bims-nurfan 2023-11-12 papers

bims-nurfan

Biomed News

on NRF2 and Neurological Diseases

Issue of 2023–11–12
twenty-one papers selected by
Arif Kamil Salihoğlu, Karadeniz Technical University

Identification of novel NRF2-dependent genes as regulators of lead and arsenic toxicity in neural progenitor cells.
LRRK2 Attenuates Antioxidant Response in Familial Parkinson's Disease Derived Neural Stem Cells.
SUMOylation Modulates Reactive Oxygen Species (ROS) Levels and Acts as a Protective Mechanism in the Type 2 Model of Diabetic Peripheral Neuropathy.
Screening approaches for the identification of Nrf2-Keap1 protein-protein interaction inhibitors targeting hot spot residues.
Natural Phenolic Compounds with Neuroprotective Effects.
Chicoric acid enhances the antioxidative defense system and protects against inflammation and apoptosis associated with the colitis model induced by dextran sulfate sodium in rats.
Modulating mitochondrial calcium channels (TRPM2/MCU/NCX) as a therapeutic strategy for neurodegenerative disorders.
Oxidative Stress and Natural Antioxidants: Back and Forth in the Neurological Mechanisms of Alzheimer's Disease.
Ginsenoside RK1 improves cognitive impairments and pathological changes in Alzheimer's disease via stimulation of the AMPK/Nrf2 signaling pathway.
Reactive oxygen species and cell signaling. Mini review.
From imbalance to impairment: the central role of reactive oxygen species in oxidative stress-induced disorders and therapeutic exploration.
Mitochondrial dysfunction and neurological disorders: A narrative review and treatment overview.
Flavonoids: the use in mental health and related diseases.
Pterostilbene accelerates wound healing response in diabetic mice through Nrf2 regulation.
A role for the cystathionine-β-synthase /H2S axis in astrocyte dysfunction in the aging brain.
4-methoxycinnamyl p-coumarate reduces neuroinflammation by blocking NF-κB, MAPK, and Akt/GSK-3β pathways and enhancing Nrf2/HO-1 signaling cascade in microglial cells.
Effect of woohwangchungsimwon and donepezil co-treatment on cognitive function and serum metabolic profiles in a scopolamine-induced model of Alzheimer's disease.
In silico and in vivo analysis of the relationship between ADHD and social isolation in pups rat model: Implication of redox mechanisms, and the neuroprotective impact of Punicalagin.
Molecular Mechanisms Associated with Neurodegeneration of Neurotropic Viral Infection.
Toxic dinoflagellate Karenia mikimotoi induces apoptosis in Neuro-2a cells through an oxidative stress-mediated mitochondrial pathway.
A systematic review exploring the mechanisms by which citrus bioflavonoid supplementation benefits blood glucose levels and metabolic complications in type 2 diabetes mellitus.

J Hazard Mater. 2023 Nov 02. pii: S0304-3894(23)02190-8. [Epub ahead of print]463 132906

Identification of novel NRF2-dependent genes as regulators of lead and arsenic toxicity in neural progenitor cells.

Hae-Ryung Park, David Azzara, Ethan D Cohen, Steven R Boomhower, Avantika R Diwadkar, Blanca E Himes, Michael A O'Reilly, Quan Lu.

  Lead (Pb) and arsenic (As) are prevalent metal contaminants in the environment. Exposures to these metals are associated with impaired neuronal functions and adverse effects on neurodevelopment in children. However, the molecular mechanisms by which Pb and As impair neuronal functions remain poorly understood. Here, we identified F2RL2, TRIM16L, and PANX2 as novel targets of Nuclear factor erythroid 2-related factor 2 (NRF2)-the master transcriptional factor for the oxidative stress response-that are commonly upregulated with both Pb and As in human neural progenitor cells (NPCs). Using a ChIP (Chromatin immunoprecipitation)-qPCR assay, we showed that NRF2 directly binds to the promoter region of F2RL2, TRIM16L, and PANX2 to regulate expression of these genes. We demonstrated that F2RL2, PANX2, and TRIM16L have differential effects on cell death, proliferation, and differentiation of NPCs in both the presence and absence of metal exposures, highlighting their roles in regulating NPC function. Furthermore, the analyses of the transcriptomic data on NPCs derived from autism spectrum disorder (ASD) patients revealed that dysregulation of F2RL2, TRIM16L, and PANX2 was associated with ASD genetic backgrounds and ASD risk genes. Our findings revealed that Pb and As induce a shared NRF2-dependent transcriptional response in NPCs and identified novel genes regulating NPC function. While further in vivo studies are warranted, this study provides a novel mechanism linking metal exposures to NPC function and identifies potential genes of interest in the context of neurodevelopment.

Keywords:  Arsenic; Lead; NRF2; Neural progenitor cells; Neurodevelopment

DOI:  https://doi.org/10.1016/j.jhazmat.2023.132906
Cells. 2023 Oct 31. pii: 2550. [Epub ahead of print]12(21):

LRRK2 Attenuates Antioxidant Response in Familial Parkinson's Disease Derived Neural Stem Cells.

Jeffrey Kim, Etienne W Daadi, Elyas Sebastien Daadi, Thomas Oh, Michela Deleidi, Marcel M Daadi.

  Parkinson's disease (PD) is the second most prevalent neurodegenerative disease, characterized by the loss of midbrain dopaminergic neurons which leads to impaired motor and cognitive functions. PD is predominantly an idiopathic disease; however, about 5% of cases are linked to hereditary mutations. The most common mutation in both familial and sporadic PD is the G2019S mutation of leucine-rich repeat kinase 2 (LRRK2). Currently, it is not fully understood how this mutation leads to PD pathology. In this study, we isolated self-renewable, multipotent neural stem cells (NSCs) from induced pluripotent stem cells (iPSCs) harboring the G2019S LRRK2 mutation and compared them with their isogenic gene corrected counterparts using single-cell RNA-sequencing. Unbiased single-cell transcriptomic analysis revealed perturbations in many canonical pathways, specifically NRF2-mediated oxidative stress response, and glutathione redox reactions. Through various functional assays, we observed that G2019S iPSCs and NSCs exhibit increased basal levels of reactive oxygen species (ROS). We demonstrated that mutant cells show significant increase in the expression for KEAP1 and decrease in NRF2 associated with a reduced antioxidant response. The decreased viability of mutant NSCs in the H2O2-induced oxidative stress assay was rescued by two potent antioxidant drugs, PrC-210 at concentrations of 500 µM and 1 mM and Edaravone at concentrations 50 µM and 100 µM. Our data suggest that the hyperactive LRRK2 G2019S kinase activity leads to increase in KEAP1, which binds NRF2 and leads to its degradation, reduction in the antioxidant response, increased ROS, mitochondria dysfunction and cell death observed in the PD phenotype.

Keywords:  Parkinson’s disease; induced pluripotent stem cells; neural stem cells; single cell transcriptomics; target identification

DOI:  https://doi.org/10.3390/cells12212550
Cells. 2023 Oct 24. pii: 2511. [Epub ahead of print]12(21):

SUMOylation Modulates Reactive Oxygen Species (ROS) Levels and Acts as a Protective Mechanism in the Type 2 Model of Diabetic Peripheral Neuropathy.

Nicolas Mandel, Michael Büttner, Gernot Poschet, Rohini Kuner, Nitin Agarwal.

  Diabetic peripheral neuropathy (DPN) is the prevalent type of peripheral neuropathy; it primarily impacts extremity nerves. Its multifaceted nature makes the molecular mechanisms of diabetic neuropathy intricate and incompletely elucidated. Several types of post-translational modifications (PTMs) have been implicated in the development and progression of DPN, including phosphorylation, glycation, acetylation and SUMOylation. SUMOylation involves the covalent attachment of small ubiquitin-like modifier (SUMO) proteins to target proteins, and it plays a role in various cellular processes, including protein localization, stability, and function. While the specific relationship between high blood glucose and SUMOylation is not extensively studied, recent evidence implies its involvement in the development of DPN in type 1 diabetes. In this study, we investigated the impact of SUMOylation on the onset and progression of DPN in a type 2 diabetes model using genetically modified mutant mice lacking SUMOylation, specifically in peripheral sensory neurons (SNS-Ubc9-/-). Behavioural measurement for evoked pain, morphological analyses of nerve fibre loss in the epidermis, measurement of reactive oxygen species (ROS) levels, and antioxidant molecules were analysed over several months in SUMOylation-deficient and control mice. Our longitudinal analysis at 30 weeks post-high-fat diet revealed that SNS-Ubc9-/- mice exhibited earlier and more pronounced thermal and mechanical sensation loss and accelerated intraepidermal nerve fibre loss compared to control mice. Mechanistically, these changes are associated with increased levels of ROS both in sensory neuronal soma and in peripheral axonal nerve endings in SNS-Ubc9-/- mice. In addition, we observed compromised detoxifying potential, impaired respiratory chain complexes, and reduced levels of protective lipids in sensory neurons upon deletion of SUMOylation in diabetic mice. Importantly, we also identified mitochondrial malate dehydrogenase (MDH2) as a SUMOylation target, the activity of which is negatively regulated by SUMOylation. Our results indicate that SUMOylation is an essential neuroprotective mechanism in sensory neurons in type 2 diabetes, the deletion of which causes oxidative stress and an impaired respiratory chain, resulting in energy depletion and subsequent damage to sensory neurons.

Keywords:  SUMOylation; high-fat diet; hyperglycaemia; malate dehydrogenase 2; reactive oxygen species; respiratory chain

DOI:  https://doi.org/10.3390/cells12212511
SLAS Discov. 2023 Nov 05. pii: S2472-5552(23)00079-5. [Epub ahead of print]

Screening approaches for the identification of Nrf2-Keap1 protein-protein interaction inhibitors targeting hot spot residues.

Wataru Asano, Rie Hantani, Toru Uhara, Francois Debaene, Akihiro Nomura, Keishi Yamaguchi, Tsuyoshi Adachi, Kazuki Otake, Kazuhito Harada, Yoshiji Hantani.

  Protein-protein interactions (PPIs) play a crucial role in most biological processes and are important targets in the development of therapeutic agents. However, small molecule drug discovery that targets PPIs remains very challenging. Targeting hot spot residues is considered the best option for inhibiting such interactions, but there are few examples of how knowledge of hot spots can be used in high throughput screening to find hit compounds. A substrate adaptor protein for a ubiquitin ligase complex, Kelch-like ECH-associated protein 1 (Keap1), negatively modulates the expression of genes involved in cellular protection against oxidative stress. Here, we focused on three arginine hot spot residues in the Keap1 substrate binding pocket (Arg380, Arg415, and Arg483), and screened the carboxylic acid library owned by Japan Tobacco Inc. for compounds that interact with the arginine residues in differential scanning fluorescence assays. Furthermore, we identified several small molecule compounds that specifically bind to the Keap1 Kelch domain hot spots by comparing binding to alanine mutant proteins (R380A, R415A, and R483A) with binding to the wild-type protein using surface plasmon resonance (SPR) screening. These compounds inhibited the protein-protein interaction between the Keap1 Kelch domain and the nuclear factor erythroid 2-related factor 2 (Nrf2) peptide, and the ubiquitination of Nrf2 catalyzed by the Cul3/RINGBox 1 E3 ligase. In addition, the binding mode of one compound (Compound 4) was determined by X-ray crystallography after validation of binding by isothermal titration calorimetry, native mass spectrometry, and nuclear magnetic resonance. Compound 4 had favorable thermodynamic properties, and noncovalently bound to Keap1 with a stoichiometry of 1:1. Our results suggest that Compound 4 could potentially be developed into effective therapeutic or preventive agents for a variety of diseases and conditions such as oxidative stress response, inflammation, and carcinogenesis. We believe that the use of a set of complementary biophysical techniques including the SPR assay with single alanine mutant of hot spots provides opportunities to identify hit compounds for developing inhibitors of PPIs.

Keywords:  Keap1; Nrf2; biophysical assay; hot spot; protein-protein interaction

DOI:  https://doi.org/10.1016/j.slasd.2023.11.001
Neurochem Res. 2023 Nov 08.

Natural Phenolic Compounds with Neuroprotective Effects.

Mansoureh Tavan, Parichehr Hanachi, María de la Luz Cádiz-Gurrea, Antonio Segura Carretero, Mohammad Hossein Mirjalili.

  Neurodegenerative disorders are characterized by mitochondrial dysfunction and subsequently oxidative stress, inflammation, and apoptosis that contribute to neuronal cytotoxicity and degeneration. Huntington's (HD), Alzheimer's (AD), and Parkinson's (PD) diseases are three of the major neurodegenerative diseases. To date, researchers have found various natural phytochemicals that could potentially be used to treat neurodegenerative diseases. Particularly, the application of natural phenolic compounds has gained significant traction in recent years, driven by their various biological activities and therapeutic efficacy in human health. Polyphenols, by modulating different cellular functions, play an important role in neuroprotection and can neutralize the effects of oxidative stress, inflammation, and apoptosis in animal models. This review focuses on the current state of knowledge on phenolic compounds, including phenolic acids, flavonoids, stilbenes, and coumarins, as well as their beneficial effects on human health. We further provide an overview of the therapeutic potential and mechanisms of action of natural dietary phenolics in curing neurodegenerative diseases in animal models.

Keywords:  Coumarins; Flavonoids; Neurodegenerative disorders; Phenolic acids; Stilbenes

DOI:  https://doi.org/10.1007/s11064-023-04046-z
Environ Sci Pollut Res Int. 2023 Nov 06.

Chicoric acid enhances the antioxidative defense system and protects against inflammation and apoptosis associated with the colitis model induced by dextran sulfate sodium in rats.

Fahad Alharthi.

  Although several anticolitic drugs are available, their application is associated with numerous side effects. Chicoric acid (CA) is a hydroxycinnamic acid found naturally in chicory (Cichorium intybus), purple coneflower (Echinacea purpurea), and basil with numerous health benefits, such as antioxidative and anti-inflammatory activities. Here, the potential anticolitic efficiency of CA against dextran sulfate sodium (DSS)-induced colitis in rats was examined in rats. Animals were randomly assigned to the following five groups: control, CA (100 mg/kg body weight), DSS [(DSS); 4% w/v], CA + DSS (100 mg/kg), and the 5-aminosalicylic acid (100 mg/kg) + DSS group. The obtained data revealed that CA significantly prevented the shortening of colon length. Meanwhile, the oxidative stress-related enzymes were increased, while malondialdehyde and nitric oxide, were markedly decreased significantly by CA. The results also indicated that CA administration decreased significantly the pro-apoptogenic indices (Bax and caspase-3) and enhanced significantly Bcl-2, the anti-apoptogenic protein. Moreover, DSS caused a significant elevation of pro-inflammatory mediators, including interleukin-1β, tumor necrosis factor-α, myeloperoxidase, cyclooxygenase II, prostaglandin E2, and peroxisome proliferator-activated receptor gamma. Interestingly, these changes were significantly decreased following the CA administration. At the molecular level, CA supplementation has increased significantly the expression level of nuclear factor erythroid 2-related factor-2 (Nrf2) and decreased the expressions of nitric oxide synthase and mitogen-activated protein kinase 14. CA has been determined to significantly lessen DSS-induced colitis by activating Nrf2 and its derived antioxidant molecules and suppressing inflammation and apoptosis cascades associated with the development of colitis; suggesting that CA could be used as an alternative naturally-derived anticolitic agent.

Keywords:  Apoptosis; Chicoric acid; Colitis; Dextran sulfate sodium; Inflammation; Nrf2

DOI:  https://doi.org/10.1007/s11356-023-30742-y
Front Neurosci. 2023 ;17 1202167

Modulating mitochondrial calcium channels (TRPM2/MCU/NCX) as a therapeutic strategy for neurodegenerative disorders.

Gretchen A Johnson, Raghu R Krishnamoorthy, Dorota L Stankowska.

  Efficient cellular communication is essential for the brain to regulate diverse functions like muscle contractions, memory formation and recall, decision-making, and task execution. This communication is facilitated by rapid signaling through electrical and chemical messengers, including voltage-gated ion channels and neurotransmitters. These messengers elicit broad responses by propagating action potentials and mediating synaptic transmission. Calcium influx and efflux are essential for releasing neurotransmitters and regulating synaptic transmission. Mitochondria, which are involved in oxidative phosphorylation, and the energy generation process, also interact with the endoplasmic reticulum to store and regulate cytoplasmic calcium levels. The number, morphology, and distribution of mitochondria in different cell types vary based on energy demands. Mitochondrial damage can cause excess reactive oxygen species (ROS) generation. Mitophagy is a selective process that targets and degrades damaged mitochondria via autophagosome-lysosome fusion. Defects in mitophagy can lead to a buildup of ROS and cell death. Numerous studies have attempted to characterize the relationship between mitochondrial dysfunction and calcium dysregulation in neurodegenerative diseases such as Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, Amyotrophic lateral sclerosis, spinocerebellar ataxia, and aging. Interventional strategies to reduce mitochondrial damage and accumulation could serve as a therapeutic target, but further research is needed to unravel this potential. This review offers an overview of calcium signaling related to mitochondria in various neuronal cells. It critically examines recent findings, exploring the potential roles that mitochondrial dysfunction might play in multiple neurodegenerative diseases and aging. Furthermore, the review identifies existing gaps in knowledge to guide the direction of future research.

Keywords:  ROS; aging; calcium; mitochondria; neurodegeneration

DOI:  https://doi.org/10.3389/fnins.2023.1202167
J Alzheimers Dis. 2023 Nov 02.

Oxidative Stress and Natural Antioxidants: Back and Forth in the Neurological Mechanisms of Alzheimer's Disease.

Shalini Mani, Rajni Dubey, I-Chun Lai, M Arockia Babu, Sakshi Tyagi, Geeta Swargiary, Deepansh Mody, Manisha Singh, Shriya Agarwal, Danish Iqbal, Sanjay Kumar, Munerah Hamed, Punya Sachdeva, Abdulmajeed G Almutary, Hind Muteb Albadrani, Shreesh Ojha, Sandeep Kumar Singh, Niraj Kumar Jha.

  Alzheimer's disease (AD) is characterized by the progressive degeneration of neuronal cells. With the increase in aged population, there is a prevalence of irreversible neurodegenerative changes, causing a significant mental, social, and economic burden globally. The factors contributing to AD are multidimensional, highly complex, and not completely understood. However, it is widely known that aging, neuroinflammation, and excessive production of reactive oxygen species (ROS), along with other free radicals, substantially contribute to oxidative stress and cell death, which are inextricably linked. While oxidative stress is undeniably important in AD, limiting free radicals and ROS levels is an intriguing and potential strategy for deferring the process of neurodegeneration and alleviating associated symptoms. Therapeutic compounds from natural sources have recently become increasingly accepted and have been effectively studied for AD treatment. These phytocompounds are widely available and a multitude of holistic therapeutic efficiencies for treating AD owing to their antioxidant, anti-inflammatory, and biological activities. Some of these compounds also function by stimulating cholinergic neurotransmission, facilitating the suppression of beta-site amyloid precursor protein-cleaving enzyme 1, α-synuclein, and monoamine oxidase proteins, and deterring the occurrence of AD. Additionally, various phenolic, flavonoid, and terpenoid phytocompounds have been extensively described as potential palliative agents for AD progression. Preclinical studies have shown their involvement in modulating the cellular redox balance and minimizing ROS formation, displaying them as antioxidant agents with neuroprotective abilities. This review emphasizes the mechanistic role of natural products in the treatment of AD and discusses the various pathological hypotheses proposed for AD.

Keywords:  Alzheimer’s disease; antioxidants; neuroprotection; oxidative stress; therapeutics; vitamins

DOI:  https://doi.org/10.3233/JAD-220700
Phytomedicine. 2023 Oct 30. pii: S0944-7113(23)00527-5. [Epub ahead of print]122 155168

Ginsenoside RK1 improves cognitive impairments and pathological changes in Alzheimer's disease via stimulation of the AMPK/Nrf2 signaling pathway.

Lingyu She, Jinfeng Sun, Li Xiong, Ankang Li, Liwei Li, Haibin Wu, Juan Ren, Wei Wang, Guang Liang, Xia Zhao.

   BACKGROUND: The pathogenesis of Alzheimer's disease (AD) is complex, resulting in unsatisfactory effects of single-target therapeutic drugs. Accumulation evidence suggests that low toxicity multi-target drugs may play effective roles in AD. Ginseng is the root and rhizome of Panax ginseng Meyer, which can be used not only as herbal medicine but also as a functional food to support body functions. Ginsenoside RK1 (RK1), obtained from ginseng plants through high-temperature treatment, has antiapoptotic, antioxidant, anti-inflammatory effects and these events are involved in the development of AD. So, we believe that RK1 may be an effective drug for the treatment of AD.
HYPOTHESIS/PURPOSE: We aimed to investigate the potential protective effects and mechanisms of RK1 in AD.
METHODS: Neuronal damage was detected by MTT assay, LDH assay, immunofluorescence and western blotting. Oxidative stress was measured by JC-1 staining, reactive oxygen species (ROS) staining, superoxide dismutase (SOD) and malonaldehyde (MDA). The cognitive deficit was measured through morris water maze (MWM) and novel object recognition (NOR) tests.
RESULTS: RK1 attenuated Aβ-induced apoptosis, restored mitochondrial membrane potential (ΔΨm), and reduced intracellular levels of ROS in both PC12 cells and primary cultured neurons. In vivo, RK1 significantly improved cognitive deficits and mitigated AD-like pathological features. Notably, RK1 demonstrated superior efficacy compared to the positive control drug, donepezil. Mechanistically, our study elucidates that RK1 modulates the phosphorylation of AMP-activated protein kinase (AMPK) and its downstream target, NF-E2-related factor 2 (Nrf2), leading to the optimization of mitochondrial membrane potential, reduction of ROS levels, and mitigation of AD-like pathology. It's noteworthy that blocking the AMPK signaling pathway attenuated the protective effects of RK1.
CONCLUSION: RK1 demonstrates superior efficacy in alleviating cognitive deficits and mitigating pathological changes compared to donepezil. These findings suggest the potential utility of RK1-based therapies in the development of treatments for AD.

Keywords:  AD-type pathologies; AMPK pathway; Alzheimer's disease; Oxidative stress; RK1

DOI:  https://doi.org/10.1016/j.phymed.2023.155168
Biochim Biophys Acta Mol Cell Res. 2023 Sep 15. pii: S0167-4889(23)00146-5. [Epub ahead of print] 119573

Reactive oxygen species and cell signaling. Mini review.

Diana Averill-Bates.

  Reactive oxygen species (ROS) is a term encompassing a group of highly reactive oxygen-derived molecules. In physiological systems, ROS production exists in concert with antioxidant defenses, which safeguard cells against higher, toxic levels of ROS. Oxidative stress, coined as "oxidative distress", is "a serious imbalance between the generation of ROS and antioxidant defenses in favor of ROS, causing excessive oxidative damage to biomolecules". At physiological levels, ROS are essential for many cellular processes, which is known as "oxidative eustress". Oxidants like hydrogen peroxide (H2O2) activate signaling pathways like mitogen-activated protein kinases (MAPK)s and phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt). ROS activate transcription factors like nuclear factor erythroid 2-related factor 2 (Nrf2), hypoxia-inducible factor 1α (HIF-1α), activator protein 1 (AP-1), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Redox signaling through H2O2 mainly occurs through reversible oxidation of protein cysteine thiolate residues (RS-) to form sulfenic acids (RSOH). An unresolved question is that the reaction rate of H2O2 with protein thiols is very low. In cells, the reaction of H2O2 with protein thiols is likely to be outcompeted by faster reactions of H2O2 with peroxiredoxins and glutathione peroxidases. A novel mechanism being explored is that H2O2 could react with peroxiredoxins that act as reactive redox sensor proteins, leading to peroxiredoxin-mediated relays. Very few redox signaling pathways have been well characterized. Improved understanding of precise mechanisms by which ROS regulate signaling pathways and the role of cellular sensors, is essential for deciphering their roles in physiological and pathological conditions.

Keywords:  Cell signaling; Nrf2; Oxidative stress; ROS; Thiol oxidation; Transcription factor

DOI:  https://doi.org/10.1016/j.bbamcr.2023.119573
Front Pharmacol. 2023 ;14 1269581

From imbalance to impairment: the central role of reactive oxygen species in oxidative stress-induced disorders and therapeutic exploration.

Sheryar Afzal, Aimi Syamima Abdul Manap, Ali Attiq, Ibrahim Albokhadaim, Mahmoud Kandeel, Sameer M Alhojaily.

  Increased production and buildup of reactive oxygen species (ROS) can lead to various health issues, including metabolic problems, cancers, and neurological conditions. Our bodies counteract ROS with biological antioxidants such as SOD, CAT, and GPx, which help prevent cellular damage. However, if there is an imbalance between ROS and these antioxidants, it can result in oxidative stress. This can cause genetic and epigenetic changes at the molecular level. This review delves into how ROS plays a role in disorders caused by oxidative stress. We also look at animal models used for researching ROS pathways. This study offers insights into the mechanism, pathology, epigenetic changes, and animal models to assist in drug development and disease understanding.

Keywords:  animal models; drug discovery; epigenetic marks; oxidative stress; reactive oxygen species

DOI:  https://doi.org/10.3389/fphar.2023.1269581
Life Sci. 2023 Nov 08. pii: S0024-3205(23)00892-5. [Epub ahead of print] 122257

Mitochondrial dysfunction and neurological disorders: A narrative review and treatment overview.

Eman E Alshial, Muhammad Idris Abdulghaney, Al-Hassan Soliman Wadan, Mohamed Abdelfatah Abdellatif, Nada E Ramadan, Aya Muhammed Suleiman, Nahla Waheed, Maha Abdellatif, Haitham S Mohammed.

  Mitochondria play a vital role in the nervous system, as they are responsible for generating energy in the form of ATP and regulating cellular processes such as calcium (Ca2+) signaling and apoptosis. However, mitochondrial dysfunction can lead to oxidative stress (OS), inflammation, and cell death, which have been implicated in the pathogenesis of various neurological disorders. In this article, we review the main functions of mitochondria in the nervous system and explore the mechanisms related to mitochondrial dysfunction. We discuss the role of mitochondrial dysfunction in the development and progression of some neurological disorders including Parkinson's disease (PD), multiple sclerosis (MS), Alzheimer's disease (AD), depression, and epilepsy. Finally, we provide an overview of various current treatment strategies that target mitochondrial dysfunction, including pharmacological treatments, phototherapy, gene therapy, and mitotherapy. This review emphasizes the importance of understanding the role of mitochondria in the nervous system and highlights the potential for mitochondrial-targeted therapies in the treatment of neurological disorders. Furthermore, it highlights some limitations and challenges encountered by the current therapeutic strategies and puts them in future perspective.

Keywords:  Alzheimer's disease; Depression; Epilepsy; Mitochondrial dysfunction; Multiple sclerosis; Parkinson's disease

DOI:  https://doi.org/10.1016/j.lfs.2023.122257
Nat Prod Res. 2023 Nov 10. 1-11

Flavonoids: the use in mental health and related diseases.

Camilla Nicolucci, Milena Padovani, Fernanda de Castro Rodrigues, Laura Nagy Fritsch, Ana Cristina Santos, Denise Gonçalves Priolli, Juliana M Sciani.

  Given the current increase in mental and neurological disorders, there is an urgent need to develop alternative treatments for patients. Flavonoids exhibit diverse biological activities, including antioxidant, anti-inflammatory and neuroprotective, and has been considered potential therapies for central nervous system diseases, such as Alzheimer's disease, Parkinson's disease, drug addiction, and stroke. Studies have shown that flavonoids protect neurons from oxidative stress, reduce inflammation, improve brain blood flow and enhance cognitive function. Moreover, its modulation of neurotransmission, such as GABAergic, dopaminergic, serotoninergic, and noradrenergic, has been studied for the treatment of mental disorders that require sedative effects, antidepressants, sleep inducers and anxiety reduction. Although more research is needed to fully understand the mechanisms and potential benefits of these compounds, the use of flavonoids for neurological diseases is a promising avenue for future research and development. This review focuses on major flavonoid subclasses and their applications in central nervous system disorders.

Keywords:  Flavonoids; herbal medicine; mental disorders; phytotherapy

DOI:  https://doi.org/10.1080/14786419.2023.2275275
Mol Immunol. 2023 Nov 03. pii: S0161-5890(23)00208-0. [Epub ahead of print]164 17-27

Pterostilbene accelerates wound healing response in diabetic mice through Nrf2 regulation.

Goutham V Ganesh, Kunka Mohanram Ramkumar.

  Pterostilbene (PTS), known for its diverse beneficial effects via Nuclear factor erythroid-2 related factor (Nrf2) activation, holds potential for Diabetic Foot Ulcer (DFU) treatment. However, PTS-mediated Nrf2 regulation in diabetic wounds has yet to be elucidated. We used IC21 macrophage-conditioned media to simulate complex events that can influence the fibroblast phenotype using L929 cells during the wound healing process under a hyperglycemic microenvironment. We found that PTS attenuated fibroblast migration and alpha-smooth muscle actin (α-SMA) levels and hypoxia-inducible factor- 1 alpha (HIF1α). Furthermore, we demonstrated that wounds in diabetic mice characterized by impaired wound closure in a heightened inflammatory milieu, such as the NOD-like receptor P3 (NLRP3) and intercellular adhesion molecule 1 (ICAM1), and deficient Nrf2 response accompanying lowered Akt signaling and heme oxygenase1 (HO1) expression along with the impaired macrophage M2 marker CD206 expression, was rescued by administration of PTS. Such an elicited response was also compared favorably with the standard treatment using Regranex, a commercially available topical formulation for treating DFUs. Our findings suggest that PTS regulates Nrf2 in diabetic wounds, triggering a pro-wound healing response mediated by macrophages. This insight holds the potential for developing targeted therapies to heal chronic wounds, including DFUs.

Keywords:  Diabetic Foot Ulcers; Fibroblast migration; Macrophage M2 response; Nuclear factor erythroid-2 related factor; Pterostilbene; Targeted therapies

DOI:  https://doi.org/10.1016/j.molimm.2023.10.010
Redox Biol. 2023 Nov 06. pii: S2213-2317(23)00359-2. [Epub ahead of print]68 102958

A role for the cystathionine-β-synthase /H2S axis in astrocyte dysfunction in the aging brain.

Anindya Dey, Pijush Kanti Pramanik, Shailendra Kumar Dhar Dwivedi, Fiifi Neizer-Ashun, Tamas Kiss, Abhrajit Ganguly, Heather Rice, Priyabrata Mukherjee, Chao Xu, Mohiuddin Ahmad, Anna Csiszar, Resham Bhattacharya.

  Astrocytic dysfunction is central to age-related neurodegenerative diseases. However, the mechanisms leading to astrocytic dysfunction are not well understood. We identify that among the diverse cellular constituents of the brain, murine and human astrocytes are enriched in the expression of CBS. Depleting CBS in astrocytes causes mitochondrial dysfunction, increases the production of reactive oxygen species (ROS) and decreases cellular bioenergetics that can be partially rescued by exogenous H2S supplementation or by re-expressing CBS. Conversely, the CBS/H2S axis, associated protein persulfidation and proliferation are decreased in astrocytes upon oxidative stress which can be rescued by exogenous H2S supplementation. Here we reveal that in the aging brain, the CBS/H2S axis is downregulated leading to decreased protein persulfidation, together augmenting oxidative stress. Our findings uncover an important protective role of the CBS/H2S axis in astrocytes that may be disrupted in the aged brain.

Keywords:  Aging; Astrocyte; Hydrogen sulfide; Oxidative stress; Protein persulfidation

DOI:  https://doi.org/10.1016/j.redox.2023.102958
Biomed Pharmacother. 2023 Nov 01. pii: S0753-3322(23)01606-2. [Epub ahead of print]168 115808

4-methoxycinnamyl p-coumarate reduces neuroinflammation by blocking NF-κB, MAPK, and Akt/GSK-3β pathways and enhancing Nrf2/HO-1 signaling cascade in microglial cells.

Mayuree Poonasri, Sakulrat Mankhong, Natthakarn Chiranthanut, Klaokwan Srisook.

  The active compound, 4-methoxycinnamyl p-coumarate (MCC), derived from the rhizome of Etlingera pavieana (Pierre ex Gagnep) R.M.Sm., has been shown to exert anti-inflammatory effects in several inflammatory models. However, its effects on microglial cells remain elusive. In the current study, we aimed to investigate the anti-neuroinflammatory activities of MCC and determine the potential mechanisms underlying its action on lipopolysaccharide (LPS)-induced BV2 microglial cells. Our results revealed that MCC significantly reduced the secretion of nitric oxide (NO) and prostaglandin E2, concomitantly inhibiting the expression levels of inducible NO synthase and cyclooxygenase-2 mRNA and proteins. Additionally, MCC effectively decreased the production of reactive oxygen species in LPS-induced BV2 microglial cells. MCC also attenuates the activation of NF-κB by suppressing the phosphorylation of IκBα and NF-κB p65 subunits and by blocking the nuclear translocation of NF-κB p65 subunits. Furthermore, MCC significantly reduced the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK), and protein kinase B (Akt)/glycogen synthase kinase-3β (GSK-3β). In addition, MCC markedly increased the expression of heme oxygenase-1 (HO-1) by upregulating the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. Collectively, our findings suggest that the anti-inflammatory activities of MCC could be attributed to its ability to suppress the activation of NF-κB, MAPK, and Akt/GSK-3β while enhancing that of Nrf2-mediated HO-1. Accordingly, MCC has promising therapeutic potential to treat neuroinflammation-related diseases.

Keywords:  4-methoxycinnamyl p-coumarate; Anti-neuroinflammatory activity; Heme oxygenase-1; Microglial cell; Nitric oxide; Prostaglandins E2

DOI:  https://doi.org/10.1016/j.biopha.2023.115808
J Ethnopharmacol. 2023 Nov 03. pii: S0378-8741(23)01229-1. [Epub ahead of print]319(Pt 3): 117359

Effect of woohwangchungsimwon and donepezil co-treatment on cognitive function and serum metabolic profiles in a scopolamine-induced model of Alzheimer's disease.

Jung-Seop Kim, Man-Gi Kim, Ji Eun Ryu, Ye-Been Lee, Quan Feng Liu, Kwang Ki Kim, Seung-Hun Cho, Sung Joon Shin, Byung-Su Koo, Hyung-Kyoon Choi.

   ETHNOPHARMACOLOGICAL RELEVANCE: Woohwangchungsimwon (WCW) is a traditional medicine used in East Asian countries to treat central nervous system disorders. Reported pharmacological properties include antioxidant effects, enhanced learning and memory, and protection against ischemic neuronal cell death, supporting its use in treating neurodegenerative diseases like Alzheimer's disease (AD).
AIM OF THE STUDY: The study aims to assess the effects of co-treatment with WCW and donepezil on cognitive functions and serum metabolic profiles in a scopolamine-induced AD model.
MATERIALS AND METHODS: Cell viability and reactive oxygen species (ROS) levels were measured in amyloid β-peptide25-35 (Aβ25-35)-induced SH-SY5Y cells. An AD model was established in ICR mice by intraperitoneal scopolamine administration. Animals underwent the step-through passive avoidance test (PAT) and Morris water maze (MWM) test. Hippocampal tissues were collected to examine specific protein expression. Serum metabolic profiles were analyzed using nuclear magnetic resonance (NMR) spectroscopy.
RESULTS: Co-treatment with WCW and donepezil increased cell viability and reduced ROS production in Aβ25-35-induced SH-SY5Y cells compared to that with donepezil treatment alone. Co-treatment improved cognitive functions and was comparable to donepezil treatment alone in the PAT and MWM tests. Pathways related to tyrosine, phenylalanine, and tryptophan biosynthesis, phenylalanine metabolism, and cysteine and methionine metabolism were altered by co-treatment. Levels of tyrosine and methionine, major serum metabolites in these pathways, were significantly reduced after co-treatment.
CONCLUSIONS: Co-treatment with WCW and donepezil shows promise as a therapeutic strategy for AD and is comparable to donepezil alone in improving cognitive function. Reduced tyrosine and methionine levels after co-treatment may enhance cognitive function by mitigating hypertyrosinemia and hyperhomocysteinemia, known risk factors for AD. The serum metabolic profiles obtained in this study can serve as a foundation for developing other bioactive compounds using a scopolamine-induced mouse model.

Keywords:  Alzheimer's disease; Co-treatment; Donepezil; NMR spectroscopy; Woohwangchungsimwon

DOI:  https://doi.org/10.1016/j.jep.2023.117359
Life Sci. 2023 Nov 05. pii: S0024-3205(23)00887-1. [Epub ahead of print] 122252

In silico and in vivo analysis of the relationship between ADHD and social isolation in pups rat model: Implication of redox mechanisms, and the neuroprotective impact of Punicalagin.

Karema Abu-Elfotuh, Alshaymaa Darwish, Heba M A Elsanhory, Hamzah Hussain Alharthi, Ahmed M E Hamdan, Amira M Hamdan, Rehab Ali Elsayed Masoud, Rana H Abd El-Rhman, Enji Reda.

  Attention deficit hyperactivity disorder (ADHD) has high incidence rate among children which may be due to excessive monosodium glutamate (MSG) consumption and social isolation (SI).
AIM: We aimed to explore the relationships between MSG, SI, and ADHD development and to evaluate the neuroprotective potential of Punicalagin (PUN).
METHODS: Eighty male rat pups randomly distributed into eight groups. Group I is the control, and Group II is socially engaged rats treated with PUN. Groups III to VII were exposed to ADHD-inducing factors: Group III to SI, Group IV to MSG, and Group V to both SI and MSG. Furthermore, Groups VI to VIII were the same Groups III to V but additionally received PUN treatment.
KEY FINDINGS: Exposure to MSG and/or SI led to pronounced behavioral anomalies, histological changes and indicative of ADHD-like symptoms in rat pups which is accompanied by inhibition of the nuclear factor erythroid 2-related factor 2 (Nrf2)/Heme-oxygenase 1 (HO-1)/Glutathione (GSH) pathway, decline of the brain-derived neurotrophic factor (BDNF) expression and activation of the Toll-like receptor 4 (TLR4)/Nuclear factor kappa B (NF-kB)/NLR Family Pyrin Domain Containing 3 (NLRP3) pathway. This resulted in elevated inflammatory biomarker levels, neuronal apoptosis, and disrupted neurotransmitter equilibrium. Meanwhile, pretreatment with PUN protected against all the previous alterations.
SIGNIFICANCE: We established compelling associations between MSG consumption, SI, and ADHD progression. Moreover, we proved that PUN is a promising neuroprotective agent against all risk factors of ADHD.

Keywords:  Attention-deficit/hyperactivity disorder; Neuroprotective; Oxidative injury; Punicalagin; Social isolation

DOI:  https://doi.org/10.1016/j.lfs.2023.122252
Mol Neurobiol. 2023 Nov 09.

Molecular Mechanisms Associated with Neurodegeneration of Neurotropic Viral Infection.

Prapimpun Wongchitrat, Theerawut Chanmee, Piyarat Govitrapong.

  Viral infections of the central nervous system (CNS) cause variable outcomes from acute to severe neurological sequelae with increased morbidity and mortality. Viral neuroinvasion directly or indirectly induces encephalitis via dysregulation of the immune response and contributes to the alteration of neuronal function and the degeneration of neuronal cells. This review provides an overview of the cellular and molecular mechanisms of virus-induced neurodegeneration. Neurotropic viral infections influence many aspects of neuronal dysfunction, including promoting chronic inflammation, inducing cellular oxidative stress, impairing mitophagy, encountering mitochondrial dynamics, enhancing metabolic rewiring, altering neurotransmitter systems, and inducing misfolded and aggregated pathological proteins associated with neurodegenerative diseases. These pathogenetic mechanisms create a multidimensional injury of the brain that leads to specific neuronal and brain dysfunction. The understanding of the molecular mechanisms underlying the neurophathogenesis associated with neurodegeneration of viral infection may emphasize the strategies for prevention, protection, and treatment of virus infection of the CNS.

Keywords:  Alzheimer’s disease; Apoptosis; Autophagy; CNS infection; Mitophagy; Neurodegeneration; Neuroinflammation; Neuronal metabolism; Neurotransmission system; Neurotropic virus; Oxidative stress; Viral infection

DOI:  https://doi.org/10.1007/s12035-023-03761-6
Ecotoxicol Environ Saf. 2023 Nov 06. pii: S0147-6513(23)01171-5. [Epub ahead of print]267 115667

Toxic dinoflagellate Karenia mikimotoi induces apoptosis in Neuro-2a cells through an oxidative stress-mediated mitochondrial pathway.

Jinfang Lu, Xiaoqin Niu, Hong Wang, He Zhang, Wanchun Guan.

  The dinoflagellate Karenia mikimotoi is a toxic bloom-forming species that threatens aquaculture and public health worldwide. Previous studies showed that K. mikimotoi induces neurotoxicity; however, the underlying mechanism is poorly understood. In this study, three neural cell lines were used to investigate the potential neurotoxicity of K. mikimotoi. The tested cells were exposed to a ruptured cell solution (RCS) of K. mikimotoi at different concentrations (0.5 × 105, 1.0 × 105, 2.0 × 105, 4.0 × 105, and 6 × 105 cells mL-1) for 24 h, and the RCS decreased cell viabilities and promoted Neuro-2a (N2A) cell apoptosis in a dose-dependent manner. The underlying mechanism was further investigated in N2A cells. At the biochemical level, the RCS stimulated reactive oxygen species (ROS) and malondialdehyde (MDA) formation, decreased SOD activity, and reduced mitochondrial membrane potential (MMP). At the gene level, the moderate RCS treatment (2.0 × 105 cells mL-1) upregulated antioxidant response genes (e.g., nrf-2, HO-1, NQO-1, and cat) to alleviate RCS-induced oxidative stress, while the high RCS treatment (4.0 × 105 cells mL-1) downregulated these genes, thereby aggravating oxidative stress. Meanwhile, apoptosis-related genes (e.g., p53, caspase 3, and bax2) were significantly upregulated and the anti-apoptotic gene bcl2 was suppressed after RCS treatment. Western blotting results for Caspase 3, Bax2 and Bcl2 were consistent with the mRNA trends. These results revealed that K. mikimotoi RCS can induce neural cell apoptosis via the oxidative stress-mediated mitochondrial pathway, providing novel insights into the neurotoxicity of K. mikimotoi.

Keywords:  Apoptosis; Karenia mikimotoi; Neuro-2a cells; Neurotoxicity; Oxidative stress

DOI:  https://doi.org/10.1016/j.ecoenv.2023.115667
Diabetes Metab Syndr. 2023 Oct 31. pii: S1871-4021(23)00180-7. [Epub ahead of print]17(11): 102884

A systematic review exploring the mechanisms by which citrus bioflavonoid supplementation benefits blood glucose levels and metabolic complications in type 2 diabetes mellitus.

Ankit Gupta, Abdulsatar Jamal, Dina A Jamil, Hayder A Al-Aubaidy.

   BACKGROUND: Citrus bioflavonoids are polyphenolic compounds that are derived from citrus fruits and vegetables. Although they are well known for their powerful antioxidant properties, their effects on glycemic control are not well understood. This review aims to highlight the potential benefits of using citrus bioflavonoids in patients with type 2 diabetes mellitus and its metabolic complications, as well as the medicinal effects of known subclasses of naturally occurring citrus bioflavonoids.
METHODS: In this systematic review, a survey of studies was conducted from January 2012 to February 2023 using various databases (PubMed, Medline, Google Scholar, and Scopus) to determine the effects of citrus bioflavonoid supplementation on reducing oxidative stress, improving lipid profiles, and glycemic index in patients with diabetes mellitus, as well as the proposed mechanisms of action.
RESULTS: The results of the survey indicate that citrus bioflavonoids may have a positive impact on reducing oxidative stress levels in patients with type 2 diabetes mellitus. In addition to reducing oxidative stress, citrus bioflavonoids may also have a positive impact on other markers of diabetes. For example, studies have shown that they can reduce non-enzymatic protein glycation, which is a process that occurs when glucose molecules bind to proteins in the body.
CONCLUSION: The reduction in oxidative stress that can be achieved using citrus bioflavonoids may help to maintain antioxidant levels in the body, thereby reducing the severity of diabetes and its complications. These findings suggest that citrus bioflavonoids may be a useful complementary therapy for patients with diabetes.

Keywords:  Antioxidants; Bioflavonoids; Blood glucose levels; Oxidative stress; Type 2 diabetes mellitus

DOI:  https://doi.org/10.1016/j.dsx.2023.102884