Toll-Like Receptor 4: A Promising Therapeutic Target for Alzheimer’s Disease

Mediators of Inflammation, Journal Year: 2022, Volume and Issue: 2022, P. 1 - 20

Published: Aug. 21, 2022

Alzheimer’s disease (AD) is a progressive neurodegenerative that primarily manifests as memory deficits and cognitive impairment has created health challenges for patients society. In AD, amyloid β-protein (Aβ) induces Toll-like receptor 4 (TLR4) activation in microglia. Activation of TLR4 downstream signaling pathways promotes the generation proinflammatory cytokines, such tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β), which also trigger astrocytes influence amyloid-dependent neuronal death. Therefore, may be an important molecular target treating AD by regulating neuroinflammation. Moreover, regulates apoptosis, autophagy, gut microbiota closely related to AD. This article reviews role pathogenesis range potential therapies targeting Elucidating regulatory mechanism provide valuable clues developing new therapeutic strategies

Language: Английский

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The key roles of reactive oxygen species in microglial inflammatory activation: Regulation by endogenous antioxidant system and exogenous sulfur-containing compounds

European Journal of Pharmacology, Journal Year: 2023, Volume and Issue: 956, P. 175966 - 175966

Published: Aug. 6, 2023

Language: Английский

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Thioredoxin-1 Promotes Mitochondrial Biogenesis Through Regulating AMPK/Sirt1/PGC1α Pathway in Alzheimer's Disease

ASN NEURO, Journal Year: 2023, Volume and Issue: 15, P. 175909142311592 - 175909142311592

Published: Jan. 1, 2023

Alzheimer's disease (AD) is the most common neurodegenerative disease. Increasing studies suggest that mitochondrial dysfunction closely related to pathogenesis of AD. Thioredoxin-1 (Trx-1), one major redox proteins in mammalian cells, plays neuroprotection However, whether Trx-1 could regulate biogenesis AD largely unknown. In present study, we found Aβ 25−35 treatment not only markedly induced excessive production reactive oxygen species and apoptosis, but also significantly decreased number mitochondria with biological activity adenosine triphosphate content mitochondria, suggesting was impaired cells. These changes were reversed by Lentivirus-mediated stable overexpression or exogenous administration recombinant human Trx-1. What's more, adeno-associated virus-mediated specific hippocampus β-amyloid precursor protein/presenilin 1 (APP/PS1) mice ameliorated learning memory attenuated hippocampal deposition. Importantly, APP/PS1 restored decrease biogenesis-associated proteins, including monophosphate -activated protein kinase (AMPK), silent information regulator factor 2-related enzyme (Sirt1) peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α). addition, rat adrenal pheochromocytoma (PC12) cells AMPK, Sirt1, PGC1α treatment. Pharmacological inhibition AMPK abolished effect on biogenesis. Taken together, our data provide evidence promoted via restoring AMPK/Sirt1/PGC1α pathway

Language: Английский

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Thioredoxin-1 Protects Neurons Through Inhibiting NLRP1-Mediated Neuronal Pyroptosis in Models of Alzheimer’s Disease

Molecular Neurobiology, Journal Year: 2024, Volume and Issue: 61(11), P. 9723 - 9734

Published: July 8, 2024

Language: Английский

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Z-ligustilide provides a neuroprotective effect by regulating the phenotypic polarization of microglia via activating Nrf2-TrxR axis in the Parkinson's disease mouse model

Redox Biology, Journal Year: 2024, Volume and Issue: 76, P. 103324 - 103324

Published: Aug. 23, 2024

The polarization phenotype of microglia is critical in the progression Parkinson's disease (PD). Molecules that can polarize toward M2 represent a promising class compounds for anti-PD medications. Z-ligustilide (ZLG) naturally occurring enol ester with diverse pharmacological properties, especially neuroprotection. For first time, we investigated effect ZLG on and elucidated its underlying mechanism. results primarily showed attenuated motor deficits mice prevented loss dopaminergic neurons substantia nigra. Mechanistically, alleviates oxidative stress-induced apoptosis by triggering endogenous antioxidant system. Besides, modulated phenotypic through activation Nrf2-TrxR axis, leading to towards phenotype. Taken together, our research prospective therapy candidate PD altering restoring redox equilibrium axis.

Language: Английский

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Time Course of Mitochondrial Antioxidant Markers in a Preclinical Model of Severe Penetrating Traumatic Brain Injury

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(3), P. 906 - 906

Published: Jan. 22, 2025

Traumatic brain injury (TBI) results from external mechanical forces exerted on the brain, triggering secondary injuries due to cellular excitotoxicity. A key indicator of damage is mitochondrial dysfunction, which associated with elevated free radicals and disrupted redox balance following TBI. However, temporal changes in homeostasis after penetrating TBI (PTBI) have not been thoroughly examined. This study aimed investigate alterations 30 min two-weeks post-injury adult male Sprague Dawley rats that experienced either PTBI or a Sham craniectomy. Redox parameters were measured at several points: min, 3 h, 6 24 d, 7 14 d post-injury. Mitochondrial samples core perilesional areas exhibited significant elevations protein modifications including 3-nitrotyrosine (3-NT) carbonyl (PC) adducts (14–53%, vs. Sham). In parallel, antioxidants such as glutathione, NADPH, peroxiredoxin-3 (PRX-3), thioredoxin-2 (TRX-2), superoxide dismutase 2 (SOD2) significantly depleted (20–80%, contrast, catalase (CAT) expression showed increase (45–75%, These findings indicate notable imbalance over two-week post-PTBI period suggesting therapeutic window employ antioxidant therapy extends well beyond h post-TBI.

Language: Английский

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Structure and Function Analyses of the Thioredoxin 2 and Thioredoxin Reductase Gene in Pacific White Shrimp (Litopenaeus vannamei)

Animals, Journal Year: 2025, Volume and Issue: 15(5), P. 629 - 629

Published: Feb. 21, 2025

The thioredoxin (Trx) system is one of the most significant systems in living organisms as it regulates cellular redox reactions and plays a pivotal protective role within cell by promoting homeostasis. Trx reductase (TrxR) are core oxidoreductases system. In this study, novel full-length cDNAs LvTrx2 LvTrxR were cloned from Litopenaeus vannamei. ORFs 453 bp 1785 bp, encoding polypeptides consisting 150 596 amino acids. Sequence alignment analysis revealed that acid sequence shared high degree identity (93%) with Penaeus chinensis, while LvTrxR, exhibited similarity level 95% previously submitted chinensis monodon sequences. Regarding tissue-specific expression patterns, showed its highest levels hepatopancreas gill. For was observed gill followed intestine. During exposure to ammonia-N, there upregulation relative mRNA gill, peak values occurring at 24 h or 48 exposure. After LPS injection, transcripts had different upregulated levels. These findings suggest play roles enhancing stress resistance bolstering antibacterial defense mechanisms L. To explore roles, knocked down vivo verify mechanism against 4-NP stress. silencing 4-NP-challenged shrimp could significantly induce gene antioxidant-related genes (except for LvTrxR) aggravate oxidative damage lipids. This study suggests involved regulating antioxidant processes, vital responses environmental

Language: Английский

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Exploring the Neuroprotective Role of Selenium: Implications and Perspectives for Central Nervous System Disorders

Exploration, Journal Year: 2025, Volume and Issue: unknown

Published: April 1, 2025

ABSTRACT Selenium (Se) is a crucial element in selenoproteins, key biomolecules for physiological function vivo. As selenium‐rich organ, the central nervous system can express all 25 kinds of which protect neurons by reducing oxidative stress and inflammatory response. However, decreased Se levels are prevalent variety neurological disorders, not conducive to treatment prognosis patients. Thus, biological study has emerged as focal point investigating pivotal role trace elements neuroprotection. This paper presents comprehensive review pathogenic mechanism diseases, protective Se, selenoproteins. Additionally, application neuroprotective agent disorder therapy, including ischemic stroke, Alzheimer's, Parkinson's, other summarized. The present aims offer novel insights methodologies prevention disorders with providing scientific basis development innovative Se‐based neuroprotectants promote their clinical against diseases.

Language: Английский

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Redox signaling and homeostasis

Published: April 1, 2025

Language: Английский

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Acetylation reader BRD4-driven TXNIP transcription enhances NLRP3 inflammasome activation in PCOS

Published: April 21, 2025

Polycystic ovary syndrome (PCOS) is an endocrine disorder characterized by the developmental arrest and dysfunction of ovarian granulosa cells (GCs), serving as a major cause infertility among women reproductive age. Persistent activation thioredoxin-interacting protein (TXNIP) due to aberrant histone acetylation modifications transcription potential trigger; however, its precise upstream regulatory mechanism remains poorly understood. In this study, we found that TXNIP was aberrantly upregulated in both dehydroepiandrosterone (DHEA)-induced PCOS-like rat model dihydrotestosterone (DHT)-induced primary GCs vitro. The TXNIP/NLRP3 inhibitor ruscogenin small interfering RNA (siRNA) targeting remarkably inhibited NLRP3 inflammasome activation, subsequently reversing metabolic phenotypes models. Further bioinformatic analysis revealed promoter region contains binding motifs bromodomain-containing 4 (BRD4) androgen receptor (AR). BRD4 AR exhibited inducible H3 acetylation-enriched promoter, whereas intervention with BRD4-selective JQ1 AR-selective attenuated binding, leading subsequent downregulation ultimately resulted suppression. Our data indicate upregulation resultant transcriptional are crucial pathways for resulting associated abnormalities from PCOS.

Language: Английский

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