM2.5-induced lung injury by activating nuclear factor erythroid 2-related factor 2 (Nrf2) to inhibit ferroptosis. However, the possible role of melatonin in PM2.5-induced liver damage remains unclear.EXPERIMENTAL APPROACH: In vitro, the effects of melatonin on PM2.5-induced oxidative stress and LX-2 cell activation were examined. In vivo, a PM2.5-induced inflammation and liver fibrosis mouse model was used to evaluate the hepatoprotective effect of melatonin.
RESULTS: In vitro, melatonin induced the expression of Nrf2 and its downstream genes and inhibited PM2.5-induced reactive oxygen species (ROS) production and mitochondrial damage. Melatonin also ameliorated the PM2.5-induced oxidative stress and fibrogenic marker upregulation. However, the antifibrotic effect of melatonin was abolished in siNrf2-treated LX-2 cells. In vivo, we observed mitochondrial abnormalities and mitochondrial fragmentation, which were accompanied by increased PTEN-induced kinase 1 (PINK1) and Parkin expression, in PM2.5-treated mouse hepatocytes. These changes were partially reversed by melatonin. In addition, melatonin activated the Nrf2 signaling pathway and protected against PM2.5-induced oxidative stress. Furthermore, melatonin alleviated inflammation and liver fibrosis. Moreover, Nrf2-KO mice exhibited more severe inflammation and liver fibrosis after PM2.5 exposure than wild-type mice, and the protective effect of melatonin on PM2.5- treated Nrf2-KO mice was greatly compromised.
CONCLUSION: These data suggest that melatonin effectively inhibits PM2.5-induced liver fibrosis by activating Nrf2 and inhibiting ROS-mediated mitophagy and inflammation.

Keywords:  Inflammation; Liver Fibrosis; Melatonin; Mitophagy; Nrf2; PM2.5

DOI:  https://doi.org/10.1016/j.ecoenv.2023.115717
Int J Neurosci. 2023 Nov 20. 1-51

Oxyberberine an Oxoderivative of Berberine Confers Neuroprotective Effects in Controlled-Cortical Impact Mouse Model of Traumatic Brain Injury.

Priya Mounika Tentu, Mohd Rabi Bazaz, Tulasi Pasam, Arbaz Sujat Shaikh, Ziaur Rahman, Atul Mourya, Venkata Rao Kaki, Jitender Madan, Manoj P Dandekar.

  BACKGROUND: Traumatic brain injury (TBI) is known as a silent epidemic that causes many deaths and disabilities worldwide. We examined the response of oxyberberine (OBB) in lipopolysaccharide-stimulated BV2 microglial cells and a controlled-cortical impact (CCI) mouse model of TBI.METHODS: We synthesized OBB from berberine, and also prepared OBB-nanocrystals (OBB-NC). Male C57BL/6 mice were used for CCI surgery, and post-CCI neurobehavioral deficits were assessed from 1 h after injury through 21 days post-injury (dpi).
RESULTS: OBB treatment reduced the lipopolysaccharide-triggered elevated levels of reactive oxygen species, nitric oxide, and nuclear factor kappa B (NF-κB) in BV2 microglial cells, indicating a neuroprotective potential. CCI-operated mice exhibited significant neurological deficits on 1, 3, and 5 dpi in neurological severity scoring and rotarod assay. OBB (25 and 50 mg/kg/day) and OBB-NC (3 mg/kg/day) ameliorated these neurological aberrations. Mice subjected to CCI surgery also displayed anxiogenic- and depression-like behaviours, and cognitive impairments in forced-swimming test and elevated-zero maze, and novel object recognition task, respectively. Administration of OBB reduced these long-term neuropsychiatric complications, and also levels of toll-like receptor 4 (TLR4), high-motility group protein 1 (HMGB1), NF-κB, tumour necrosis factor-alpha and interleukin 6 cytokines in the ipsilateral cortex of mice.
CONCLUSION: We suggest that the administration of OBB offers neuroprotective effects via inhibition of HMGB1-mediated TLR4/NFκB pathway.

Keywords:  BV2 cells; HMGB1; NF-κB; Oxyberberine; TLR4; neuroinflammation; traumatic brain injury

DOI:  https://doi.org/10.1080/00207454.2023.2286209
Redox Biol. 2023 Nov 19. pii: S2213-2317(23)00366-X. [Epub ahead of print]68 102965

Thiosulfate sulfurtransferase deficiency promotes oxidative distress and aberrant NRF2 function in the brain.

Yang Luo, Laurent Chatre, Shaden Melhem, Zayana M Al-Dahmani, Natalie Z M Homer, Anneke Miedema, Leo E Deelman, Matthew R Groves, Martin Feelisch, Nicholas M Morton, Amalia Dolga, Harry van Goor.

  Thiosulfate sulfurtransferase (TST, EC 2.8.1.1) was discovered as an enzyme that detoxifies cyanide by conversion to thiocyanate (rhodanide) using thiosulfate as substrate; this rhodanese activity was subsequently identified to be almost exclusively located in mitochondria. More recently, the emphasis regarding its function has shifted to hydrogen sulfide metabolism, antioxidant defense, and mitochondrial function in the context of protective biological processes against oxidative distress. While TST has been described to play an important role in liver and colon, its function in the brain remains obscure. In the present study, we therefore sought to address its potential involvement in maintaining cerebral redox balance in a murine model of global TST deficiency (Tst-/- mice), primarily focusing on characterizing the biochemical phenotype of TST loss in relation to neuronal activity and sensitivity to oxidative stress under basal conditions. Here, we show that TST deficiency is associated with a perturbation of the reactive species interactome in the brain cortex secondary to altered ROS and RSS (specifically, polysulfide) generation as well as mitochondrial OXPHOS remodeling. These changes were accompanied by aberrant Nrf2-Keap1 expression and thiol-dependent antioxidant function. Upon challenging mice with the redox-active herbicide paraquat (25 mg/kg i.p. for 24 h), Tst-/- mice displayed a lower antioxidant capacity compared to wildtype controls (C57BL/6J mice). These results provide a first glimpse into the molecular and metabolic changes of TST deficiency in the brain and suggest that pathophysiological conditions associated with aberrant TST expression and/or activity renders neurons more susceptible to oxidative stress-related malfunction.

Keywords:  Antioxidant; Nrf2 signaling; Oxidative distress; Reactive species; Thiosulfate sulfurtransferase (TST)

DOI:  https://doi.org/10.1016/j.redox.2023.102965
Naunyn Schmiedebergs Arch Pharmacol. 2023 Nov 21.

Current advancement in the preclinical models used for the assessment of diabetic neuropathy.

Tanishk Saini, Papiya Mitra Mazumder.

  Diabetic neuropathy is one of the prevalent and debilitating microvascular complications of diabetes mellitus, affecting a significant portion of the global population. Relational preclinical animal models are essential to understand its pathophysiology and develop effective treatments. This abstract provides an overview of current knowledge and advancements in such models. Various animal models have been developed to mimic the multifaceted aspects of human diabetic neuropathy, including both type 1 and type 2 diabetes. These models involve rodents (rats and mice) and larger animals like rabbits and dogs. Induction of diabetic neuropathy in these models is achieved through chemical, genetic, or dietary interventions, such as diabetogenic agents, genetic modifications, or high-fat diets. Preclinical animal models have greatly contributed to studying the intricate molecular and cellular mechanisms underlying diabetic neuropathy. They have shed light on hyperglycemia-induced oxidative stress, neuroinflammation, mitochondrial dysfunction, and altered neurotrophic factor signaling. Additionally, these models have allowed for the investigation of morphological changes, functional alterations, and behavioral manifestations associated with diabetic neuropathy. These models have also been crucial for evaluating the efficacy and safety of potential therapeutic interventions. Novel pharmacological agents, gene therapies, stem cell-based approaches, exercise, dietary modifications, and neurostimulation techniques have been tested using these models. However, limitations and challenges remain, including physiological differences between humans and animals, complex neuropathy phenotypes, and the need for translational validation. In conclusion, preclinical animal models have played a vital role in advancing our understanding and management of diabetic neuropathy. They have enhanced our knowledge of disease mechanisms, facilitated the development of novel treatments, and provided a platform for translational research. Ongoing efforts to refine and validate these models are crucial for future treatment developments for this debilitating condition.

Keywords:  Diabetes; Diabetic neuropathy; Neuropathy; Preclinical models

DOI:  https://doi.org/10.1007/s00210-023-02802-0
Neuroscience. 2023 Nov 21. pii: S0306-4522(23)00516-X. [Epub ahead of print]

Celastrol Alleviates Mitochondrial Oxidative Stress and Brain Injury after Intracerebral Hemorrhage by Promoting OPA1-Dependent Mitochondrial Fusion.

Chunyan Diao, Zhengxuan Yang, Qing Hu, Pengfei Yao, Xiaodong Qu, Changdong Li, Shenghao Zhang, Jie Zhou.

  Mitochondrial oxidative stress is one of the characteristics of secondary brain injury (SBI) after intracerebral hemorrhage (ICH), contributing largely to the apoptosis of neurons. Celastrol, a quinone methide triterpene that possesses antioxidant and mitochondrial protective properties, has emerged as a neuroprotective agent. However, the activity of celastrol has not been tested in ICH-induced SBI. In this study, we found that celastrol could effectively alleviate neurological function deficits and reduce brain oedema and neuronal apoptosis caused by ICH. Through electron microscopy, we found that celastrol could significantly attenuate mitochondrial morphology impairment. Therefore, we tested the regulatory proteins of mitochondrial dynamics and found that celastrol could reverse the downwards trend of OPA1 expression after ICH. In view of this, by culturing OPA1-deficient primary neurons and constructing neuron-specific OPA1 conditional knockout mice, we found that the protective effects of celastrol on mitochondrial morphology and function after ICH were counteracted in the absence of OPA1. Further experiments also showed that OPA1 is indispensable for the protective effects of celastrol on ICH-induced secondary brain injury. In summary, we have demonstrated that celastrol is a potential drug for the treatment of ICH and have revealed a novel mechanism by which celastrol exerts its antioxidant effects by promoting OPA1-mediated mitochondrial fusion.

Keywords:  Celastrol; ICH; Mitochondria; OPA1; Oxidative stress

DOI:  https://doi.org/10.1016/j.neuroscience.2023.11.022
CNS Neurosci Ther. 2023 Nov 21.

Icaritin greatly attenuates β-amyloid-induced toxicity in vivo.

Liangxian Li, Zaiwa Wei, Yafang Tang, Mingyue Jin, Hua Yao, Xia Li, Qinghua Li, Jie Tan, Bo Xiao.

  AIMS: The accumulation and deposition of β-amyloid (Aβ) has always been considered a major pathological feature of Alzheimer's disease (AD). The latest and mainstream amyloid cascade hypothesis indicates that all the main pathological changes in AD are attributed to the accumulation of soluble Aβ. However, the exploration of therapeutic drugs for Aβ toxicity has progressed slowly. This study aims to investigate the protective effects of Icaritin on the Aβ-induced Drosophila AD model and its possible mechanism.METHODS: To identify the effects of Icaritin on AD, we constructed an excellent Drosophila AD model named Aβarc (arctic mutant Aβ42 ) Drosophila. Climbing ability, flight ability, and longevity were used to evaluate the effects of Icaritin on AD phenotypes. Aβarc was determined by immunostaining and ELISA. To identify the effects of Icaritin on oxidative stress, we performed the detection of ROS, hydrogen peroxide, MDA, SOD, catalase, GST, and Caspase-3. To identify the effects of Icaritin on energy metabolism, we performed the detection of ATP and lactate. Transcriptome analysis and qRT-PCR verifications were used to detect the genes directly involved in oxidative stress and energy metabolism. Mitochondrial structure and function were detected by an electron microscopy assay, a mitochondrial membrane potential assay, and a mitochondrial respiration assay.
RESULTS: We discovered that Icaritin almost completely rescues the climbing ability, flight ability, and longevity of Aβarc Drosophila. Aβarc was dramatically reduced by Icaritin treatment. We also found that Icaritin significantly reduces oxidative stress and greatly improves impaired energy metabolism. Importantly, transcriptome analysis and qRT-PCR verifications showed that many key genes, directly involved in oxidative stress and energy metabolism, are restored by Icaritin. Next, we found that Icaritin perfectly restores the integrity of mitochondrial structure and function damaged by Aβarc toxicity.
CONCLUSION: This study suggested that Icaritin is a potential drug to deal with the toxicity of Aβarc, at least partially realized by restoring the mitochondria/oxidative stress/energy metabolism axis, and holds potential for translation to human AD.

Keywords:  Alzheimer's disease; Icaritin; energy metabolism; mitochondria; oxidative stress

DOI:  https://doi.org/10.1111/cns.14527
Int J Mol Sci. 2023 Nov 18. pii: 16474. [Epub ahead of print]24(22):

Reactive Oxygen Species Mediate Transcriptional Responses to Dopamine and Cocaine in Human Cerebral Organoids.

Thomas T Rudibaugh, Samantha R Stuppy, Albert J Keung.

  Dopamine signaling in the adult ventral forebrain regulates behavior, stress response, and memory formation and in neurodevelopment regulates neural differentiation and cell migration. Excessive dopamine levels, including those due to cocaine use in utero and in adults, could lead to long-term adverse consequences. The mechanisms underlying both homeostatic and pathological changes remain unclear, in part due to the diverse cellular responses elicited by dopamine and the reliance on animal models that exhibit species-specific differences in dopamine signaling. In this study, we use the human-derived ventral forebrain organoid model of Xiang-Tanaka and characterize their response to cocaine or dopamine. We explore dosing regimens of dopamine or cocaine to simulate acute or chronic exposure. We then use calcium imaging, cAMP imaging, and bulk RNA-sequencing to measure responses to cocaine or dopamine exposure. We observe an upregulation of inflammatory pathways in addition to indicators of oxidative stress following exposure. Using inhibitors of reactive oxygen species (ROS), we then show ROS to be necessary for multiple transcriptional responses of cocaine exposure. These results highlight novel response pathways and validate the potential of cerebral organoids as in vitro human models for studying complex biological processes in the brain.

Keywords:  RNA-seq; acute-chronic; cerebral organoids; cocaine; dopamine; epigenetics; reactive oxygen species (ROS)

DOI:  https://doi.org/10.3390/ijms242216474
Int Immunopharmacol. 2023 Nov 18. pii: S1567-5769(23)01509-6. [Epub ahead of print]126 111183

Knockdown of Smox protects the integrity of the blood-brain barrier through antioxidant effect and Nrf2 pathway activation in stroke.

Guangtian Wang, Zhihui Li, Peng Lin, Huishu Zhang, Yanyan Wang, Tongshuai Zhang, Hui Wang, Heming Li, Lexun Lin, Yuehui Zhao, Lina Jia, Yang Chen, Hong Ji, Wenran Zhao, Zhongqiu Fu, Zhaohua Zhong.

  Once an ischemic stroke occurs, reactive oxygen species (ROS) and oxidative stress degrade the tight connections between cerebral endothelial cells resulting in their damage. The expression of antioxidant genes may be enhanced, and ROS formation may be reduced following Nrf2 activation, which is associated with protection against ischemic stroke. Overexpression of spermine oxidase (Smox) in the neocortex led to increased H2O2 production. However, how Smox impacts the regulation of the blood-brain barrier (BBB) through antioxidants has not been examined yet. We conducted experiments both in the cell level and in the transient middle cerebral artery occlusion (tMCAO) model to evaluate the effect of Smox siRNA lentivirus (si-Smox) knockdown on BBB protection against ischemic stroke. Mice treated with si-Smox showed remarkably decreased BBB breakdown and reduced endothelial inflammation following stroke. The treatment with si-Smox significantly elevated the Bcl-2 to Bax ratio and decreased the production of cleaved caspase-3 in the tMCAO model. Further investigation revealed that the neuroprotective effect was the result of the antioxidant properties of si-Smox, which reduced oxidative stress and enhanced CD31+ cells in the peri-infarct cortical areas. Of significance, si-Smox activated Nrf2 in both bEnd.3 cells and tMCAO animals, and blocking Nrf2 with brusatol diminished the protective effects of si-Smox. The study findings suggest that si-Smox exerts neuroprotective effects and promotes angiogenesis by activating the Nrf2 pathway, thus decreasing oxidative stress and apoptosis caused by tMCAO. As a result, si-Smox may hold potential as a therapeutic candidate for preserving BBB integrity while treating ischemic stroke.

Keywords:  Blood brain barrier; Integrity; Ischemic stroke; Nrf2; ROS; Smox

DOI:  https://doi.org/10.1016/j.intimp.2023.111183
Funct Integr Genomics. 2023 Nov 24. 23(4): 345

Nrf2 attenuates oxidative stress to mediate the protective effect of ciprofol against cerebral ischemia-reperfusion injury.

Xia Liu, Miao Ren, Anqi Zhang, Changshun Huang, Junlu Wang.

  Neuroinflammation and oxidative stress damage are involved in the pathogenesis of cerebral ischemia-reperfusion injury (CIRI). Ferroptosis emerged as a new player in the regulation of lipid peroxidation processes. This study aimed at exploring the potential involvement of ciprofol on ferroptosis-associated CIRI and subsequent neurological deficits in the mouse model of transient cerebral ischemia and reperfusion. Cerebral ischemia was built in male C57BL/6 J wild-type (WT) and Nrf2-knockout (Nrf2 KO) mice in the manner of middle cerebral artery occlusion (MCAO) followed by reperfusion. Ciprofol improved autonomic behavior, alleviated reactive oxygen species output and ferroptosis-induced neuronal death by nucleus transportation of NFE2 like BZIP transcription factor 2 (Nrf2) and the promotion of heme oxygenase 1 (Ho-1), solute carrier family 7 member 11 (SLC7A11/xCT), and glutathione peroxidase 4 (GPX4). Additionally, ciprofol improved neurological scores and reduced infarct volume, brain water content, and necrotic neurons. Cerebral blood flow in MCAO-treated mice was also improved. Furthermore, absence of Nrf2 abrogated the neuroprotective actions of ciprofol on antioxidant capacity and sensitized neurons to oxidative stress damage. In vitro, the primary-cultured cortical neurons from mice were pre-treated with oxygen-glucose deprivation/reperfusion (OGD/R), followed by ciprofol administration. Ciprofol effectively reversed OGD/R-induced ferroptosis and accelerated transcription of GPX4 and xCT. In conclusion, we investigated the ciprofol-induced inhibition effect of ferroptosis-sheltered neurons from lipid preoxidation in the pathogenesis of CIRI via Nrf2-xCT-GPX4 signaling pathway.

Keywords:  Cerebral ischemia–reperfusion injury; Ciprofol; Ferroptosis; MCAO; Nrf2; OGD/R

DOI:  https://doi.org/10.1007/s10142-023-01273-z
Int J Mol Sci. 2023 Nov 18. pii: 16480. [Epub ahead of print]24(22):

Glucose Transport and Utilization in the Hippocampus: From Neurophysiology to Diabetes-Related Development of Dementia.

Caio Yogi Yonamine, Maria Luiza Estimo Michalani, Rafael Junges Moreira, Ubiratan Fabres Machado.

  The association of diabetes with cognitive dysfunction has at least 60 years of history, which started with the observation that children with type 1 diabetes mellitus (T1D), who had recurrent episodes of hypoglycemia and consequently low glucose supply to the brain, showed a deficit of cognitive capacity. Later, the growing incidence of type 2 diabetes mellitus (T2D) and dementia in aged populations revealed their high association, in which a reduced neuronal glucose supply has also been considered as a key mechanism, despite hyperglycemia. Here, we discuss the role of glucose in neuronal functioning/preservation, and how peripheral blood glucose accesses the neuronal intracellular compartment, including the exquisite glucose flux across the blood-brain barrier (BBB) and the complex network of glucose transporters, in dementia-related areas such as the hippocampus. In addition, insulin resistance-induced abnormalities in the hippocampus of obese/T2D patients, such as inflammatory stress, oxidative stress, and mitochondrial stress, increased generation of advanced glycated end products and BBB dysfunction, as well as their association with dementia/Alzheimer's disease, are addressed. Finally, we discuss how these abnormalities are accompained by the reduction in the expression and translocation of the high capacity insulin-sensitive glucose transporter GLUT4 in hippocampal neurons, which leads to neurocytoglycopenia and eventually to cognitive dysfunction. This knowledge should further encourage investigations into the beneficial effects of promising therapeutic approaches which could improve central insulin sensitivity and GLUT4 expression, to fight diabetes-related cognitive dysfunctions.

Keywords:  Alzheimer’s disease; cognitive dysfunction; glucose transporters; insulin resistance; obesity

DOI:  https://doi.org/10.3390/ijms242216480
Int J Mol Sci. 2023 Nov 19. pii: 16501. [Epub ahead of print]24(22):

Antioxidant and Hypoglycemic Potential of Essential Oils in Diabetes Mellitus and Its Complications.

Simona Gabriela Bungau, Cosmin Mihai Vesa, Cristian Bustea, Anamaria Lavinia Purza, Delia Mirela Tit, Mihaela Cristina Brisc, Andrei-Flavius Radu.

  Since the earliest times, essential oils (EOs) have been utilized for medicinal and traditional purposes. However, in recent decades, an increasing interest has developed due to the need to rediscover herbal remedies and adjuvant therapies for the management of various diseases, particularly chronic ones. The present narrative review examines the potential for EOs to exert hypoglycemic and antioxidant effects in diabetes mellitus, analyzing the main publications having evaluated plant species with potentially beneficial effects through their phytocompounds in diabetes mellitus and its complications. Numerous species have shown promising characteristics that can be used in diabetes management. The hypoglycemic effects of these EOs are attributed to their capacity to stimulate glucose uptake, suppress glucose production, and increase insulin sensitivity. Moreover, EOs can alleviate the oxidative stress by manifesting their antioxidant effects via a variety of mechanisms, including the scavenging of free radicals, the regulation of antioxidant enzymes, and the decreasing of lipid peroxidation, due to their diverse chemical composition. These findings demonstrate the possible benefits of EOs as adjuvant therapeutic agents in the management of diabetes and its complications. The use of EOs in the treatment of diabetes shows good potential for the development of natural and effective strategies to enhance the health outcomes of people with this chronic condition, but additional experimental endorsements are required.

Keywords:  antioxidants; bibliometric analysis; diabetes mellitus; essential oil; phytochemistry

DOI:  https://doi.org/10.3390/ijms242216501