Frontiers in Pharmacology
·
2020
·
IF 4.225
Tsai Yun,Xia Changbo,Sun Zhongwen
Lung cancer is the most common malignant tumor and is the leading cause of cancer-related deaths worldwide. Extraction of bioactive substances from herbs is considered as an alternative method to traditional treatment. 6-Gingerol is a naturally occurring phenol found in ginger that can be used to treat tumors and suppress inflammation. To determine whether 6-Gingerol can be used as a therapeutic agent for tumors. In this study, tumor-bearing mice were used as an animal model and A549 as a cell model. Western blot was used to detect the expression of autophagy related proteins ubiquitin-specific peptidase 14 (USP14), Beclin1, microtubule-associated protein light chain 3 (LC3) and ferroptosis related proteins nuclear receptor coactivator 4 (NCOA4), ferritin heavy chain 1 (FTH1), transferrin receptor 1 (TfR1), glutathione peroxidase 4 (GPX4), activating transcription factor4 (ATF4) in vivo and in vitro. MTT and EdU were used to detect the viability of A549 cells. H&E and immunofluorescence were used to localize and detect the expression of proteins. The detection of reactive oxygen species was performed using fluorescence probes. It was found that the administration of 6-Gingerol decreased the expression of USP14, greatly increased the number of autophagosomes, reactive oxygen species (ROS) and iron concentration, decreased the survival and proliferation rate of A549 cells, and significantly decreased tumor volume and weight. The results indicate that 6-Gingerol inhibits lung cancer cell growth via suppression of USP14 expression and its downstream regulation of autophagy-dependent ferroptosis, revealing the function and efficacy of 6-Gingerol as a therapeutic compound in A549 and its possible mechanism of action.
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FOOD CHEMISTRY
·
2025
·
IF 9.8
Chen Liu,Yihong Liao,Meiyi Ning,Hong Chen,Yang Yang,Qian Tang,Daiwen Chen
Instant tea powder is a convenient, shelf-stable product with growing global popularity, yet the impact of cultivar type on its composition and functionality remains underexplored. This study compared two instant green tea powders from green-leaf (ZYQ) and purple-leaf (ZY) cultivars in terms of metabolite profiles, sensory attributes, and anti-inflammatory effects. Metabolomics and sensory evaluation revealed distinct characteristics: ZYQ contained higher levels of epicatechin, proanthocyanidins, total flavonoids, etc., while ZY was enriched in anthocyanin glycosides and EGCG. ZYQ showed greater umami, sweetness, and harmony, whereas ZY exhibited stronger bitterness, astringency, and a purplish-red infusion. Both powders significantly alleviated LPS-induced inflammation in RAW 264.7 macrophages by inhibiting NF-κB and ferroptosis-related oxidative stress, reducing ROS, MDA, iron, and inflammatory mediators. ZY induced stronger upregulation of Nrf2 , Gpx4 , and Txnrd1 , indicating enhanced antioxidant defense. These findings demonstrate that cultivar selection shapes instant tea's flavour and bioactivity, with purple-leaf products offering distinctive functional advantages.
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Clinical and Translational Medicine
·
2026
·Vol. 16
·期 2
·e70619
·
IF 7.9
Yifan Ren,Yuxuan Lu,Qing Cui,Hao Shang,Meng Fan,Yun Sun,Xiali Shi,Rongqian Wu,Hongwei Lu
During AP, MFG‐E8 expression in pancreatic acinar cells is downregulated, resulting in disruption of the ABCE1/MFG‐E8 complex. This impairment leads to defective mitophagy flux, accumulation of lipid peroxides, endoplasmic reticulum stress and ferroptosis, ultimately contributing to pancreatic damage .
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MOLECULAR AND CELLULAR BIOCHEMISTRY
·
2026
·
IF 4.7
Hou Xiaoxiao,Chen Ying,Xu Qixun,Zhong Jiaxin,Long Yudan,Liu Kai
Myocardial ischemia-reperfusion (I/R) injury is a complex condition characterized by oxidative stress, inflammation, and mitochondrial dysfunction. Ferroptosis, an iron-dependent form of regulated cell death, plays a critical role in cardiomyocyte damage during I/R. Inhibiting ferroptosis has been shown to reduce myocardial injury and improve cardiac function, making it a promising therapeutic target for enhancing clinical outcomes. An in vivo I/R model was established, and infarct size was assessed using triphenyltetrazolium chloride (TTC) staining. Histological changes were analyzed using hematoxylin and eosin (H&E) staining, Masson, immunohistochemistry (IHC), and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assays. Cellular experiments included analyses of reactive oxygen species (ROS), lipid peroxidation, and iron content using specific fluorescent probes, as well as enzymatic markers measured with commercial assay kits. Cell viability and senescence were evaluated using the Cell Counting Kit-8 (CCK-8) assay and senescence-associated β-galactosidase (SA–β-gal) staining, respectively. Mitochondrial ultrastructure was examined using transmission electron microscopy (TEM), while molecular mechanisms, including DNA methylation, were investigated using methylation-specific polymerase chain reaction (MSP). Interactions among pleckstrin homology-like domain family A member 3 (PHLDA3), DNA (cytosine-5)-methyltransferase 3 A (DNMT3a), and polypyrimidine tract binding protein 1 (PTBP1) were evaluated using chromatin immunoprecipitation (ChIP) and RNA pull-down assays. Silencing of PHLDA3 demonstrated protective effects against I/R injury by attenuating cardiomyocyte ferroptosis and cardiac microvascular endothelial cells (CMECs) senescence under hypoxia/reoxygenation (H/R) conditions in vitro and I/R injury in vivo. Mechanistically, downregulated DNMT3a was responsible for PHLDA3 hypomethylation. Furthermore, PTBP1 was identified as an upstream RNA-binding protein that destabilized DNMT3a mRNA during H/R injury, indirectly enhancing PHLDA3 expression. Our findings suggest that PTBP1-mediated DNMT3a downregulation contributes to PHLDA3 hypomethylation, which may promote cardiomyocyte ferroptosis and subsequent microvascular endothelial cell senescence during I/R injury.
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Antioxidants
·
2026
·Vol. 15
·期 7
·888
·
IF 8.2
Yin Liu,Yan Wang,Xinyu Shi,Ruomei Che,Xiaoli He
Background:Danshen–Gegen is a classic herb pair in traditional Chinese medicine, which has been used to treat cardiovascular and cerebrovascular diseases. Ischemic stroke (IS) is a prevalent cerebrovascular condition; ferroptosis is one of the contributing factors driving the progression of IS. This study aims to determine the underlying mechanism and examine if Danshen–Gegen (DG) extract may prevent cerebral ischemia–reperfusion injury by preventing ferroptosis.Methods:The comprehensive compositional characterization of DG was analyzed by ultra-high-performance liquid chromatography coupled with hybrid quadrupole-orbitrap high-resolution mass spectrometry (UPLC-Q-orbitrap MS). The experiments were conducted in middle cerebral artery occlusion/reperfusion (MCAO/R) rats and oxygen-glucose deprivation/re-oxygenation (OGD/R) cells. The neuroprotective effects of DG on IS were assessed by examining rat survival rates, infarct volume, behavioral scores, and cerebral water content. Then, we tested the accumulation of Fe2+and lipid peroxidation products such as reactive oxygen species (ROS), glutathione (GSH), malondialdehyde (MDA), myeloperoxidase (MPO), and 4-hydroxynonenal (4-HNE) in rats and cells. The expression of nuclear factor erythroid-derived 2-like 2 (Nrf2), Solute Carrier Family 7 Member 11 (-xCT), Glutathione peroxidase 4 (GPX4), Cyclooxygenase-2 (COX-2), Transferrin Receptor 1 (TFR1), and Long-chain-fatty-acid–CoA ligase 4 (ACSL4) was also assessed in vivo and in vitro.Results:UPLC-Q-orbitrap MS analysis was performed to characterize the chemical profile of DG, and a total of 33 chemical constituents were successfully identified. DG significantly alleviated the ischemic damage to brain tissue, reduced infarct volume, and improved neurological dysfunction. The content of Fe2+and lipid peroxidation products was markedly decreased. Furthermore, DG could restore the expression of Nrf2, -xCT, and GPX4 with the inhibition of COX-2, TFR1, and ACSL4, thus achieving a suppressive effect on ferroptosis.Conclusions:The regulatory influence of DG via the Nrf2/System xc-/GPX4 axis may play a crucial role in alleviating ferroptosis and enhancing recovery from cerebral ischemia injury.
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BIOCHEMICAL PHARMACOLOGY
·
2026
·
IF 6.5
Tianyue Guan,Audrey Dela,Yichen Jin,Juqin Song,Tingyan Wang,Yu Zhu,Jingquan Dong,Panpan Zhao
Sepsis-induced acute lung injury (ALI) remains a critical factor contributing to mortality in intensive care units, and effective therapeutic strategies are still lacking. The present research explores the defensive impacts and associated mechanisms of Tubuloside A (TA), an active phenanthrenoid glycoside extracted from Cistanche deserticola, in sepsis-induced ALI. Utilizing both a cecal ligation and puncture (CLP) mouse model and LPS-stimulated MLE-12 alveolar epithelial cells, we found that TA markedly attenuated lung injury, as indicated by improved histopathological features, reduced pulmonary edema, and maintenance of alveolar structure. Mechanistically, TA provided multifaceted protection by concurrently inhibiting oxidative stress, ferroptosis, and inflammatory signaling—critical drivers of sepsis-induced ALI. Treatment with TA diminished lipid peroxidation, restored GPX4 expression, and inhibited pro-inflammatory cytokines (TNF-α, IL-6, IL-1β). Network pharmacology identified NFKB1 as a therapeutic target of TA against ALI. Molecular docking predicted and SPR analysis verified that TA binds to NF-κB p50. Notably, functional validation via NF-κB p50 overexpression abolished TA-mediated protection and re-sensitized cells to ferroptosis, confirming NF-κB p50 as a central regulatory node. Furthermore, TA activated Nrf2 signaling in an NF-κBp50–dependent manner, as demonstrated by nuclear translocation assays and rescue experiments. Calcein AM imaging and iron chelation studies confirmed that TA’s anti-ferroptotic effect requires functional NF-κB/Nrf2/GPX4 crosstalk. Collectively, our findings reveal that TA ameliorates sepsis-ALI by targeting the NF-κBp50–Nrf2/GPX4 axis to coordinately inhibit inflammation, oxidative stress, and ferroptosis, highlighting its potential as a multi-target phytotherapeutic agent for acute respiratory disorders
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Animal Nutrition
·
2026
·
IF 8.3
Anran Wang,Jie Xu,Haoyue Guo,Dongxu Luo,Zhen Zhang,Chao Ran,Shuyan Miao,Zhigang Zhou
Fish oil is an essential lipid source in aquafeed due to its high polyunsaturated fatty acid content. However, its susceptibility to oxidation can harm aquatic animal health and growth. This study investigated the effects of oxidized fish oil (OFO) diet on hepatopancreas health of Macrobrachium rosenbergii , and the mechanism by which Cetobacterium somerae protects against oxidative damage induced by OFO diet. A total of 240 juvenile prawns (3.36 ± 0.02 g) were randomly allocated to three dietary treatments with four replicates of 20 prawns each for 8 weeks: Control (control diet with fresh fish oil diet), OFO (OFO diet), and OFO + Cet (OFO diet supplemented with C. somerae at 1.52 × 10 7 CFU/g). Compared with the OFO group, C. somerae intervention significantly reduced the levels of lipid peroxidation-related markers, including malondialdehyde (MDA), 5-hydroperoxyeicosatetraenoic acid (5-HETE), leukotriene B4 (LTB4), prostaglandins (PGs), and thromboxanes (TXs), while increasing hepatopancreatic antioxidant indicators, including total antioxidant capacity (T-AOC), superoxide dismutase (SOD), catalase (CAT), glutathione S-transferase (GST), and glutathione peroxidase (GSH-Px) ( P < 0.05). Moreover, it also reversed the OFO diet-induced alterations in the relative mRNA expression levels of ferroptosis-related genes ( acsl4 , tfr1 , gpx4 , and slc7a11 ) ( P < 0.05), potentially via the adenosine monophosphate (AMP)-activated protein kinase (AMPK)-sirtuin1 (SIRT1)-peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) signaling pathway. Serum acetic acid, a C. somerae metabolite, exhibited the most pronounced alteration in the C. somerae -treated group ( P = 0.004). Furthermore, 160 juvenile prawns (2.62 ± 0.12 g) were randomly divided into two groups with four replicates of 20 prawns in each for 4 weeks: OFO diet, OFO + 0.15% sodium acetate (0.15% NaAc). Supplementation with 0.15% NaAc in the OFO diet also effectively decreased the peroxides (MDA, 5-HETE, LTB4, and TXs) and reversed the OFO diet-induced alterations in the relative mRNA expression levels of ferroptosis-related genes ( acsl4 , tfr1 , gpx4 , and slc7a11 ) compared with OFO group ( P < 0.05), suggesting a contributory role of acetate in the functionality of C. somerae . Meanwhile, the elevated AMP/adenosine triphosphate (ATP) ratio and upregulated relative mRNA expression levels of acss1/2 , ampk, sirt1 , and pgc-1α ( P < 0.05) indicated that C. somerae- derived acetate activates AMP production, thereby activating the AMPK-SIRT1-PGC-1α signaling pathway . Overall, C. somerae protects against OFO diet-induced hepatopancreatic injury by mitigating ferroptosis via acetate-mediated activation of the AMPK-SIRT1-PGC-1α signaling pathway.
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EUROPEAN JOURNAL OF PHARMACOLOGY
·
2025
·
IF 4.7
Hong Yang,Yongxin Chen,Guoping Wu,Pengyan Ren,Tingting Chen,Jia Liu,Bao Zhang,Xiao Ma,Feng Jiang,Yue Li,Ling Tao,Xiangchun Shen
Fructus Alpiniae Zerumbet (FAZ), a folk medicinal herb used by the Miao people in Guizhou, China, is rich in 1,8-Cineole — a bioactive monoterpene oxide with antioxidant and neuroprotective properties. However, its therapeutic potential against pancreatic β cells dysfunction, a hallmark of type 2 diabetes mellitus (T2DM), remains unexplored. This study investigated the molecular mechanism by which 1,8-Cineole mitigates hyperglycemia induced β cells ferroptosis. Using high-fat and high-sugar diet / streptozotocin (HFSD/STZ) diabetes mellitus type 2-induced model (DM) and high glucose (HG)-treated β cells model. We demonstrated that 1,8-Cineole ameliorated pancreatic islet structural disorganization and pathological glycogen deposition in diabetic mice. Mechanistically, 1,8-Cineole suppressed lipid peroxidation and iron overload while restoring the expression of ferroptosis markers (GPX4 and COX2). It concurrently resolved autophagy deficiency, evidenced by upregulated LC3II/I ratio, enhanced Beclin-1 expression, and stabilized p62. Bioinformatic analysis of diabetic pancreatic transcriptomes (GEO dataset GSE25724) linked ferroptosis and PI3K/AKT/mTOR signaling to β cells dysfunction. Cellular thermal shift assay (CETSA) and molecular docking confirmed direct binding of 1,8-Cineole to PI3K with favorable binding energy at the catalytic site. Pharmacological validation using 740-YP (YP, a PI3K agonist) and LY294002 (LY, a PI3K inhibitor) revealed that 1,8-Cineole exerted its anti-ferroptotic effects via PI3K/AKT/mTOR pathway activation. Co-treatment with 740-YP synergistically enhanced β cells protection, whereas LY294002 abrogated 1,8-Cineole’s efficacy. Collectively, these findings unveil 1,8-Cineole as a novel PI3K/AKT/mTOR activator that rescues β cells function via coordinated regulation of autophagy and ferroptosis, thereby providing a mechanistic foundation for its therapeutic application in DM.
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PHYTOMEDICINE
·
2026
·
IF 11.3
Li Zhen,Jianhong Peng,Huimin Cui,Junhong Tao,Yaping Liu,Jianxin Cao,Hesham R El-Seedi,Guiguang Cheng,Zhengxuan Wang
Background The flowers of Rosa chinensis cv. ‘JinBian’ (RCF) has been utilized as a herbal tea for millennia to prevent aging-related diseases. RCF is enriched in flavonoids and exhibits significant antioxidant effects for anti-aging potential. However, the specific bioactive compounds and their underlying anti-aging mechanisms remain unclear. Purpose This study aimed to investigate the bioactive ingredients and neuroprotective mechanisms of RCF extracts. Methods The study obtained dichloromethane (RD), ethyl acetate (RE), n-butanol (RB), and residual water (RW) fractions from RCF after liquid-liquid extraction. It investigated their neuroprotective effect in in vitro and in vivo experiments. UHPLC-ESI-HRMS/MS analysis was used to identify phytochemicals in RE. In vitro assays included measuring phenolic and flavonoid contents, ABTS⁺ and DPPH + scavenging capacities, and effects on H₂O₂-induced SHSY-5Y cells. In vivo , D-galactose-induced mice were used and assessed through the Morris water maze test and the crucifixion anxiety test. Molecular pathways and gut microbiota were analyzed. Results Among the fractions, RE had the highest phenolic and flavonoid contents, the strongest ABTS⁺ and DPPH + scavenging capacities, and significantly inhibited ROS accumulation by increasing antioxidants (glutathione, catalase, superoxide dismutase) in H₂O₂-induced SHSY-5Y cells. UHPLC-ESI-HRMS/MS analysis identified 28 phytochemicals in RE, primarily gallic acid derivatives and flavonoid derivatives. In D-galactose-induced mice, RE alleviated memory impairment and anxiety-like behavior. RE ameliorated brain damage by activating the Keap1/Nrf2-regulated antioxidant pathway (increasing T-AOC, GSH, GPX4, NQO1, SOD1, HO-1), suppressing ferroptosis, inhibiting acetylcholinesterase activity, attenuating GSK-3β/Tau/Bcl-2 axis-regulated apoptosis, and modulating AMPK-regulated autophagy. Additionally, RE improved gut microbiota diversity, particularly increasing beneficial bacteria such as Lactobacillus and Bifidobacterium . Conclusions Therefore, RE could alleviate the cognitive deficit associated with age-related neurodegenerative diseases by targeting ferroptosis-related oxidative stress, apoptosis, and autophagy, as well as modulating the gut microbiota.
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Frontiers in Pharmacology
·
2026
·
IF 5.4
Jiayi Gu,Manhui Zhu,Lele Li,Xin Cao,Xiaoli Yu,Xiaobo Huang,Lili Huang,Qi Cai,Yan Zhu,Wendie Li,Yong Wang
Introduction Diabetic retinopathy (DR) represents a prevalent and severe eye complication in diabetic patients. With DR progresses, destruction of tight junctions (TJs) in RPE cells leads to irreversible visual impairment. Gypenoside XLIX (Gyp XLIX) is a dammarane-type glycoside, which can suppress inflammation and oxidative stress. This study sought to investigate and verify the mechanism underlying the regulatory effects of Gyp XLIX in the early protection of junctional integrity of DR. Methods We combined bioinformatics and network pharmacology to pinpoint the core therapeutic targets of Gyp XLIX for DR. Mice with diabetes mellitus (DM) and high glucose (HG)-stimulated ARPE-19 cells were treated with Gyp XLIX. Its impact on TJ integrity in RPE cells and ferroptosis was evaluated via Western blotting, immunofluorescence staining, and assays for iron content, lipid peroxidation, and glutathione (GSH) levels. Prostaglandin-endoperoxide synthase 2 (PTGS2) was overexpressed to elucidate the mechanism of action of Gyp XLIX in the early protection of junctional integrity of DR. Results Among the shared targets between Gyp XLIX and DR, ALB, VEGFA, JUN, ESR1, PTGS2, STAT3, MMP9, HSP90AA1, BCL2L1 and AR were identified. Western blotting and immunofluorescence staining revealed that Gyp XLIX preserved TJ integrity in RPE cells. In addition, iron, lipid peroxidation and GSH assays revealed that Gyp XLIX inhibited ferroptosis in both mice with DM and HG-stimulated ARPE-19 cells. Overexpression of PTGS2 partially reversed the protective impacts induced by Gyp XLIX. Discussion This study demonstrated that Gyp XLIX suppressed ferroptosis and preserved TJ integrity in RPE cells, with these effects being closely associated with the downregulation of PTGS2, thereby exerting early protective effects on junctional integrity of DR.
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NATURAL PRODUCT RESEARCH
·
2026
·
IF 1.8
Wen-Kai Zhao,Tao-Li Hao,Ya-Zhou Kuang,Tong Sun,Hong-Bing Zhang,Yu-Ming Liu
By combining NMR fingerprint with rapid activity screening of eight crude fractions, eleven guanidine alkaloids were obtained from Buthus martensii Karsch, including one new natural product 7 and one new compound 10. Fraction 6 (IC50 = 141.40 ± 0.21 μg/mL) and Fraction 7 (IC50 = 50.89 ± 1.43 μg/mL) showed radical scavenging activity, and compound 8 exhibited the most potent free radical scavenging activity with an IC50 value of 5.09 ± 0.12 μg/mL. Their anti-ferroptotic capacities were validated across FerroOrange staining, which revealed that compounds 1 and 7 significantly inhibited erastin-induced ferroptosis in H9c2 cardiomyocytes. Through network pharmacology, these alkaloids appeared to exert their effects by modulating core targets related to ferroptosis, such as AKT1, EGFR, SRC, HSP90AA1, CASP3, and ESR1, with the notable impacts on the PI3K-Akt signalling pathway and Lipid and atherosclerosis. Molecular docking analysis confirmed the strong binding affinities and stabilities between guanidine alkaloids and these targets.
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CHEMICO-BIOLOGICAL INTERACTIONS
·
2024
·
IF 4.7
Yan-Ting Lv,Tian-Bin Liu,Yue Li,Zhen-Yong Wang,Cai-Yu Lian,Lin Wang
Cadmium (Cd), a prevalent environmental contaminant, has attracted widespread attention due to its serious health hazards. Ferroptosis is a form of iron-dependent oxidative cell death that contributes to the development of various kidney diseases. However, the mechanisms underlying the occurrence of ferroptosis in Cd-induced renal tubular epithelial cells (TECs) have not been fully elucidated. Hereby, both in-vitro and in-vivo experiments were established to elucidate this issue. In this study, we found that Cd elicited accumulation of lipid peroxides due to intracellular ferrous ion (Fe 2+ ) overload and glutathione depletion, contributing to ferroptosis. Inhibition of ferroptosis via chelation of Fe 2+ or reduction of lipid peroxidation can significantly mitigate Cd-induced cytotoxicity. Renal transcriptome analysis revealed that the activation of heme oxygenase 1 (HO-1) was closely related to ferroptosis in Cd-induced TECs injury . Cd-induced ferroptosis and resultant TECs injury are significantly alleviated due to HO-1 inhibition, demonstrating the crucial role of HO-1 in Cd-triggered ferroptosis. Further studies showed that accumulation of lipid peroxides due to iron overload and mitochondrial ROS (mtROS) generation was responsible for HO-1-triggered ferroptosis in Cd-induced cytotoxicity. In conclusion, the current study demonstrates that excessively upregulating HO-1 promotes iron overload and mtROS overproduction to trigger ferroptosis in Cd-induced TECs injury, highlighting that targeting HO-1-mediated ferroptosis may provide new ideas for preventing Cd-induced nephrotoxicity .
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