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After PM2.5 stimulation, Nrf2‐KO mice showed more significant disruption of iron metabolism and lung damage than WT mice. C57BL/6 WT mice and Nrf2‐KO mice were stimulated with PM2.5 (20 mg·kg⁻¹) or normal saline, by nasal gavage. After seven days, the mice were killed and lung tissues, serum and BALF were collected. HE (a) and PAS (b) staining showed lung damage, inflammatory cells and goblet cells in the airway epithelium. The levels of IL‐6 (c) and TNF‐α (d) in BALF were measured. (e) Iron metabolism was assessed by measuring the serum levels of iron ions. (f) DAB staining was used to assess iron accumulation in lung tissues. (g–i) Western blotting was used to evaluate Nrf2, NQO1, HO‐1, TFRC, FTH‐1, and FTL expression levels in lung tissues. *P ≤ 0.05, significantly different from the control group, #P ≤ 0.05, significantly different from the PM2.5 treatment group; NS, not significant. The results shown were acquired from five experimental replicates.
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Background and Purpose
Our previous research showed that ferroptosis plays a crucial role in the pathophysiology of PM2.5‐induced lung injury. The present study aimed to investigate the protective role of the Nrf2 signalling pathway and its bioactive molecule tectoridin in PM2.5‐induced lung injury by regulating ferroptosis.
Experimental Approach...
Citations
... Moreover, the downregulation of BECN1 or the inhibition of AMPK was found to attenuate PM2.5-induced ferroptosis and ALI [67]. Furthermore, tectoridin, astragaloside IV, melatonin, rosavin, and sipeimine were identified as having the capacity to ameliorate PM2.5-induced lung injury by inhibiting ferroptosis in a manner that is dependent on Nrf2 [66,[71][72][73][74]. Furthermore, astaxanthin has been demonstrated to protect against PM2.5-induced lung injury by inhibiting both ferroptosis and apoptosis [75]. ...
Environmental pollution represents a significant public health concern, with the potential health risks associated with environmental pollutants receiving considerable attention over an extended period. In recent years, a substantial body of research has been dedicated to this topic. Since the discovery of ferroptosis, an iron-dependent programmed cell death typically characterized by lipid peroxidation, in 2012, there have been significant advances in the study of its role and mechanism in various diseases. A growing number of recent studies have also demonstrated the involvement of ferroptosis in the damage caused to the organism by environmental pollutants, and the molecular mechanisms involved have been partially elucidated. The targeting of ferroptosis has been demonstrated to be an effective means of ameliorating the health damage caused by PM2.5, organic and inorganic pollutants, and ionizing radiation. This review begins by providing a summary of the most recent and important advances in ferroptosis. It then proceeds to offer a critical analysis of the health effects and molecular mechanisms of ferroptosis induced by various environmental pollutants. Furthermore, as is the case with all rapidly evolving research areas, there are numerous unanswered questions and challenges pertaining to environmental pollutant-induced ferroptosis, which we discuss in this review in an attempt to provide some directions and clues for future research in this field.
... Furthermore, Astragaloside IV reduces the levels of pro-inflammatory cytokines interleukin (IL)-6, IL-1β, and tumour necrosis factor-α by modulating the Nrf2 signalling pathway. Melatonin and tectoridin reportedly have the same beneficial effects [100,101]. Sipeimine and rosavin prevent ferroptosis by reducing the levels of Fe 2+ , MDA, and inflammatory factors, offering therapeutic benefits in lung injury through phosphoinositide-3-kinase (PI3K)/protein kinase B (AKT)-mediated Nrf2 expression. Research indicates that AKT enhances Nrf2 expression and regulates ferroptosis in lung injury [102]. ...
Ferroptosis is a distinctive process of cellular demise that is linked to amino acid metabolism, lipid oxidation, and iron oxidation. The ferroptosis cascade genes, which are closely associated with the onset of lung diseases, are among the regulatory targets of nuclear factor erythroid 2-related factor 2 (Nrf2). Although the regulation of ferroptosis is mostly mediated by Nrf2, the precise roles and underlying regulatory mechanisms of ferroptosis and Nrf2 in lung illness remain unclear. This review provides new insights from recent discoveries involving the modulation of Nrf2 and ferroptosis in a range of lung diseases. It also systematically describes regulatory mechanisms involving lipid peroxidation, intracellular antioxidant levels, ubiquitination of Nrf2, and expression of FSP1 and GPX4. Finally, it summarises active ingredients and drugs with potential for the treatment of lung diseases. With the overarching aim of expediting improvements in treatment, this review provides a reference for novel therapeutic mechanisms and offers suggestions for the development of new medications for a variety of lung disorders.
... SIRT3 agonist melatonin was found to reduce PM 2.5 -induced ferroptosis in a murine model by activating Nrf2 signalling [209,210]. In addition to the abovementioned epigenetic modifiers, tectoridin, a phytochemical isolate from Belamcanda chinensis, has been shown to have a protective effect by activating Nrf2 signalling and positively impacting PM 2.5 -induced lung injury in mice [211]. ...
Air pollution is one of the leading causes of early deaths worldwide, with particulate matter (PM) as an emerging factor contributing to this trend. PM is classified based on its physical size, which ranges from PM 10 (diameter ≤10 μm) to PM 2.5 (≤2.5 μm) and PM 0.5 (≤0.5 μm). Smaller-sized PM can move freely through the air and readily infiltrate deep into the lungs, intensifying existing health issues and exacerbating complications. Lung complications are the most common issues arising from PM exposure due to the primary site of deposition in the respiratory system. Conditions such as asthma, COPD, idiopathic pulmonary fibrosis, lung cancer and various lung infections are all susceptible to worsening due to PM exposure. PM can epigenetically modify specific target sites, further complicating its impact on these conditions. Understanding these epigenetic mechanisms holds promise for addressing these complications in cases of PM exposure. This involves studying the effect of PM on different gene expressions and regulation through epigenetic modifications, including DNA methylation, histone modifications and microRNAs. Targeting and manipulating these epigenetic modifications and their mechanisms could be promising strategies for future treatments of lung complications. This review mainly focuses on different epigenetic modifications due to PM 2.5 exposure in the various lung complications mentioned above.
... For example, tectoridin and protocatechuic acid are compounds that were retained after digestion. Although these compounds did not exhibit ABTS antioxidant activity, they may been absorbed into epithelial cells to alleviate oxidative damage via their reported Nrf2 signalling activities (Table S1) (Dong et al., 2023;Varì et al., 2011). ...
... This leads to the attenuation of ferroptosis and the restoration of downregulated proteins involved in ferroptosis, such as GPX4, HO-1, and SLC7A11 [140]. Tectoridin, a flavonoid from the rhizome of Belamcanda chinensis, activates the Nrf2 signaling pathway to prevent ferroptosis in lung damage [141]. Similarly, rosavin, a key glycoside from Rhodiola plants, protects against PM2.5-induced lung injury by activating the PI3K/Akt/Nrf2 pathway to inhibit ferroptosis [142]. ...
Respiratory diseases, marked by structural changes in the airways and lung tissues, can lead to reduced respiratory function and, in severe cases, respiratory failure. The side effects of current treatments, such as hormone therapy, drugs, and radiotherapy, highlight the need for new therapeutic strategies. Traditional Chinese Medicine (TCM) offers a promising alternative, leveraging its ability to target multiple pathways and mechanisms. Active compounds from Chinese herbs and other natural sources exhibit anti-inflammatory, antioxidant, antitumor, and immunomodulatory effects, making them valuable in preventing and treating respiratory conditions. Ferroptosis, a unique form of programmed cell death (PCD) distinct from apoptosis, necrosis, and others, has emerged as a key area of interest. However, comprehensive reviews on how natural products influence ferroptosis in respiratory diseases are lacking. This review will explore the therapeutic potential and mechanisms of natural products from TCM in modulating ferroptosis for respiratory diseases like acute lung injury (ALI), asthma, pulmonary fibrosis (PF), chronic obstructive pulmonary disease (COPD), lung ischemia–reperfusion injury (LIRI), pulmonary hypertension (PH), and lung cancer, aiming to provide new insights for research and clinical application in TCM for respiratory health.
... This effect is achieved through the scavenging of hydroxyl and superoxide anion radicals [35]. Furthermore, tectoridin reverses lipid peroxidation induced by PM2.5 by activating the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway [36]. The antioxidant activity of esculin, a coumarin glucoside found in Cortex Fraxini, has been widely studied. ...
The extracts of Corydalis heterocarpa, a salt-tolerant plant, exhibit diverse physiological properties, including anti-inflammatory, anticancer, and antiadipogenic effects. However, the anti-aging effects of C. heterocarpa extract (CHE) on human skin cells have not yet been investigated. In the present study, we determined that CHE inhibited senescence-associated β-galactosidase (SA-β-gal)-stained senescent human dermal fibroblasts (HDFs). Furthermore, CHE markedly suppressed the expression of major regulatory proteins involved in senescence, including p53, p21, and caveolin-1. Interestingly, CHE promoted autophagic flux, as confirmed by the formation of microtubule-associated protein 1 light chain 3B (LC3B) puncta and lysosomal activity. Notably, using RNA sequencing (RNA-seq), we showed that CHE selectively regulated the gene expression of leucine-rich repeat and sterile alpha motif-containing 1 (LRSAM1), an important regulator of autophagy. The adenosine-monophosphate activated protein kinase/mammalian target of rapamycin (AMPK/mTOR) pathway, which is essential for autophagy regulation, was also modulated by CHE. LRSAM1 depletion not only inhibited LC3B expression but also decreased the autophagy flux induced by CHE. Moreover, the knockdown of LRSAM1 suppressed the reversal of CHE-induced senescence in old HDFs. Collectively, our study has revealed the rejuvenating effects and molecular mechanisms of CHE, suggesting that CHE may be a promising anti-aging agent.
... 33 Furthermore, oral administration of TEC prevents ferroptosis-stimulated changes in a mouse model of lung injury by augmenting the antioxidative Nrf2 signaling pathway. 34 Collectively, these studies underscore the diverse protective effects of TEC against various ailments, highlighting its potential as a multifaceted therapeutic agent. ...
Bladder cancer (BC) is a common and malignant tumor of the urinary tract, and its treatment options are limited. Tectoridin (TEC) has antitumor activity against prostate and colon cancer, but its effects on BC are poorly understood. BC cells were treated with increasing concentrations of TEC, and its effects on cell proliferation, migration, invasiveness, and apoptosis were assessed. Xenograft mouse model was used to evaluate the influences of TEC on BC tumor growth. Western blot analysis was conducted to explore the downstream pathways affected by TEC. TEC treatment decreased BC cell viability in a dose‐dependent manner (IC50 ≈ 25 μM), and inhibited cell proliferation, migration, and invasiveness while promoting apoptosis. Clinical analysis revealed high expression of RAB27B in BC tumor tissues, particularly in advanced stages, correlating with an unfavorable prognosis. In vitro experiments demonstrated that TEC suppressed the PI3K/MAPK pathway by targeting RAB27B, and overexpression of RAB27B counteracted the antitumor effects of TEC. In xenograft models, TEC administration suppressed tumor growth, reduced tumor volume, inhibited cell proliferation, and suppressed the PI3K/MAPK pathway, highlighting its potential as an inhibitor of tumor growth. TEC suppresses BC tumor growth by targeting RAB27B and inactivating the PI3K/MAPK signaling and may provide a promising therapeutic target for BC treatment.
... Besides, Nrf2 signaling pathway is of utmost importance in the regulation of ferroptosis (Dodson et al., 2019). Study has found that both SCL7A11 and GPX4 can be upregulated by activating Nrf2 signaling pathway, which can directly decompose lipid peroxidation products (Dong et al., 2023). Many proteins participate in iron storage and transport, such as FTH1, FTL1, TFR1 and FPN1, are also regulated by Nrf2 (Wang et al., 2022c). ...
Cadmium (Cd) and high molybdenum (Mo) are injurious to the body. Previous research has substantiated that Cd and Mo exposure caused testicular injury of ducks, but concrete mechanism is not fully clarified. To further survey the toxicity of co-exposure to Cd and Mo in testis, 40 healthy 8-day-old Shaoxing ducks (Anas platyrhyncha) were stochasticly distributed to 4 groups and raised with basic diet embracing Cd (4 mg/kg Cd) or Mo (100 mg/kg Mo) or both. At the 16th wk, testis tissues were gathered. The characteristic ultrastructural changes related to apoptosis and ferroptosis were observed in Mo or Cd or both groups. Besides, Mo or Cd or both repressed nuclear factor erythroid 2-related factor 2 (Nrf2) pathway via decreasing Nrf2, Heme oxygenase-1 (HO-1), NAD(P)H quinone oxidoreductase 1 (NQO1), Glutamate-cysteine ligase catalytic subunit (GCLC) and Glutamate-cysteine ligase modifier subunit (GCLM) mRNA expression of and Nrf2 protein expression, then stimulated apoptosis by elevating Bcl-2 antagonist/killer-1 (Bak-1), Bcl-2-associated X-protein (Bax), Cytochrome complex (Cyt-C), caspase-3 mRNA expression, cleaved-caspase-3 protein expression and apoptosis rate, as well as reducing B-cell lymphoma-2 (Bcl-2) mRNA expression and ratio of Bcl-2 to Bax, and triggered ferroptosis by upregulating Acyl-CoA Synthetase Long Chain Family Member 4 (ACSL4), transferrin receptor (TFR1) and Prostaglandin-Endoperoxide Synthase 2 (PTGS2) expression levels, and downregulating ferritin heavy chain 1 (FTH1), ferritin light chain 1 (FTL1), ferroportin 1 (FPN1), solute carrier family 7 member 11 (SCL7A11) and glutathione peroxidase 4 (GPX4) expression levels. The most obvious changes of these indexes were observed in co-treated group. Altogether, the results announced that Mo or Cd or both evoked apoptosis and ferroptosis by inhibiting Nrf2 pathway in the testis of ducks, and co-exposure to Mo and Cd exacerbated these variations.
... A recent study also showed that Nrf2 protects PM2.5 (20mg/kg)-induced lung injury through its regulation of iron-dependent cellular death or ferroptosis. This is supported by the observation that ferroptosis and lung injury in response to PM2.5 are more severe in Nrf2-deficient mouse lung tissue and cellular model [68]. Similarly, Tectoridin (50-100 mg/kg), a bioactive molecule, also ameliorates PM2.5 (20mg/kg for 7 days)-induced lung injury in mice as revealed by decreased morphological damage, necrosis, edema and inflammation with decreased IL-6 and TNF- through stimulation of antioxidant gene regulator Nrf2 and antioxidant genes like GSH and GPX4. ...
... Similarly, Tectoridin (50-100 mg/kg), a bioactive molecule, also ameliorates PM2.5 (20mg/kg for 7 days)-induced lung injury in mice as revealed by decreased morphological damage, necrosis, edema and inflammation with decreased IL-6 and TNF- through stimulation of antioxidant gene regulator Nrf2 and antioxidant genes like GSH and GPX4. In addition, pretreatment of BEAS-2B cells with Tectoridin (25, 50 and 100µM for 1 h) reduces PM2.5 (400 µg/ml for 24h)-induced ROS generation through activation of Nrf2, GSH and inhibition of PM2.5-induced inflammatory MDA [68]. These results suggest that Tectoridin has potential to controlling PM2.5-induced oxidative stress, ferroptosis, and lung pathologies. ...
Today, air pollution is one of the greatest threats to organismal healthspan. The environmental air of earth is contaminated with a wide variety of artificially generated pollutants like fine particulate matter (PM2.5) emitting from industry, fuel engine vehicles, biomass combustion, fumes from blasting, crop residue burning, and wildfire. The air pollutant PM2.5 induces massive oxidative stress and inflammation, the major contributors in initiation and progression of numerous diseases including pulmonary, cardiovascular, renal, hepatic, reproductive, neurological, mental, and accelerated biological aging. The provocative question is the following: how can we solve this air pollution associated problem? As it is not realistic to clean the environment at once from artificially generated toxic pollution, initiatives have been undertaken to develop novel therapeutic approaches to control air-pollutant-induced oxidative stress and inflammation and associated devastating diseases. The primary goal of this review article is to discuss systematically the key findings of numerous recent preclinical studies documenting first, the role of air pollutant PM2.5 in augmentation of inflammation, oxidative stress, and associated diseases; and second, the efficacies of different natural and synthetic compounds in amelioration of PM2.5-induced oxidative stress, inflammation, pyroptosis, and associated pathologies. Further investigation on the safety of these compounds will be helpful to select effective and non-toxic compound(s) for clinical trial and drug development.
... A recent study also showed that Nrf2 protects PM2.5 (20mg/kg)-induced lung injury through its regulation of iron-dependent cellular death or ferroptosis. This is supported by the observation that ferroptosis and lung injury in response to PM2.5 are more severe in Nrf2-deficient lung tissue and cellular model [68]. Similarly, Tectoridin (50-100 mg/kg), a bioactive molecule, also ameliorates PM2.5 (20mg/kg for 7 days)-induced lung injury as revealed by decreased morphological damage, necrosis, edema and inflammation with decreased IL-6 and TNF-through stimulation of antioxidant gene regulator Nrf2 and antioxidant genes like GSH and GPX4. ...
... Similarly, Tectoridin (50-100 mg/kg), a bioactive molecule, also ameliorates PM2.5 (20mg/kg for 7 days)-induced lung injury as revealed by decreased morphological damage, necrosis, edema and inflammation with decreased IL-6 and TNF-through stimulation of antioxidant gene regulator Nrf2 and antioxidant genes like GSH and GPX4. Similarly, pretreatment of BEAS-2B cells with Tectoridin (25, 50 and 100 uM for 1 h) reduces PM2.5 (400µg/ml for 24h)-induced ROS generation through activation of Nrf2, GSH and inhibition of PM2.5-induced inflammatory MDA [68]. These results suggest that Tectoridin has potential to controlling PM2.5-induced oxidative stress, ferroptosis, and lung pathologies. ...
Today, air pollution is the greatest threat to organismal healthspan. The environment of our planet earth, the habitat of over eight billion humans and estimated twenty billion billions other animals, is contaminated with a wide variety of pollutants. Unfortunately, humans, out of billions and billions of living organisms on earth, are solely responsible for polluting the environment through emitting pollutants like particulate matter from industry, fuel engine vehicles, biomass combustion, toxic fumes from blasting, and wildfire. In the modern world, human-caused air pollutants induce massive oxidative stress and inflammation, the major contributors in initiation and progression of many diseases including pulmonary, cardiovascular, renal, hepatic, reproductive, neurological, mental, and accelerated biological aging. The provocative question is the following: how can we solve this human-created problem? As it is not realistic to clean the environment at once from human-caused pollution, initiatives have been undertaken to develop novel therapeutic approaches to control air-pollutant-induced oxidative stress and inflammation to protect humans from pollution-induced devastating diseases. In this article, I discuss the key findings of numerous recent preclinical studies documenting first, the role of air pollutant PM2.5 in augmentation of inflammation, oxidative stress, and associated diseases; and second, the efficacies of different natural and synthetic compounds in amelioration of PM2.5-induced oxidative stress, inflammation, pyroptosis, and associated pathologies.
