Nrf2 Pathway Research Articles

Introduction: Diabetic cardiomyopathy (DCM) is associated with the development of overt heart failure driven by complex, interdependent pathophysiological mechanisms. Although a self-perpetuating cycle of oxidative stress and inflammation is implicated in the development and progression of DCM, the precise underlying causal mechanisms remain unclear, with limited, largely nonspecific treatment options. Hypothesis: Regulating redox status in db/db mice using the MPO inhibitor and redox-modulating agent N-acetyl lysyltyrosylcysteine amide (KYC) improves heart function by shaping the immune response towards a more regulated state. Methods: After two weeks of habituation, 8-week-old male type 2 diabetic db/db mice were randomly assigned to daily treatment with KYC (subcutaneous, 10 mg/kg/d) or vehicle (PBS) for 12 weeks. Additionally, sex-matched 8-week-old C57BL/6J mice were used as a control. After treatment, left ventricular function was assessed with echocardiography. Left ventricle morphologies were evaluated with hematoxylin and eosin staining; the myocardial fibrosis content was quantified with Masson’s trichrome staining. The absolute counts of total lymphocytes, monocytes, and neutrophils in the peripheral blood were measured, and splenic T cells were determined with flow cytometry. Cardiac oxidative stress, inflammatory, and regulatory marker expression were evaluated by qPCR. Results: Treatment of db/db mice with KYC improved cardiac function and was associated with dampened systemic and cardiac inflammation. Histopathological studies of the hearts of db/db mice at 20 weeks of age revealed that KYC treatment decreased cardiomyocyte size and myocardial fibrosis. Importantly, splenic T cell characterization revealed that KYC treatment resulted in a significantly higher proportion of CD4+CD25+Foxp3+ (forkhead box P3) regulatory T cells (Tregs) and a lower ratio of both effector CD4 and CD8 T cells (Teffs) and Treg than the vehicle-treated diabetic mice. Cardiac transcriptomic analysis revealed that db/db mice exhibited an inflammatory profile, whereas those treated with KYC displayed regulatory and antioxidative defense pathways, including the Nrf2 pathway. Conclusions: KYC improved cardiac function by expanding CD4+CD25+FoxP3+ T regulatory cells (Tregs) and limiting oxidative stress and inflammation in db/db mice. These results suggest that targeting oxidative stress and inflammation has therapeutic potential for delaying cardiac dysfunction.

Regulatory mechanism of quercitrin on oxidative stress and histone acetylation changes in PRV infected 3D4/2cells.

Acute Cu exposure induces neurotoxicity via DAF-16/FoxO and SKN-1/Nrf2 pathway.

Allergic asthma is a heterogeneous respiratory disease characterized by recurring chest tightness, wheezing, coughing, and shortness of breath. Inflammation in asthma can be characterized into two types: T2 inflammation (Eosinophilic asthma) and non-T2 inflammation (Neutrophilic asthma). T2 inflammation is mediated by T helper type 2 cells (Th2) And innate lymphoid type 2 cells (ILC2), whereas the involvement of neutrophils, macrophages, and cytokines such as IL-2, IL-6, and IL-17 characterizes non-T2 inflammation. Asthma pathophysiology is complexly linked to the dysregulation of key intracellular signaling pathways, including NF-κB, JAK-STAT, MAPK, PI3K, and Nrf2. NF-κB plays an important role in the maintenance of the chronic inflammatory response by increased expression of cytokines in the airway epithelium. In contrast, the MAPK signaling pathway, through the involvement of MAPKs, which belong to the family of serine/threonine protein kinases, contributes to inflammatory responses through responding to various stimuli such as osmotic stress, heat shock, mitogens, and the inflammatory cytokines, which result in the regulation of cell proliferation, cell survival, cell differentiation, and apoptosis. JAK-STAT signaling mediates cytokine responses critical for Th2-driven asthma phenotypes, while the PI3K pathway exacerbates inflammation and oxidative stress through several processes, e.g., cell growth, proliferation, survival, differentiation, and migration. Conversely, the Nrf2 pathway is a protective mechanism, regulating antioxidant defenses to counter oxidative damage in asthmatic airways. Exploring the interesting crosstalk between these pathways offers profound insights into asthma's intricate molecular mechanisms, thereby paving the way for targeted and personalized therapeutic interventions.

Astragaloside IV: a natural shield against ochratoxin A-induced hepatotoxicity in chicks by targeting the NRF2/NLRP3 signaling pathway.

Synthesis and biological evaluation of Sulforaphane derivatives with dual functions: Ischemia-reperfusion injury protection and antitumor effects.

Dose-dependent immunomodulation by dietary conjugated linoleic acid (CLA) in black seabream (Acanthopagrus schlegelii) via Keap1/Nrf2 and NF-κB pathways.

Collagen peptides from Skipjack tuna (Katsuwonus pelamis) bones: Composition, characterization, and mechanism of high-fat diet-induced NAFLD amelioration.

CX-5461 inhibits cell proliferation and induces ferroptosis of colorectal cancer cells by inactivating Nrf2 pathway.

Atraric acid attenuates chronic intermittent hypoxia-induced lung injury by inhibiting ferroptosis through activation of the NRF2 pathway.

Neuroprotective alpha-linolenic acid derived from black pepper targets PGK1 and activates the Nrf2 pathway in PC12cells and mice.

Ulcerative colitis (UC) is a chronic inflammatory disorder of the colon, characterized by persistent mucosal inflammation and epithelial barrier disruption. This study investigated the therapeutic efficacy of Scopoletin, a natural coumarin derivative with established anti-inflammatory and antioxidant properties, in a DSS-induced colitis model in Balb/c mice. A total of five experimental groups were established: a normal control, a DSS+ vehicle group, two Scopoletin-treated groups (10 and 30 mg/kg), and a reference group treated with Sulfasalazine (200 mg/kg). Network pharmacology analyses identified key inflammatory and immune-regulatory pathways potentially modulated by Scopoletin. In vivo assessments encompassed body weight monitoring, DAI scoring, colon length measurement, and histopathological evaluation using H&E, PAS, and Alcian blue staining. Scopoletin (30 mg/kg) treatment significantly ameliorated clinical and histological manifestations of colitis, including body weight loss and colonic shortening. Mechanistically, Scopoletin (30 mg/kg) attenuated the expression of pro-inflammatory cytokines such as TNF-α and IL-1β, suppressed NF-κB activation, MMP-9, COX-2 and enhanced the Nrf2 expression, leading to upregulation of antioxidant enzymes HO-1 and NQO1. Notably, Scopoletin (30 mg/kg) restored the expression of tight junction proteins such as Occludin and ZO-1, indicating reinforcement of epithelial barrier integrity. These findings demonstrated that Scopoletin protects against UC by suppressing inflammation, enhancing antioxidant defenses, and preserving mucosal barrier integrity, highlighting its potential as a therapeutic candidate for UC.

Effect of egg white peptides‑selenium chelate against APAP-induced damage in HepG2 cells and C. elegans via Nrf2 signaling.

IL4I1 attenuates myocardial infarction by inhibiting macrophage ferroptosis via the I3P/AHR/NRF2 signaling pathway.

Angiogenesis plays a key role in tissue regeneration by delivering oxygen and nutrients to the injury site. In diabetes mellitus, various factors, including hyperglycemia, neuropathy, increased reactive oxygen species, and proinflammatory cytokines, decrease the levels of proangiogenic factors, and increase levels of antiangiogenic factors, hamper angiogenesis and hinder wound healing. Reconstruction of the vasculature of the wound bed is crucial for promoting diabetic wound healing and improving the quality of life of patients. Given the urgent need for innovative therapies to promote angiogenesis and accelerate the repair of diabetic wounds, researchers have increasingly focused on identifying herbal products and their active constituents with promising proangiogenic activity. The aim of this review is to present verified data on the current knowledge on the effect of herbal products and their active constituents on angiogenesis processes in diabetic wounds. The electronic databases were searched for articles published from 2014 to present. The 38 articles comparing topically used herbal products /active constituents on angiogenesis in diabetic wound healing treatment versus control treatments (placebo or active therapy) were selected. Herbal products and their active constituents are rich sources of novel angio-modulators that may affect the angiogenesis process in diabetic wound healing via different mechanisms of action, including stimulation of VEGF, HRMs and activation of the Nrf2, PI3K/AKT, and HIF-1α signaling pathways. Topical applications of herbal products and their active constituents, especially when incorporated into wound dressings, show promising proangiogenic activity and represent a potential alternative for the treatment of diabetic wounds.

Astilbin (ATB) is a newly discovered natural compound with anti-inflammatory and immunomodulatory effects. However, its effects and underlying mechanisms in acute lung injury (ALI) remain unclear. An ALI model was established by intratracheal injection of lipopolysaccharide (LPS) into the trachea of C57BL/6 mice. In vitro, MLE-12 cells were stimulated with LPS. ATB was administered as a pretreatment to C57BL/6 mice and MLE-12 cells. ATB significantly alleviated ALI and suppressed the inflammatory response induced by LPS. Further data suggested that ATB inhibited LPS-induced ferroptosis in epithelial cells by increasing GPX4 and xCT expression. Moreover, ATB promoted NRF2 nuclear translocation in the LPS-treated group, while NRF2 inhibition significantly reversed the protective effects of ATB on ferroptosis and inflammation. NRF2 knockout in vivo abolished the protective effects of ATB against ALI and epithelial cell ferroptosis. Mechanistically, ATB increased NRF2 activity by binding to the Val608 amino acid of NRF2. The effect of ATB in improving ALI and ferroptosis was significantly reduced in NRF2 Val608 mutant mice. ATB mitigated ALI by suppressing epithelial cell ferroptosis and activating the NRF2 pathway via binding to Val608 of NRF2.

Increased intraocular pressure (IOP) is a significant risk factor for primary open-angle glaucoma (POAG). Physiologically, the trabecular meshwork (TM) controls IOP and the secretion of aqueous humor. A change in resistance to aqueous outflow is related to the phagocytic ability of trabecular meshwork cells (TMCs); in addition, alterations in extracellular matrix can also affect the function of TMCs. However, their application has certain limitations due to the nondirected differentiation and tumorigenic effect of stem cells, while their exosomes can reduce side effects and exert the same effects. The effects of mesenchymal stem cell exosomes on the extracellular environment and the function of human trabecular meshwork cells were observed, and glaucomato-related proteins as well as the NRF2 signaling pathway were detected. The exosomes could improve the phagocytosis of TMCs, reduce the damage, and lead to some changes in the pathways related to oxidative stress.

Background Chronic bronchitis (CB) is a common yet heterogeneous condition characterized by persistent inflammation, oxidative stress, airway hyperresponsiveness, and mucus hypersecretion. As an early stage of various severe pulmonary diseases, current therapeutic strategies remain unsatisfactory. Substantial evidence indicates that medicinal plants and compounds hold potential for treating inflammatory lung disorders. This study aims to consolidate recent and reliable evidence concerning the multi-targeted roles and underlying molecular mechanisms of these natural products in the treatment of CB. Methods This systematic review followed a prospectively registered protocol (PROSPERO ID: CRD42024588912). A comprehensive literature search encompassed multiple electronic databases, including PubMed, Scopus, Embase, Web of Science, VIP, Wan-fang, SinoMed, and the China National Knowledge Infrastructure Study selection strictly adhered to the PICOS principles to systematically identify medicinal plants and compounds with therapeutic potential against Chronic bronchitis. Results The results identified 13 medicinal plants and 19 compounds that exhibited anti-inflammatory activity. Additionally, 8 plants and 12 compounds demonstrated further therapeutic effects, including antioxidant, anti-mucus, and potential bronchodilatory activities. The underlying mechanisms primarily involved the NF-κB, PI3K/AKT/mTOR, TLR4, MAPK, and Nrf2 pathways. Ursolic acid emerged as the most promising clinical candidate. Conclusion This review represents the first comprehensive synthesis of experimentally verified efficacy and mechanisms associated with medicinal plants and compounds in CB treatment. Preclinical animal studies have confirmed the therapeutic benefits of these natural agents in alleviating CB symptoms, establishing a solid foundation for novel drug development and underscoring their considerable translational potential.

ABSTRACTBackgroundTyrosinase is the rate‐limiting enzyme in melanin biosynthesis, and its overactivity contributes to hyperpigmentation disorders. Existing tyrosinase inhibitors are often limited by poor potency against human tyrosinase (hTYR) or safety concerns.AimsTo evaluate the inhibitory potency, safety, and multifunctional activity of KT‐939, a newly synthesized human tyrosinase inhibitor, compared with established depigmenting agents.Patients/MethodsKT‐939 was synthesized and tested in vitro for tyrosinase inhibition, melanin suppression in human melanocytes, antioxidant activity (DPPH radical scavenging, NRF2 pathway activation), and anti‐inflammatory activity (cytokine expression in LPS‐stimulated macrophages). Safety was assessed in multiple skin‐related cell lines. A 28‐day, single‐center clinical study in healthy women with sensitive skin assessed the effects of 0.2% KT‐939 lotion on pigmentation and tolerability.ResultsKT‐939 strongly inhibited hTYR (IC₅₀ = 0.07 μM), demonstrating ~4‐fold greater potency than Thiamidol and far surpassing other comparators. In melanocytes, KT‐939 reduced melanin production (IC₅₀ = 0.36 μM) with reversible effects upon withdrawal. KT‐939 also displayed antioxidant activity, NRF2 activation, and suppression of pro‐inflammatory cytokines, without cytotoxicity up to 50 μM. Clinically, 28 days of KT‐939 lotion use improved skin spot lightening, tone uniformity, and overall brightness, with good tolerability in sensitive skin.ConclusionsKT‐939 is a potent and safe human tyrosinase inhibitor with additional antioxidant and anti‐inflammatory activity. These findings support its potential in cosmetic skin brightening and as a therapeutic candidate for hyperpigmentation disorders.

Traditional Chinese medicine (TCM) has been used in the treatment of vascular cognitive impairment and dementia caused by chronic cerebral hypoperfusion (CCH) in patients for hundreds of years. Ethnopharmacological researches have been conducted in recent years to elucidate their therapeutic effects on cognitive deficits and potential mechanisms in animal models. This manuscript critically reviewed recent 5-year experimental researches from PubMed on the topic, including 11 TCM formulae, 8 herb extracts, and 21 pure compounds extracted from TCM, including polyphenols, flavonoids, alkaloids, terpenoids, saponins, iridoid glycosides, glucosides, and others in rodent CCH models, using bilateral common carotid artery occlusion (BCCAO, 2VO), bilateral common carotid artery stenosis (BCAS), and unilateral common carotid artery occlusion (UCCAO). The underlying mechanisms are multiple, including the maintenance of blood brain barrier and endothelium integrity, the increase in cerebral blood flow, the amelioration of white matter lesions, the modulation of microglia M1/M2 phenotype, the scavenge of reactive oxidative oxygen species and reduction of proinflammatory factors, the maintenance of mitochondrial function, the inhibition of apoptosis, ferroptosis and pyroptosis, and the promotion of neuronal regeneration and angiogenesis through the regulation of gene/protein expressions, including the Toll, NF-κB, MAPK, PPARγ, and/or Nrf2 pathways. These mechanisms are not mutually exclusive, rather they play an integrated role to fortify the multi-components, multi-targets feature of TCM in the treatment of CCH and human vascular cognitive impairments.