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Nuclear factor erythroid 2-related factor-mediated signaling alleviates ferroptosis during cerebral ischemia-reperfusion injury
Spinal cord injury (SCI) induces severe functional impairments and involves intricate secondary injury mechanisms. Tanshinone IIA (TIIA), a key bioactive component of Salvia miltiorrhiza, exhibits neuroprotective potential, yet its role in ferroptosis regulation post-SCI remains undefined. This study explored the protective effects and underlying mechanisms of TIIA in SCI. In a rat SCI model, TIIA markedly enhanced hind limb motor function and preserved histopathological integrity while mitigating mitochondrial damage, ferroptosis, and oxidative stress. TIIA attenuated ferroptosis by reducing reactive oxygen species (ROS), malondialdehyde (MDA), and acyl-CoA synthetase long-chain family member 4 (ACSL4) while elevating glutathione (GSH), superoxide dismutase (SOD), and glutathione peroxidase 4 (GPX4) levels. Mechanistically, TIIA suppressed ferroptosis through modulation of the GPX4/ACSL4 axis. The ferroptosis inducer RSL3 abrogated these protective effects, further validating this mechanism. These findings highlight the therapeutic potential of TIIA in SCI by targeting the GPX4/ACSL4 pathway to attenuate ferroptosis and promote functional recovery.
Glutathione (GSH), a tripeptide synthesized intracellularly, serves as a pivotal antioxidant, neutralizing reactive oxygen species (ROS) and reactive nitrogen species (RNS) while maintaining redox homeostasis and detoxifying xenobiotics. Its potent antioxidant properties, particularly attributed to the sulfhydryl group (-SH) in cysteine, are crucial for cellular health across various organelles. The glutathione-glutathione disulfide (GSH-GSSG) cycle is facilitated by enzymes like glutathione peroxidase (GPx) and glutathione reductase (GR), thus aiding in detoxification processes and mitigating oxidative damage and inflammation. Mitochondria, being primary sources of reactive oxygen species, benefit significantly from GSH, which regulates metal homeostasis and supports autophagy, apoptosis, and ferroptosis, playing a fundamental role in neuroprotection. The vulnerability of the brain to oxidative stress underscores the importance of GSH in neurological disorders and regenerative medicine. Nebulization of glutathione presents a novel and promising approach to delivering this antioxidant directly to the central nervous system (CNS), potentially enhancing its bioavailability and therapeutic efficacy. This method may offer significant advantages in mitigating neurodegeneration by enhancing nuclear factor erythroid 2-related factor 2 (NRF2) pathway signaling and mitochondrial function, thereby providing direct neuroprotection. By addressing oxidative stress and its detrimental effects on neuronal health, nebulized GSH could play a crucial role in managing and potentially ameliorating conditions such as Parkinson’s Disease (PD) and Alzheimer’s Disease (AD). Further clinical research is warranted to elucidate the therapeutic potential of nebulized GSH in preserving mitochondrial health, enhancing CNS function, and combating neurodegenerative conditions, aiming to improve outcomes for individuals affected by brain diseases characterized by oxidative stress and neuroinflammation.
Ischemic stroke involves various pathological processes, among which ferroptosis is crucial. Previous studies by our group have indicated that electroacupuncture (EA) mitigates ferroptosis after ischemic stroke; however, the precise mechanism underlying this effect remains unclear. In the present study, we developed a rat model of middle cerebral artery occlusion/reperfusion. We chose the main acupoint of the treatment methods of the “Awakening and Opening of the Brain”. Rats’ neurological function and motor coordination were evaluated by neurological function score and the rotarod test, respectively, and the volume of cerebral infarction was analyzed by 2,3,5-triphenyltetrazolium chloride Staining. The cerebrovascular conditions were visualized by time-of-flight magentic resonance angiography. In addition, we detected changes in lipid peroxidation and endogenous antioxidant activity by measuring the malondialdehyde, glutathione, superoxide dismutase activities, glutathione/oxidized glutathione and reduced nicotinamide adenine dinucleotide phosphate/oxidized nicotinamide adenine dinucleotide phosphate ratios. Inductively coupled plasma-mass spectrometry, western blot, reverse transcription-polymerase chain reaction, fluoro-jade B staining, immunofluorescence analysis, and transmission electron microscopy were utilized to examine the influence of EA. The results indicate that EA treatment was effective in reversing neurological impairment, neuronal damage, and protecting mitochondrial morphology and decreasing the cerebral infarct volume in the middle cerebral artery occlusion/reperfusion rat model. EA reduced iron levels, inhibited lipid peroxidation, increased endogenous antioxidant activity, modulated the expression of several ferroptosis-related proteins, and promoted nuclear factor-E2-related factor 2 (Nrf2) nuclear translocation. However, the protective effect of EA was hindered by the Nrf2 inhibitor ML385. These findings suggest that EA can suppress ferroptosis and decrease damage caused by cerebral ischemia/reperfusion by activating Nrf2 and increasing the protein expression of solute carrier family 7 member 11 and glutathione peroxidase 4.
Citation: El-Gohary, R.M.; Okasha, A.H.; Abd El-Azeem, A.H.; Abdel Ghafar, M.T.; Ibrahim, S.; Hegab, I.I.; Farghal, E.E.; Shalaby, S.A.F.; Elshora, O.A.; ElMehy, A.E.; et al. Uncovering the Cardioprotective Potential of Diacerein in Doxorubicin Cardiotoxicity: Mitigating Ferritinophagy-Mediated Ferroptosis via Upregulating NRF2/SLC7A11/GPX4 Axis. Antioxidants 2024, 13, 493. https:// Abstract: Doxorubicin (DOX)-induced cardiotoxicity (DIC) is a life-threatening clinical issue with limited preventive approaches, posing a substantial challenge to cancer survivors. The anthraquinone diacerein (DCN) exhibits significant anti-inflammatory, anti-proliferative, and antioxidant actions. Its beneficial effects on DIC have yet to be clarified. Therefore, this study investigated DCN's car-dioprotective potency and its conceivable molecular targets against DIC. Twenty-eight Wister rats were assigned to CON, DOX, DCN-L/DOX, and DCN-H/DOX groups. Serum cardiac damage indices, iron assay, oxidative stress, inflammation, endoplasmic reticulum (ER) stress, apoptosis, ferritinophagy, and ferroptosis-related biomarkers were estimated. Nuclear factor E2-related factor 2 (NRF2) DNA-binding activity and phospho-p53 immunoreactivity were assessed. DCN administration effectively ameliorated DOX-induced cardiac cytomorphological abnormalities. Additionally, DCN profoundly combated the DOX-induced labile iron pool expansion alongside its consequent lethal lipid peroxide overproduction, whereas it counteracted ferritinophagy and enhanced iron storage. Indeed, DCN valuably reinforced the cardiomyocytes' resistance to ferroptosis, mainly by restoring the NRF2/solute carrier family 7 member 11 (SLC7A11)/glutathione peroxidase 4 (GPX4) signaling axis. Furthermore, DCN abrogated the cardiac oxidative damage, inflamma-tory response, ER stress, and cardiomyocyte apoptosis elicited by DOX. In conclusion, for the first time, our findings validated DCN's cardioprotective potency against DIC based on its an-tioxidant, anti-inflammatory, anti-ferroptotic, and anti-apoptotic imprint, chiefly mediated by the NRF2/SLC7A11/GPX4 axis. Accordingly, DCN could represent a promising therapeutic avenue for patients under DOX-dependent chemotherapy. Antioxidants 2024, 13, 493. https://doi.org/10.3390/antiox13040493 https://www.mdpi.com/journal/antioxidants Antioxidants 2024, 13, 493 2 of 18 Keywords: doxorubicin cardiotoxicity; iron; nuclear receptor coactivator 4-dependent ferritinophagy; ferroptosis; ferritin heavy chain polypeptide 1; oxidative stress; nuclear factor E2-related factor 2/solute carrier family 7 member 11/ glutathione peroxidase 4 axis; diacerein
Doxorubicin (DOX)-induced cardiotoxicity (DIC) is a life-threatening clinical issue with limited preventive approaches, posing a substantial challenge to cancer survivors. The anthraquinone diacerein (DCN) exhibits significant anti-inflammatory, anti-proliferative, and antioxidant actions. Its beneficial effects on DIC have yet to be clarified. Therefore, this study investigated DCN’s cardioprotective potency and its conceivable molecular targets against DIC. Twenty-eight Wister rats were assigned to CON, DOX, DCN-L/DOX, and DCN-H/DOX groups. Serum cardiac damage indices, iron assay, oxidative stress, inflammation, endoplasmic reticulum (ER) stress, apoptosis, ferritinophagy, and ferroptosis-related biomarkers were estimated. Nuclear factor E2-related factor 2 (NRF2) DNA-binding activity and phospho-p53 immunoreactivity were assessed. DCN administration effectively ameliorated DOX-induced cardiac cytomorphological abnormalities. Additionally, DCN profoundly combated the DOX-induced labile iron pool expansion alongside its consequent lethal lipid peroxide overproduction, whereas it counteracted ferritinophagy and enhanced iron storage. Indeed, DCN valuably reinforced the cardiomyocytes’ resistance to ferroptosis, mainly by restoring the NRF2/solute carrier family 7 member 11 (SLC7A11)/glutathione peroxidase 4 (GPX4) signaling axis. Furthermore, DCN abrogated the cardiac oxidative damage, inflammatory response, ER stress, and cardiomyocyte apoptosis elicited by DOX. In conclusion, for the first time, our findings validated DCN’s cardioprotective potency against DIC based on its antioxidant, anti-inflammatory, anti-ferroptotic, and anti-apoptotic imprint, chiefly mediated by the NRF2/SLC7A11/GPX4 axis. Accordingly, DCN could represent a promising therapeutic avenue for patients under DOX-dependent chemotherapy.
Citation: El-Gohary, R.M.; Okasha, A.H.; Abd El-Azeem, A.H.; Abdel Ghafar, M.T.; Ibrahim, S.; Hegab, I.I.; Farghal, E.E.; Shalaby, S.A.F.; Elshora, O.A.; ElMehy, A.E.; et al. Uncovering the Cardioprotective Potential of Diacerein in Doxorubicin Cardiotoxicity: Mitigating Ferritinophagy-Mediated Ferroptosis via Upregulating NRF2/SLC7A11/GPX4 Axis. Antioxidants 2024, 13, 493. https:// Abstract: Doxorubicin (DOX)-induced cardiotoxicity (DIC) is a life-threatening clinical issue with limited preventive approaches, posing a substantial challenge to cancer survivors. The anthraquinone diacerein (DCN) exhibits significant anti-inflammatory, anti-proliferative, and antioxidant actions. Its beneficial effects on DIC have yet to be clarified. Therefore, this study investigated DCN's car-dioprotective potency and its conceivable molecular targets against DIC. Twenty-eight Wister rats were assigned to CON, DOX, DCN-L/DOX, and DCN-H/DOX groups. Serum cardiac damage indices, iron assay, oxidative stress, inflammation, endoplasmic reticulum (ER) stress, apoptosis, ferritinophagy, and ferroptosis-related biomarkers were estimated. Nuclear factor E2-related factor 2 (NRF2) DNA-binding activity and phospho-p53 immunoreactivity were assessed. DCN administration effectively ameliorated DOX-induced cardiac cytomorphological abnormalities. Additionally, DCN profoundly combated the DOX-induced labile iron pool expansion alongside its consequent lethal lipid peroxide overproduction, whereas it counteracted ferritinophagy and enhanced iron storage. Indeed, DCN valuably reinforced the cardiomyocytes' resistance to ferroptosis, mainly by restoring the NRF2/solute carrier family 7 member 11 (SLC7A11)/glutathione peroxidase 4 (GPX4) signaling axis. Furthermore, DCN abrogated the cardiac oxidative damage, inflamma-tory response, ER stress, and cardiomyocyte apoptosis elicited by DOX. In conclusion, for the first time, our findings validated DCN's cardioprotective potency against DIC based on its an-tioxidant, anti-inflammatory, anti-ferroptotic, and anti-apoptotic imprint, chiefly mediated by the NRF2/SLC7A11/GPX4 axis. Accordingly, DCN could represent a promising therapeutic avenue for patients under DOX-dependent chemotherapy. Antioxidants 2024, 13, 493. https://doi.org/10.3390/antiox13040493 https://www.mdpi.com/journal/antioxidants Antioxidants 2024, 13, 493 2 of 18 Keywords: doxorubicin cardiotoxicity; iron; nuclear receptor coactivator 4-dependent ferritinophagy; ferroptosis; ferritin heavy chain polypeptide 1; oxidative stress; nuclear factor E2-related factor 2/solute carrier family 7 member 11/ glutathione peroxidase 4 axis; diacerein
Doxorubicin (DOX)-induced cardiotoxicity (DIC) is a life-threatening clinical issue with limited preventive approaches, posing a substantial challenge to cancer survivors. The anthraquinone diacerein (DCN) exhibits significant anti-inflammatory, anti-proliferative, and antioxidant actions. Its beneficial effects on DIC have yet to be clarified. Therefore, this study investigated DCN’s cardioprotective potency and its conceivable molecular targets against DIC. Twenty-eight Wister rats were assigned to CON, DOX, DCN-L/DOX, and DCN-H/DOX groups. Serum cardiac damage indices, iron assay, oxidative stress, inflammation, endoplasmic reticulum (ER) stress, apoptosis, ferritinophagy, and ferroptosis-related biomarkers were estimated. Nuclear factor E2-related factor 2 (NRF2) DNA-binding activity and phospho-p53 immunoreactivity were assessed. DCN administration effectively ameliorated DOX-induced cardiac cytomorphological abnormalities. Additionally, DCN profoundly combated the DOX-induced labile iron pool expansion alongside its consequent lethal lipid peroxide overproduction, whereas it counteracted ferritinophagy and enhanced iron storage. Indeed, DCN valuably reinforced the cardiomyocytes’ resistance to ferroptosis, mainly by restoring the NRF2/solute carrier family 7 member 11 (SLC7A11)/glutathione peroxidase 4 (GPX4) signaling axis. Furthermore, DCN abrogated the cardiac oxidative damage, inflammatory response, ER stress, and cardiomyocyte apoptosis elicited by DOX. In conclusion, for the first time, our findings validated DCN’s cardioprotective potency against DIC based on its antioxidant, anti-inflammatory, anti-ferroptotic, and anti-apoptotic imprint, chiefly mediated by the NRF2/SLC7A11/GPX4 axis. Accordingly, DCN could represent a promising therapeutic avenue for patients under DOX-dependent chemotherapy.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid‐beta plaques and neurofibrillary tangles, leading to neuronal loss. Curcumin, a polyphenolic compound derived from Curcuma longa, has shown potential neuroprotective effects due to its anti‐inflammatory and antioxidant properties. This review aims to synthesize current preclinical data on the anti‐neuroinflammatory mechanisms of curcumin in the context of AD, addressing its pharmacokinetics, bioavailability, and potential as a therapeutic adjunct. An exhaustive literature search was conducted, focusing on recent studies within the last 10 years related to curcumin's impact on neuroinflammation and its neuroprotective role in AD. The review methodology included sourcing articles from specialized databases using specific medical subject headings terms to ensure precision and relevance. Curcumin demonstrates significant neuroprotective properties by modulating neuroinflammatory pathways, scavenging reactive oxygen species, and inhibiting the production of pro‐inflammatory cytokines. Despite its potential, challenges remain regarding its limited bioavailability and the scarcity of comprehensive human clinical trials. Curcumin emerges as a promising therapeutic adjunct in AD due to its multimodal neuroprotective benefits. However, further research is required to overcome challenges related to bioavailability and to establish effective dosing regimens in human subjects. Developing novel delivery systems and formulations may enhance curcumin's therapeutic potential in AD treatment.
Background
Ferroptosis, a non-apoptotic form of cell death induced by accumulation of free iron ions and lipid peroxidation, its importance for cancer treatment is gradually being recognized. Research on the anti-cancer mechanism of juglone is accumulating. However, the specific mechanism by which it directs glioblastoma (GBM) to death is unknown.
Methods
We used in vitro and in vivo experiments to explore the anti-GBM effect generated by juglone through the ferroptosis pathway.
Results
Juglone mainly causes cell death by inducing ferroptosis. Mechanistically, juglone can significantly activate the phosphorylation of p38MAPK. According to transcriptome sequencing and protein interaction analysis, the Nrf2-GPX4 signaling pathway is identified as the primary pathway through which juglone mediates ferroptosis. In vitro and in vivo experiments further verified that juglone induces the ferroptosis of GBM by activating the phosphorylation of p38MAPK and negatively regulating the Nrf2-GPX4 signaling pathway.
Conclusion
Juglone induces ferroptosis and inhibits the growth of GBM by targeting the Nrf2/Gpx4 signaling pathway and thus holds promise as a novel ferroptosis inducer or anti-GBM drug.
Arterial occlusion-induced ischemic stroke (IS) is a highly frequent stroke subtype. Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor that modulates antioxidant genes. Its role in IS is still unelucidated. The current study focused on constructing a transient middle cerebral artery occlusion (tMCAO) model for investigating the NRF2-related mechanism underlying cerebral ischemia/reperfusion (I/R) injury. Each male C57BL/6 mouse was injected with/with no specific NRF2 activator post-tMCAO. Changes in blood–brain barrier (BBB)-associated molecule levels were analyzed using western-blotting, PCR, immunohistochemistry, and immunofluorescence analysis. NRF2 levels within cerebral I/R model decreased at 24-h post-ischemia. NRF2 activation improved brain edema, infarct volume, and neurological deficits after MCAO/R. Similarly, sulforaphane (SFN) prevented the down-regulated tight junction proteins occludin and zonula occludens 1 (ZO-1) and reduced the up-regulated aquaporin 4 (AQP4) and matrix metalloproteinase 9 (MMP9) after tMCAO. Collectively, NRF2 exerted a critical effect on preserving BBB integrity modulating ferroptosis and inflammation. Because NRF2 is related to BBB injury regulation following cerebral I/R, this provides a potential therapeutic target and throws light on the underlying mechanism for clinically treating IS.
Cerebral ischemia/reperfusion injury (CIRI) is a major contributor to poor prognosis of ischemic stroke. Flavonoids are a broad family of plant polyphenols which are abundant in traditional Chinese medicine (TCM) and have beneficial effects on several diseases including ischemic stroke. Accumulating studies have indicated that flavonoids derived from herbal TCM are effective in alleviating CIRI after ischemic stroke in vitro or in vivo, and exhibit favourable therapeutical potential. Herein, we systematically review the classification, metabolic absorption, neuroprotective efficacy, and mechanisms of TCM flavonoids against CIRI. The literature suggest that flavonoids exert potential medicinal functions including suppressing excitotoxicity, Ca²⁺ overloading, oxidative stress, inflammation, thrombin’s cellular toxicity, different types of programmed cell deaths, and protecting the blood-brain barrier, as well as promoting neurogenesis in the recovery stage following ischemic stroke. Furthermore, we identified certain matters that should be taken into account in future research, as well as proposed difficulties and opportunities in transforming TCM-derived flavonoids into medications or functional foods for the treatment or prevention of CIRI. Overall, in this review we aim to provide novel ideas for the identification of new prospective medication candidates for the therapeutic strategy against ischemic stroke.
Recent studies have demonstrated that ferroptosis, a novel form of nonapoptotic regulated cell death plays an important role in doxorubicin (DOX)-induced cardiotoxicity (DoIC). Hydrogen sulfide (H2S) is emerging as the third important gaseous mediator in cardiovascular system. However, whether H2S has an effect on DOX-induced ferroptosis remains unknown. Here, we found that DOX not only triggered cardiomyocyte ferroptosis but also significantly inhibited the synthesis of endogenous H2S in the murine model of chronic DoIC. Application of NaHS, an H2S donor obviously activated the SLC7A11/GSH/GPx4 antioxidant pathway and thus alleviated DOX-induced ferroptosis and cardiac injury in mice. In contrast, cardiac-specific knockout of cystathionine γ-lyase gene (Cse) in mice (Csef/f/Cre⁺) to abolish the cardiac synthesis of endogenous H2S evidently exacerbated DOX-induced ferroptosis and cardiac dysfunction. A further suppression of SLC7A11/GSH/GPx4 pathway was obtained in Csef/f/Cre⁺ mice with DoIC, as compared to Csef/f/Cre⁻ mice with DoIC. The aggravation caused by cardiac-specific Cse deficiency was remarkably rescued by exogenous supplementation of NaHS. Moreover, in DOX-stimulated H9c2 cardiomyocytes, pretreatment with NaHS dose-dependently enhanced the activity of SLC7A11/GSH/GPx4 pathway and subsequently mitigated ferroptosis and mitochondrial impairment. On the contrary, transfection with Cse siRNA in DOX-stimulated H9c2 cardiomyocytes markedly inhibited SLC7A11/GSH/GPx4 pathway, thus leading to aggravated ferroptosis and more damage to mitochondrial structure and function. In addition, the protective effect of NaHS on DOX-induced ferroptosis was closely related to the S-sulfhydrated Keap1, which in turn promoted nuclear translocation of Nrf2 and the transcription of SLC7A11 and GPx4. In conclusion, our findings suggest that H2S may exert protective effect on DoIC by inhibiting DOX-induced ferroptosis via Keap1/Nrf2-dependent SLC7A11/GSH/GPx4 antioxidant pathway.
Cognitive impairment poses a significant burden on individuals, families, and society worldwide. Despite the lack of effective treatment strategies, emerging evidence suggests that the microbiome–gut–brain (MGB) axis may play a critical role in the pathogenesis of cognitive impairment. While targeted treatment is not yet comprehensive, recently, acupuncture and moxibustion therapy has participated increasingly in the treatment of degenerative diseases and has achieved a certain therapeutic effect. In this review, the possible mechanisms by which acupuncture and moxibustion therapy may improve cognitive impairment through the MGB axis are reviewed, including regulating gut microbial homeostasis, improving intestinal inflammation mediated by the neuroendocrine–immune system, and enhancing intestinal barrier function. We also discuss common acupoints and corresponding mechanism analysis to provide insights into further exploration of mechanisms that target the MGB axis and thereby intervene in cognitive impairment.
This work aimed to study the role and mechanism of SIRT5 regulation of ferroptosis in cerebral ischemia-reperfusion (I/R) injury. A model of middle cerebral artery occlusion in rats was prepared using the method of thread occlusion. The ferroptosis inhibitor was injected intraperitoneally while the SIRT5 interfering lentivirus were injected into the brain, and neurological disorders were scored in the rats. TTC staining was used to detect infarct volume, and immunohistochemistry was used to detect the expression of SIRT5 in tissues. Rat hippocampal neuronal cells H19-7 were transduced with SIRT5 interfering lentivirus and ferroptosis was induced using erastin. The CCK8 detection kit was used to detect cell viability. Commercial kits were used to detect levels of iron ions, ROS, MDA, SOD, and inflammatory factor (TNF-α and IL-6) in brain tissue or cell supernatant. Western blot was used to detect the expression changes of ferroptosis related proteins GPX4, Nrf2, and HO-1 in tissues or cells. Compared with the sham group, the MCAO model group showed higher levels of neurological impairment score, increased cerebral infarction volume, iron ions, inflammatory factors, and oxidative stress levels in rats. Compared with the MCAO group, the MCAO + fer-1 group exhibited lower levels of neurological impairment scores, cerebral infarction volume, decreased iron ions, inflammatory factors, and oxidative stress levels in rats. Meanwhile, compared with the MCAO + DMSO/LV-shRNA group, the MCAO + fer-1/LV-shSIRT5 group showed a significant decrease in neurological impairment scores, cerebral infarction volume, iron ions, inflammatory factors, and oxidative stress levels in rats. In vitro experiments have found that LV-shSIRT5 can prevent erastin-induced cell ferroptosis. In summary, SIRT5 regulates ferroptosis through the Nrf2/HO-1 signaling axis to participate in ischemia-reperfusion injury in ischemic stroke.
Cerebral infarction is one of the most common diseases for aged people. Compound Tongluo Decoction (CTLD), a classic traditional Chinese Medicine prescription, has been widely used in the treatment of ischemic cerebral infarction. Transient middle cerebral artery occlusion (tMCAO) rat model is established for the animal experiment and oxygen‐glucose deprivation and reperfusion (OGD/R) human umbilical vein endothelial cells (HUVECs) model are established for the cell experiment. This also use Nrf2‐/‐ rats to detect the role of nuclear factor erythroid 2‐related factor 2 (Nrf2). Longa score, Evans blue staining, brain water content measurement, and histological observation are done. The levels of reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD), and other ferroptosis‐related components are detected respectively. In the vivo experiment, CTLD relieved ischemia‐reperfusion (IR) injury symptoms and attenuated IR injury in brain tissues of tMCAO rats by relieving peroxidation injury in brain tissues and inhibiting ferroptosis in tMCAO rats. Moreover, CTLD reversed OGD/R‐induced oxidative damage of endothelial cells via suppressing ferroptosis. After knocking out the Nrf2 gene, the protective effect of CTLD is sharply reduced. This study put forward that CTLD can inhibit ferroptosis in I/R‐injured vascular endothelium by regulating Nrf2/ARE/SLC7A11 signaling to improve the relative symptoms of rats after cerebral I/R injury, thus providing a viable treatment option for cerebrovascular disease.
Diabetic nephropathy (DN) is a serious microvascular complication of diabetes. Ferroptosis, a new form of cell death, plays a crucial role in the pathogenesis of DN. Renal tubular injury triggered by ferroptosis might be essential in this process. Numerous studies demonstrate that the vitamin D receptor (VDR) exerts beneficial effects by suppressing ferroptosis. However, the underlying mechanism has not been fully elucidated. Thus, they verified the nephroprotective effect of VDR activation and explored the mechanism by which VDR activation suppressed ferroptosis in db/db mice and high glucose‐cultured proximal tubular epithelial cells (PTECs). Paricalcitol (PAR) is a VDR agonist that can mitigate kidney injury and prevent renal dysfunction. PAR treatment could inhibit ferroptosis of PTECs through decreasing iron content, increasing glutathione (GSH) levels, reducing malondialdehyde (MDA) generation, decreasing the expression of positive ferroptosis mediator transferrin receptor 1 (TFR‐1), and enhancing the expression of negative ferroptosis mediators including ferritin heavy chain (FTH‐1), glutathione peroxidase 4 (GPX4), and cystine/glutamate antiporter solute carrier family 7 member 11 (SLC7A11). Mechanistically, VDR activation upregulated the NFE2‐related factor 2/heme oxygenase‐1 (Nrf2/HO‐1) signaling pathway to suppress ferroptosis in PTECs. These findings suggested that VDR activation inhibited ferroptosis of PTECs in DN via modulating the Nrf2/HO‐1 signaling pathway.
Neuroinflammation and oxidative stress damage are involved in the pathogenesis of cerebral ischemia–reperfusion injury (CIRI). Ferroptosis emerged as a new player in the regulation of lipid peroxidation processes. This study aimed at exploring the potential involvement of ciprofol on ferroptosis-associated CIRI and subsequent neurological deficits in the mouse model of transient cerebral ischemia and reperfusion. Cerebral ischemia was built in male C57BL/6 J wild-type (WT) and Nrf2-knockout (Nrf2 KO) mice in the manner of middle cerebral artery occlusion (MCAO) followed by reperfusion. Ciprofol improved autonomic behavior, alleviated reactive oxygen species output and ferroptosis-induced neuronal death by nucleus transportation of NFE2 like BZIP transcription factor 2 (Nrf2) and the promotion of heme oxygenase 1 (Ho-1), solute carrier family 7 member 11 (SLC7A11/xCT), and glutathione peroxidase 4 (GPX4). Additionally, ciprofol improved neurological scores and reduced infarct volume, brain water content, and necrotic neurons. Cerebral blood flow in MCAO-treated mice was also improved. Furthermore, absence of Nrf2 abrogated the neuroprotective actions of ciprofol on antioxidant capacity and sensitized neurons to oxidative stress damage. In vitro, the primary-cultured cortical neurons from mice were pre-treated with oxygen–glucose deprivation/reperfusion (OGD/R), followed by ciprofol administration. Ciprofol effectively reversed OGD/R-induced ferroptosis and accelerated transcription of GPX4 and xCT. In conclusion, we investigated the ciprofol-induced inhibition effect of ferroptosis-sheltered neurons from lipid preoxidation in the pathogenesis of CIRI via Nrf2-xCT-GPX4 signaling pathway.
Immunotherapy has good potential to eradicate tumors in the long term. However, due to the low immunogenicity of tumor cells, current cancer immunotherapies are not effective. To address this limitation, we constructed a BSA-FA functionalized iron-containing metal-organic framework (TPL@TFBF) that triggers a potent systemic anti-tumor immune response by inducing ferroptosis and pyroptosis in tumor cells and releasing large quantities of damage-associated molecular patterns (DAMPs) to induce immunogenicity, and showing excellent efficacy against melanoma lung metastases in vivo. This nanoplatform forms a metal-organic framework through the coordination between tannic acid (TA) and Fe³⁺ and is then loaded with triptolide (TPL), which is coated with FA-modified BSA. The nanoparticles target melanoma cells by FA modification, releasing TPL, Fe³⁺ and TA. Fe³⁺ is reduced to Fe²⁺ by TA, triggering the Fenton reaction and resulting in ROS production. Moreover, TPL increases the production of intracellular ROS by inhibiting the expression of nuclear factor erythroid-2 related factor (Nrf2). Such simultaneous amplification of intracellular ROS induces the cells to undergo ferroptosis and pyroptosis, releasing large amounts of DAMPs, which stimulate antigen presentation of dendritic cells (DCs) and the proliferation of cytotoxic T lymphocytes (CD4+/CD8 + T cells) to inhibit tumor and lung metastasis. In addition, combining nanoparticle treatment with immune checkpoint blockade (ICB) further inhibits melanoma growth. This work provides a new strategy for tumor immunotherapy based on various combinations of cell death mechanisms.
As a major contributor to neonatal death and neurological sequelae, hypoxic-ischemic encephalopathy (HIE) lacks a viable medication for treatment. Oxidative stress induced by hypoxic-ischemic brain damage (HIBD) predisposes neurons to ferroptosis due to the fact that neonates accumulate high levels of polyunsaturated fatty acids for their brain developmental needs but their antioxidant capacity is immature. Ferroptosis is a form of cell death caused by excessive accumulation of iron-dependent lipid peroxidation and is closely associated with mitochondria. Mitophagy is a type of mitochondrial quality control mechanism that degrades damaged mitochondria and maintains cellular homeostasis. In this study we employed mitophagy agonists and inhibitors to explore the mechanisms by which mitophagy exerted ferroptosis resistance in a neonatal rat HIE model. Seven-days-old neonatal rats were subjected to ligation of the right common carotid artery, followed by exposure to hypoxia for 2 h. The neonatal rats were treated with a mitophagy activator Tat-SPK2 peptide (0.5, 1 mg/kg, i.p.) 1 h before hypoxia, or in combination with mitochondrial division inhibitor-1 (Mdivi-1, 20 mg/kg, i.p.), and ferroptosis inhibitor Ferrostatin-1 (Fer-1) (2 mg/kg, i.p.) at the end of the hypoxia period. The regulation of ferroptosis by mitophagy was also investigated in primary cortical neurons or PC12 cells in vitro subjected to 4 or 6 h of OGD followed by 24 h of reperfusion. We showed that HIBD induced mitochondrial damage, ROS overproduction, intracellular iron accumulation, lipid peroxidation and ferroptosis, which were significantly reduced by the pretreatment with Tat-SPK2 peptide, and aggravated by the treatment with Mdivi-1 or BNIP3 knockdown. Ferroptosis inhibitors Fer-1 and deferoxamine B (DFO) reversed the accumulation of iron and lipid peroxides caused by Mdivi-1, hence reducing ferroptosis triggered by HI. We demonstrated that Tat-SPK2 peptide-activated BNIP3-mediated mitophagy did not alleviate neuronal ferroptosis through the GPX4-GSH pathway. BNIP3-mediated mitophagy drove the P62-KEAP1-NRF2 pathway, which conferred ferroptosis resistance by maintaining iron and redox homeostasis via the regulation of FTH1, HO-1, and DHODH/FSP1-CoQ10-NADH. This study may provide a new perspective and a therapeutic drug for the treatment of neonatal HIE.
Patient-derived organoids (PDOs) have emerged as a promising platform for clinical and translational studies. A strong correlation exists between clinical outcomes and the use of PDOs to predict the efficacy of chemotherapy and/or radiotherapy. To standardize interpretation and enhance scientific communication in the field of cancer precision medicine, we revisit the concept of PDO-based drug sensitivity testing (DST). We present an expert consensus-driven approach for medication selection aimed at predicting patient responses. To further standardize PDO-based DST, we propose guidelines for clarification and characterization. Additionally, we identify several major challenges in clinical prediction when utilizing PDOs.
Aging can cause degenerative changes in multiple tissues and organs. Gastrointestinal diseases and dysfunctions are common in the elderly population. In this study, we investigated the effects of Astragalus membranaceus polysaccharide (APS) and Astragalus membranaceus ethanol extract (AEE) on age-related intestinal dysfunction and gut microbiota dysbiosis in naturally aging mice. The energy expenditure and physical activity of 23-month-old C57BL6/J mice were recorded using a metabolic cage system. Pathological changes in the intestine were evaluated using Alcian blue staining. The protein levels of leucine-rich repeats containing G protein-coupled receptor 5 (Lgr5) and Stat3 in the small intestine were determined using immunohistochemistry. The intestinal cell migration distance was assessed using bromodeoxyuridine (BrdU) immunofluorescence staining. The gene transcription levels of intestinal stem cell (ISC) markers and ISC-related signaling pathways were detected using quantitative real-time PCR (qRT-PCR). Microbiota analysis based on 16S rDNA was performed to evaluate the composition of the gut microbiota. APS and AEE improved a series of aging phenotypes in female but not in male aging mice. APS and AEE ameliorate intestinal dysfunction and histopathological changes in aging mice. APS had a more significant anti-aging effect than AEE, particularly on intestinal dysfunction. APS promotes ISC regeneration by activating the IL-22 signaling pathway. Cohousing (CH) experiments further confirmed that APS induced the IL-22 signaling pathway by increasing the abundance of Lactobacillus, thereby promoting the regeneration of ISCs. Our results show that APS may serve as a promising agent for improving age-related intestinal dysfunction.
Mitophagy plays an important role in the maintenance of mitochondrial homeostasis and can be categorized into two types: ubiquitin-mediated and receptor-mediated pathways. During receptor-mediated mitophagy, mitophagy receptors facilitate mitophagy by tethering the isolation membrane to mitochondria. Although at least five outer mitochondrial membrane proteins have been identified as mitophagy receptors, their individual contribution and interrelationship remain unclear. Here, we show that HeLa cells lacking BNIP3 and NIX, two of the five receptors, exhibit a complete loss of mitophagy in various conditions. Conversely, cells deficient in the other three receptors show normal mitophagy. Using BNIP3/NIX double knockout (DKO) cells as a model, we reveal that mitophagy deficiency elevates mitochondrial reactive oxygen species (mtROS), which leads to activation of the Nrf2 antioxidant pathway. Notably, BNIP3/NIX DKO cells are highly sensitive to ferroptosis when Nrf2-driven antioxidant enzymes are compromised. Moreover, the sensitivity of BNIP3/NIX DKO cells is fully rescued upon the introduction of wild-type BNIP3 and NIX, but not the mutant forms incapable of facilitating mitophagy. Consequently, our results demonstrate that BNIP3 and NIX-mediated mitophagy plays a role in regulating mtROS levels and protects cells from ferroptosis.
Growing evidence supports the analgesic efficacy of electroacupuncture (EA) in managing chronic neuropathic pain (NP) in both patients and NP models induced by peripheral nerve injury. However, the underlying mechanisms remain incompletely understood. Ferroptosis, a novel form of programmed cell death, has been found to be activated during NP development, while EA has shown potential in promoting neurological recovery following acute cerebral injury by targeting ferroptosis. In this study, to investigate the detailed mechanism underlying EA intervention on NP, male Sprague‐Dawley rats with chronic constriction injury (CCI)‐induced NP model received EA treatment at acupoints ST36 and GV20 for 14 days. Results demonstrated that EA effectively attenuated CCI‐induced pain hypersensitivity and mitigated neuron damage and loss in the spinal cord of NP rats. Moreover, EA reversed the oxidative stress‐mediated spinal ferroptosis phenotype by upregulating reduced expression of xCT, glutathione peroxidase 4 (GPX4), ferritin heavy chain (FTH1) and superoxide dismutase (SOD) levels, and downregulating increased expression of acyl‐CoA synthetase long‐chain family member 4 (ACSL4), malondialdehyde levels and iron overload. Furthermore, EA increased the immunofluorescence co‐staining of GPX4 in neurons cells of the spinal cord of CCI rats. Mechanistic analysis unveiled that the inhibition of antioxidant pathway of Nrf2 signalling via its specific inhibitor, ML385, significantly countered EA's protective effect against neuronal ferroptosis in NP rats while marginally diminishing its analgesic effect. These findings suggest that EA treatment at acupoints ST36 and GV20 may protect against NP by inhibiting neuronal ferroptosis in the spinal cord, partially through the activation of Nrf2 signalling.
Background:
Traumatic Brain Injury (TBI) has high disability and mortality rate. Oxidative stress and ferroptosis are important pathophysiological characteristics after TBI. Orexin-A (OXA) can alleviate neuronal damage in diverse neurological disorders. Nevertheless, the role and mechanism of OXA in TBI stay unknown.
Objectives:
The research investigated protection influence of OXA on TBI and its potential mechanisms.
Methods:
Male Sprague-Dawley rats were randomly grouped into: sham, TBI, TBI + normal saline (NS) and TBI+OXA groups. TBI model was constructed in rat via modified Feeney's approach, and OXA treatment was administered following construction of TBI model.
Results:
Relative to TBI+NS group, TBI+OXA group displayed greatly recovered tissue damage and neurological deficits. Additionally, OXA eased oxidative stress as well as ferroptosis in cerebral cortex of rats following TBI. Furthermore, OXA increased Nrf2 expression and regulating factors HO-1 and NQO1 in cerebral cortex of TBI rats.
Conclusions:
Our research found OXA may restrain ferroptosis via Nrf2/HO-1 signaling pathway activation, thereby reducing brain injury after TBI.
There are few effective and safe neuroprotective agents for the treatment of ischemic stroke currently. Caffeic acid is a phenolic acid that widely exists in a number of plant species. Previous studies show that caffeic acid ameliorates brain injury in rats after cerebral ischemia/reperfusion. In this study we explored the protective mechanisms of caffeic acid against oxidative stress and ferroptosis in permanent cerebral ischemia. Ischemia stroke was induced on rats by permanent middle cerebral artery occlusion (pMCAO). Caffeic acid (0.4, 2, 10 mg·kg-1·d-1, i.g.) was administered to the rats for 3 consecutive days before or after the surgery. We showed that either pre-pMCAO or post-pMCAO administration of caffeic acid (2 mg·kg-1·d-1) effectively reduced the infarct volume and improved neurological outcome. The therapeutic time window could last to 2 h after pMCAO. We found that caffeic acid administration significantly reduced oxidative damage as well as neuroinflammation, and enhanced antioxidant capacity in pMCAO rat brain. We further demonstrated that caffeic acid down-regulated TFR1 and ACSL4, and up-regulated glutathione production through Nrf2 signaling pathway to resist ferroptosis in pMCAO rat brain and in oxygen glucose deprivation/reoxygenation (OGD/R)-treated SK-N-SH cells in vitro. Application of ML385, an Nrf2 inhibitor, blocked the neuroprotective effects of caffeic acid in both in vivo and in vitro models, evidenced by excessive accumulation of iron ions and inactivation of the ferroptosis defense system. In conclusion, caffeic acid inhibits oxidative stress-mediated neuronal death in pMCAO rat brain by regulating ferroptosis via Nrf2 signaling pathway. Caffeic acid might serve as a potential treatment to relieve brain injury after cerebral ischemia. Caffeic acid significantly attenuated cerebral ischemic injury and resisted ferroptosis both in vivo and in vitro. The regulation of Nrf2 by caffeic acid initiated the transcription of downstream target genes, which were shown to be anti-inflammatory, antioxidative and antiferroptotic. The effects of caffeic acid on neuroinflammation and ferroptosis in cerebral ischemia were explored in a primary microglia-neuron coculture system. Caffeic acid played a role in reducing neuroinflammation and resisting ferroptosis through the Nrf2 signaling pathway, which further suggested that caffeic acid might be a potential therapeutic method for alleviating brain injury after cerebral ischemia.