ACTA PHARMACOLOGICA SINICA
·
2025
·
IF 8.4
Ye Hua,Wu Lin,Liu Yan-mei,Zhang Jun-xia,Hu Huan-tao,Dong Mao-long,Ren Jun
Septic cardiomyopathy (SCM), a severe complication in sepsis, significantly increases the mortality of septic patients. Ferroptosis, an iron-regulated cell death, has been implicated in the development of SCM. Wogonin, a flavonoid from the root of the skullcap, exhibits anti-inflammatory, anti-allergic, and anti-apoptotic activities. In this study, we investigated the effects of wogonin on SCM and associated cardiomyocyte ferroptosis. Cecal ligation and puncture (CLP) surgery was performed in mice to establish a SCM model. Wogonin (20, 40 and 60 mg·kg −1 , i.p.) was administered 2 h prior to CLP surgery. We showed that wogonin pretreatment dose-dependently mitigated CLP-induced cardiac dysfunction, myocardial damage, and deranged cardiomyocyte contractility. Furthermore, wogonin pretreatment ameliorated cardiac inflammation, oxidative stress, and mitochondrial dysfunction in CLP-challenged mice. We demonstrated that wogonin exerted the cardioprotective effects through suppressing cardiomyocyte ferroptosis both in vivo and in vitro. We revealed that wogonin directly bound to and inhibited ALOX15 (arachidonic acid 15-lipoxygenase), a lipoxygenase that governed the oxidation of polyunsaturated fatty acids to initiate ferroptosis. Pharmacological inhibition of ALOX15 using a specific inhibitor ML351 (10 mg·kg −1 ·d −1 , i.p. for 7 days prior to CLP surgery) markedly diminished cardiac abnormalities and cardiomyocyte ferroptosis in CLP-challenged mice. In LPS-challenged HL-1 cardiomyocytes, overexpression of ALOX15 or supplement of its downstream metabolite 15-HpETE (1 μM) diminished the anti-ferroptotic effects of wogonin. Our results demonstrate that wogonin protects against SCM through inhibition of ALOX15-meditated ferroptosis.
研究领域:
药理学
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病理学
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心血管医学
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DOI
PubMed
高影响因子
TRANSPLANTATION
·
2024
·
IF 5.3
Jia Degong,Wu Kun,Luo Jiefu,Xu Xuesong,Pan Wei,Zhao Minjie,Li Shengwei,Gong Jianping,Gong Junhua
Background. Donation after circulatory death livers are more susceptible to ischemia/reperfusion injury (IRI) because of a longer period of warm ischemia. Growing evidence now suggests that ferroptosis plays a key regulatory role in the development of IRI, so targeting ferroptosis may be an effective strategy to alleviate IRI in liver transplantation (LT). Methods. Using donation after circulatory death LT models in rats and oxygen-glucose deprivation/reoxygenation (OGD/R) models in BRL-3A cells, we tested the effect of the Chinese medicine monomer wogonin on liver IRI and explored the specific mechanism. Results. Wogonin attenuated liver IRI and increased the survival rate of rats by inhibiting lipid peroxidation and ferroptosis. Mechanistically, arachidonic acid 15-lipoxygenase-1 (ALOX15) and inducible nitric oxide synthase (iNOS) were identified as potential targets of baicalein through bioinformatics analysis combined with in vivo and in vitro experiments. This result was further confirmed by molecular docking and cellular thermal shift assays. Finally, we silenced ALOX15 and iNOS in the OGD/R cell model and found that silencing ALOX15 and iNOS could reproduce the regulatory effect of wogonin and abrogate the regulatory effect of wogonin. Conclusions. In brief, this study emphasizes that wogonin exerts a protective effect in liver IRI through the regulation of ALOX15- and iNOS-mediated ferroptosis. ALOX15 and iNOS are potential targets for intervention in IRI induced by LT, and wogonin is a drug candidate for LT patients. Export
研究领域:
移植医学
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药理学
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分子生物学
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DOI
PubMed
高影响因子
NEUROSCIENCE
·
2022
·
IF 3.708
Jie Zhao,Yue Wu,Shanshan Liang,Xiangyu Piao
Ferroptosis, an iron-dependent form of non-apoptotic cell death, is reportedly responsible for cerebral ischemia/reperfusion (I/R) injury. Evidence has shown that spermidine/spermine N1-acetyltransferase 1 (SSAT1) activation-induced ferroptosis is associated with upregulation of arachidonate 15-Lipoxygenase (ALOX15). Our previous study has revealed that upregulation of ALOX15 contributes to cerebral I/R injury via inducing microglial activation. The current study aimed to investigate the role of SSAT1/ALOX15 axis in neuronal ferroptosis after I/R. We found that the expression of SSAT1 was upregulated in the cortical penumbra of mice subjected to transient middle cerebral artery occlusion and reperfusion (tMCAO/R). Knockdown of SSAT1 mitigated I/R-induced cerebral infarction and neurological impairments, as well as decreased cortical iron contents, reactive oxygen species (ROS) generation and 4-Hydroxynonenal (4-HNE) level. Further in vitro evidence revealed that knockdown of SSAT1 downregulated the expression of ALOX15 in the primary cortical neurons exposed to tertbutyl-hydroksyperoxide (TBH). In addition, loss of neuronal viability and production of lipid hydroperoxides were inhibited in TBH-treated neurons when SSAT1 was knocked down. Mechanistically, SSAT1 overexpression decreased the expression levels of two key ferroptotic repressors, glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11) in TBH-stimulated neurons. Treatment with the ALOX15 inhibitor PD146176 or ferroptosis inhibitor ferrostatin-1 partially reversed SSAT1 upregulation-induced ferroptosis and viability loss in TBH-treated neurons. These results together indicate that the activation of SSAT1/ALOX15 axis may aggravate cerebral I/R injury via triggering neuronal ferroptosis, providing novel insights into cerebral injury associated with lipid peroxidation.
研究领域:
神经科学
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细胞生物学
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药理学
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病理生理学
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DOI
PubMed
高影响因子
ANTIOXIDANTS & REDOX SIGNALING
·
2025
·
IF 6.1
Wenhui Yan,Xin Cui,Tingli Guo,Na Liu,Zhuanzhuan Wang,Yuzhuo Sun,Yuanrui Shang,Jieyun Liu,Yuanyuan Zhu,Yangyang Zhang,Lina Chen
Aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent hepatic disorder worldwide. Arachidonic acid 15-lipoxygenase (ALOX15), an enzyme catalyzing the peroxidation of polyunsaturated fatty acids, plays a crucial role in various diseases. Here, we sought to investigate the involvement of ALOX15 in MASLD.Results: In this study, we observed upregulation of ALOX15 in the liver of high-fat diet (HFD)- and streptozotocin (STZ)-induced mice. Metabolomic analysis revealed elevated levels of ALOX15 metabolites, 12(S)-hydroperoxyeicosatetraenoic acid and 15(S)-hydroperoxyeicosatetraenoic acid. Transcriptomic analysis showed that the increased fatty acid uptake regulated by the PPARγ/CD36 pathway predominated in lipid accumulation. To elucidate the mechanism underlying ALOX15-induced lipid accumulation, HepG2 cells were transfected with a lentivirus expressing ALOX15 or small interfering RNA targeting ALOX15 and exposed to palmitic acid (PA). Both ALOX15 overexpression and PA exposure led to increased intracellular free fatty acid and triglyceride, resulting in lipotoxicity. ALOX15 overexpression aggravated the effect of PA, while the knockdown of ALOX15 attenuated PA-induced lipotoxicity. Moreover, the treatment with PPARγ antagonist GW9662 or CD36 inhibitor sulfosuccinimidyl oleate sodium effectively reduced lipid accumulation and lipotoxicity resulting from ALOX15 overexpression and PA exposure, indicating the involvement of the PPARγ/CD36 pathway in ALOX15-mediated lipid accumulation. Furthermore, liraglutide, a widely used glucagon-like peptide 1 receptor (GLP-1R) agonist (GLP-1RA), improved hepatic lipid accumulation in HFD/STZ-induced mice by suppressing the ALOX15/PPARγ/CD36 pathway.Innovation and Conclusion: Our study underscores the potential of ALOX15 as an emerging therapeutic target for MASLD. In addition, the GLP-1RA may confer hepatoprotection by regulating ALOX15, enhancing our comprehension of the mechanisms underpinning their protection on MASLD. Antioxid. Redox Signal. 00, 000–000.
研究领域:
肝病学
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内分泌学
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分子生物学
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药理学
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DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2026
·
IF 6.7
Xiao-Min Lin,Ya-Jing Han,Wei-Xi Li,Yi-Ning Chen,Cheng Zhang,Ding-Wei Su,Shi-Sheng Chen,Jian-Wen Ye,Chun-Hua Liu,Wan-Yang Sun,Hiroshi Kurihara,Wei Bi,Hai-Biao Gong,Yi-Fang Li,Rong-Rong He
Abstract Coffee beans are widely consumed worldwide and are known for their central nervous system-stimulating effects, mainly attributed to caffeine and other small molecules. However, the neuroprotective potential of coffee bean-derived peptides remains largely unexplored. In this study, coffee bean protein hydrolysates (CBPH) exhibited protective effects against RSL3- and 6-OHDA-induced neuronal injury. Virtual screening and molecular docking targeting 15-lipoxygenase (ALOX15), a key enzyme involved in oxidative neuronal damage, identified eight candidate inhibitory peptides. Among them, FAR and FPSFRE showed significant ALOX15 inhibitory activity, reducing enzyme activity by 51.73 ± 21.54% and 91.61 ± 2.43%, respectively (p < 0.05). Consistently, both peptides significantly improved neuronal viability and attenuated oxidative stress-induced injury. Their direct interactions with ALOX15 were further confirmed by cellular thermal shift assay and molecular dynamics simulations. Moreover, FAR and FPSFRE ameliorated locomotor deficits in a 6-OHDA-induced zebrafish model, highlighting their potential as natural neuroprotective agents and functional food ingredients.
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DOI
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2026
·
IF 6.2
Jia-Gen Cui,Hao Zhang,Ming-Shan Chen,Jia-Xin Wang,Xue-Nan Li,Jin-Long Li
Lycopene (LYC), a natural antioxidant compound abundant in tomatoes, has established neuroprotective roles due to its antioxidant and anti-inflammatory properties. Di (2-ethylhexyl) phthalate (DEHP), a common plasticizer, is known to exert neurotoxic effects. However, the mechanisms of DEHP-induced neurotoxicity remain unclear. Furthermore, effective preventive strategies against this neurotoxicity are still lacking. This study, employing in vitro (BV2 cells) and in vivo (ICR mouse) models, demonstrates that LYC prevents DEHP-induced cerebellar damage by suppressing the triggering of dose-dependent microglial ferroptosis and neuroinflammation. Mechanistically, LYC inhibited the phosphatidylethanolamine-binding protein 1 (PEBP1)/arachidonate 15-lipoxygenase (ALOX15) axis (supported by immunofluorescence and Western blot assays), leading to reduced reactive oxygen species by approximately 48% in the cerebellum, which ultimately prevented neuroinflammation. Our findings reveal that LYC prevents DEHP-induced neurotoxicity by inhibiting microglial ferroptosis via the PEBP1/ALOX15 axis. Furthermore, our findings highlight the clinical promise of LYC as a novel neuroprotective treatment against environmental toxicant-induced damage.
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PubMed
高影响因子
Signal Transduction and Targeted Therapy
·
2022
·Vol. 7
·期 1
·1-13
·
IF 38.104
Ma Xiao-Hui,Liu Jiang-Han-Zi,Liu Chun-Yu,Sun Wan-Yang,Duan Wen-Jun,Wang Guan,Kurihara Hiroshi,He Rong-Rong,Li Yi-Fang,Chen Yang,Shang Hongcai
Myocardial ischemia/reperfusion (I/R) injury is a classic type of cardiovascular disease characterized by injury to cardiomyocytes leading to various forms of cell death. It is believed that irreversible myocardial damage resulted from I/R occurs due to oxidative stress evoked during the reperfusion phase. Here we demonstrate that ischemia triggers a specific redox reaction of polyunsaturated fatty acids (PUFA)-phospholipids in myocardial cells, which acts as a priming signaling that initiates the outbreak of robust oxidative damage in the reperfusion phase. Using animal and in vitro models, the crucial lipid species in I/R injury were identified to be oxidized PUFAs enriched phosphatidylethanolamines. Using multi-omics, arachidonic acid 15-lipoxygenase-1 (ALOX15) was identified as the primary mediator of ischemia-provoked phospholipid peroxidation, which was further confirmed using chemogenetic approaches. Collectively, our results reveal that ALOX15 induction in the ischemia phase acts as a “burning point” to ignite phospholipid oxidization into ferroptotic signals. This finding characterizes a novel molecular mechanism for myocardial ischemia injury and offers a potential therapeutic target for early intervention of I/R injury.
研究领域:
心血管疾病
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分子生物学
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细胞生物学
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药理学
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DOI
PubMed
高影响因子
FASEB JOURNAL
·
2026
·Vol. 40
·期 15
·e72061
·
IF 4.3
Wei Liu,Yuqin Wang,Jiayuan Wu,Caihong He,Zhengwei Zhou
Lactate, a metabolic byproduct of glycolysis, accumulates during myocardial infarction and ischemia/reperfusion (I/R) injury, acting as both a metabolic stress marker and a signaling molecule that influences inflammation and cell fate. Lactate can induce histone lysine lactylation (Kla), a novel post‐translational modification that regulates gene transcription and immune responses. Despite this discovery, its role in I/R injury remains unclear. To investigate the effects of lactate and histone lactylation, both in vivo myocardial I/R injury and in vitro hypoxia/reoxygenation (H/R) injury models using cardiomyocytes were established. Lipid peroxidation, LDH, MDA, SOD, and iron levels were quantified using specialized fluorescent probes and commercial kits. MeRIP and RIP assays were performed to investigate WTAP, YTHDF1, and ALOX15 interactions. TEM was utilized to examine mitochondrial ultrastructure and morphology. Lactate levels were elevated in I/R rats, and reducing lactate levels effectively mitigated ferroptosis and myocardial injury. Furthermore, lactate promoted Kla of WTAP, resulting in upregulation of WTAP protein expression compared to the I/R group. Global m 6 A RNA methylation levels increased by lactate treatment. Elevated WTAP levels, or overexpression of YTHDF1, facilitated m6A modification of ALOX15 mRNA, leading to upregulation of ALOX15 expression and enhanced ferroptosis during I/R injury. Notably, overexpression of ALOX15 reversed the protective effects of WTAP knockdown. Finally, we validated the involvement of the WTAP‐YTHDF1‐ALOX15 regulatory axis in vivo. Lactate‐induced Kla of WTAP led to its upregulation, which, together with YTHDF1, facilitated the m6A modification of ALOX15 mRNA. This modification increased ALOX15 expression, triggering cardiomyocyte ferroptosis and worsening myocardial I/R injury. These findings highlight the potential of targeting lactate‐induced Kla and its downstream effectors, including WTAP, YTHDF1, and ALOX15, as therapeutic strategies. Lactate accumulation during myocardial ischemia–reperfusion injury enhances histone lactylation and WTAP expression, promoting m 6 A modification of ALOX15 mRNA through YTHDF1. This regulatory axis increases ALOX15 expression, lipid peroxidation, and ferroptosis, thereby aggravating myocardial injury. Targeting WTAP lactylation or the WTAP/YTHDF1/ALOX15 pathway may provide a potential therapeutic strategy for myocardial ischemia–reperfusion injury.
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DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2026
·
IF 11.3
Xiao-Hui Ma,Jiang-Han-Zi Liu,Chang-Lun Chen,Cai-Sheng Wu,Di Lu,Liang-Liang He,Yan-Ping Wu,Yang Chen,Rong-Rong He,Tianhui Yuan
Background Wendan Tablet (WDT) is a traditional Chinese herbal compound formulation clinically employed in the management of coronary heart disease (CHD). Purpose This study aimed to elucidate the therapeutic mechanism of WDT in treating CHD and to identify its corresponding active constituents. Methods The primary components of WDT were identified, and a quantitative analytical method was established for quality control using UHPLC-QTOF-MS. We comprehensively evaluated the cardioprotective effects of WDT against ischemic injury and investigated its role in modulating phospholipid peroxidation of myocardial cells. Potential key molecular targets of WDT were predicted via molecular docking, and these predictions were subsequently validated through biochemical assays and transgenic mouse models. Results Mechanistically, WDT significantly improved cardiac function, reduced myocardial pathological damage, and suppressed lipid peroxidation. Specifically, it markedly downregulated the expression of arachidonate 15-lipoxygenase (ALOX15), a key enzyme involved in lipid peroxidation. Isocurcumenol was identified as the principal active component in WDT, demonstrating strong binding affinity for ALOX15. It effectively inhibited ALOX15 enzymatic activity and subsequently attenuated lipid peroxidation. While isocurcumenol conferred significant cardioprotection in the context of ALOX15 overexpression, both isocurcumenol and WDT lost their protective effects in ALOX15-deficient models. Conclusion This study demonstrates that WDT alleviates myocardial ischemia by inhibiting ALOX15 to reduce lipid peroxidation. We identified isocurcumenol as its key active component, which directly binds to and inhibits ALOX15. These findings establish ALOX15 not only as a crucial mechanistic target but also as a potential biomarker for the cardioprotective application of WDT and isocurcumenol in CHD management.
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PubMed
高影响因子
Food Bioscience
·
2025
·
IF 5.9
Mengni Shu,Guoyong Jiang,Chunchao Nie,Yi Chen
Pre-laboratory studies demonstrate that polysaccharide from Ganoderma atrum (PSG-1) exerts a protective effect against acrylamide (AA)-induced liver injury in rats. However, the mechanism underlying PSG-1-mediated hepatoprotection remains unclear. Herein, we employed an integrated metabolomics and proteomics approach to elucidate the molecular mechanisms of AA-induced liver injury using an in vivo rat model. Consequently, our analysis revealed that two key metabolic pathways—namely, arachidonic acid metabolism and retinol metabolism—mediate the protective effects of PSG-1. Furthermore, Phenylalanyl-Threonine, L-cis-Cyclo (aspartylphenylalanyl), bilirubin, and palmitic amide could serve as potential biomarkers for AA-induced liver injury, and the hepatoprotective effects of PSG-1 were mediated via target proteins Cyp3a1, Cyp2c7, Alox15, and Adh6. These findings elucidate the molecular mechanisms underlying PSG-1-mediated hepatoprotection and establish a framework for deciphering the therapeutic mechanisms by which functional foods counteract dietary toxicants.
研究领域:
药理学
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毒理学
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分子生物学
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生物化学
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营养科学
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功能食品
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系统生物学
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产品关联
DOI
高影响因子
PHYTOMEDICINE
·
2023
·
IF 7.9
Xiaohui Ma,Qi Wang,Chunyu Liu,Jianghanzi Liu,Ganqing Luo,Liangliang He,Tianhui Yuan,Rong-Rong He,Zhihong Yao
Background Phospholipid peroxidation signaling was recently revealed as a novel pathological mechanism of coronary heart disease (CHD), and small molecules involved in this redox-metabolic pathway are suggested as the potential anti-CHD drugs. Danlou Tablet (DLT), a famous traditional Chinese medicine (TCM) formula characterized by multi-component and multi-target regulation, is widely used in the clinical treatment of CHD by regulating lipid metabolism. However, little information is available addressing the corresponding pharmacological mechanisms and associated active components of DLT. Purpose To study whether phospholipid peroxidation involves a novel mechanism of DLT for the therapeutic effect of CHD and to explain the essential active components. Methods Firstly, the HPLC fingerprint was constructed to ensure the controllability of the quality of DLT. Then, a CHD animal model with the characteristics of lipid disorder and myocardial ischemia was established by a high-fat diet (HFD) combined with left anterior descending coronary artery (LAD) ligation. The therapeutic effect of DLT was further evaluated based on the results of the rat survival rate, cardiac function, cardiac histopathology, and myocardial ischemia indicators. Correspondingly, whether DLT can regulate the key indicators (ALOX15, GPX4, MDA, GSH, and NADPH) of the phospholipid peroxidation pathway was investigated, and Alox15 −/− mice have been applied to confirm the mechanism of DLT. Finally, the target-mediated characterization strategy based on ALOX15, including the integration of in vivo component characterization, network pharmacology, molecular docking analysis, and activity verification, has been further implemented to reveal the key bio-active components in DLT. Results In this study, a high-fat diet (HFD) combined with left anterior descending coronary artery (LAD) ligation was utilized to generate a CHD model, and DLT significantly improved the cardiac dysfunction and reduced the myocardial cell death susceptibility. Further results revealed that DLT reversed the protein expression of ALOX15 and GPX4, the key proteins of phospholipid peroxidation pathways, which subsequently influenced the parameters of phospholipid peroxidation (MDA, GSH, and NADPH). The ALOX15 knockout transgenic animal model confirmed that Alox15 −/− mice lost their cardioprotective effects with DLT, suggesting that DLT exerted therapeutic effects on CHD by regulating ALOX15-mediated phospholipid peroxidation. Finally, the target-mediated characterization strategy identified that daidzein is an active component in DLT against CHD by modulating ALOX15. Conclusion Innovatively, ALOX15-mediated phospholipid peroxidation was identified as one of the critical mechanisms of DLT exerting cardioprotective effects. Our findings elucidate a novel mechanism of DLT and provide some new drug evaluation targets and therapeutic strategies for CHD.
研究领域:
中医药
·
心血管疾病
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药理学
·
分子生物学
·
动物模型
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DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）