INTERNATIONAL IMMUNOPHARMACOLOGY
·
2025
·
IF 4.7
Wenwei Li,Yang Liu,Ming Wei,Zhichao Yang,Hao Tang,Wei Huang
α-Solanine, a glycoalkaloid (GA) extracted from the stems of the potato plant, exhibits bioactivity and medicinal potential that necessitate further investigation. The impact and underlying mechanisms of α-Solanine on osteoarthritis (OA) remain to be elucidated. To achieve enhanced therapeutic outcomes, we have designed and synthesized a UIO-66-NH 2 @α-Solanine@PEI charged particle (USP) that amplifies the therapeutic effects of α-Solanine, demonstrating superior efficacy. Our approach involved the synthesis of a novel drug delivery system, the USP, to augment the therapeutic potential of α-Solanine in the treatment of OA. An OA rat model was established, and USP treatment was administered. The therapeutic effects were verified through histochemical staining and micro-CT. In vitro, α-Solanine significantly suppressed the expression of proteins related to glycolysis and notably inhibited ferroptosis. RNA sequencing revealed hypoxia-inducible factor-1α (HIF-1α) as a potential pathway mediating the effects of α-Solanine, and it was found that the co-addition of cycloheximide (CHX) led to a shortened decay time of HIF-1α. In vivo, rats with OA demonstrated significant inhibition of glycolysis and ferroptosis following treatment with USP, along with improvements in OA characteristics. These findings suggest that α-Solanine can inhibit the intense glycolysis associated with OA via the HIF-1α pathway and alleviate ferroptosis in chondrocytes. Treatment with USP demonstrated superior efficacy in the management of OA, providing a new therapeutic strategy for the disease.
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高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2025
·
IF 5.4
Qimeng Tian,Hong Jiang,Yajun Luan,Jingge Sun,Yihang Sui,Ling Chen,Yongxiang Wang,Ninghua Tan
Ethnopharmacological relevance Suhuang antitussive capsule (SH) is the only clinically approved traditional Chinese patent medicine for the treatment of post-infectious cough (PIC). During the past decade, our lab has conducted intensive researches on SH, including its efficacy and mechanism on PIC, and determined that SH has favorable anti-inflammatory, antitussive, expectorant, and anti-asthmatic pharmacological effects. Recently, we found that vicenin-2 (VIC-2) could be detected in SH and showed activity in vitro primary screening on PIC. Aim of the study To investigate the therapeutic effects of VIC-2 on PIC and its potential mechanisms, and want to elucidate VIC-2 as one of the efficacious components of SH. Materials and methods The PIC mouse model was established with lipopolysaccharide (LPS)-induced combined cigarette smoke (CS)-exposed ICR mice, while the in vitro assay was constructed to induce BEAS-2B cells with cigarette smoke extract (CSE). The therapeutic effects of VIC-2 on PIC in vitro and in vivo were assessed by pathological sections, cough assay, immune cell counting, and quantitative-polymerase chain reaction (Q-PCR). The mechanisms of VIC-2 on ferroptosis and mitophagy in PIC were further explored by cell viability assay, Prussian blue staining, lipid peroxidation assessment, confocal laser scanning microscopy, and western blotting. Subsequently, virtual docking, cellular thermal shift assay (CETSA), and drug affinity responsive target stability (DARTS) verified the target relationship between VIC-2 and LDL receptor-related protein 1 (LRP1). In addition, the link between LRP1 and mitophagy-dependent ferroptosis was explored by knocking down LRP1. Results VIC-2 significantly improved lung inflammation, oxidative stress, and airway remodeling in PIC and inhibited mitophagy-dependent ferroptosis, confirming that it is one of the antitussive components of SH for the treatment of PIC. LRP1 is one of the pharmacological targets of VIC-2, in which VIC-2 exerted the above effects through up-regulating LRP1 by influencing the LRP1-Parkin interaction. The blockade of LRP1 reversed the both in vitro and in vivo pharmacological activities of VIC-2 . Furthermore, our results showed for the first time that defects in LRP1 lead to ferroptosis. Conclusion This study demonstrates that VIC-2 inhibits mitophagy-dependent ferroptosis via LRP1 for the treatment of PIC, constituting one of the antitussive components of SH.
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高影响因子
CELL PROLIFERATION
·
2025
·
IF 5.6
Changsen Bai,Jialei Hua,Donghua Meng,Yue Xu,Benfu Zhong,Miao Liu,Zhaosong Wang,Wei Zhou,Liming Liu,Hailong Wang,Yang Liu,Lifang Li,Xiuju Chen,Yueguo Li
Glutaminase-1 (GLS1) has garnered considerable interest as a metabolic target in cancer due to its heightened involvement and activity. However, the precise fate of glutaminolysis catalysed by GLS1 in cancer cells remains elusive. We found that GLS1 knockout led to significant suppression of cancer cell proliferation, which can be reversed or partially restored by supplementation of glutamate or non-essential amino acids that can be converted into glutamate. The addition of spliceosomal KGA or GAC ameliorates cancer cell growth in vitro and in vivo, providing both simultaneously completely reverse the effect. The primary metabolic fate of glutamate produced through glutaminolysis in cancer cells is mainly used to produce glutathione (GSH) for redox homeostasis, not entering the tricarboxylic acid cycle or synthesising nucleotides. GSH monoethyl ester (GSH-MEE) effectively rescues the inhibition of cancer cell proliferation caused by GLS1 knockout. Deletion of GLS1 results in an elevation of reactive oxygen species (ROS) and malondialdehyde (MDA), a reduction of NADPH/NADP + ratio, and an augmented susceptibility of cells to ferroptosis. Glutathione Peroxidase 4 (GPX4) and GPX1 exhibit complementary roles in redox regulation, with GLS1 knockout promoting GPX4 degradation. Pharmacological inhibition of GLS1 synergises with GPX4 inhibitor to suppress tumour growth. Dual targeting of GPX4 and GPX1 presents a potent anti-cancer strategy. This metabolic mechanism facilitates a deeper comprehension of the abnormal glutamine metabolism in cancer cells, establishing a theoretical basis for the potential clinical utilisation of GLS1 inhibitors and presenting novel perspectives for advancing combinatorial therapeutic approaches.
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高影响因子
Advanced Healthcare Materials
·
2022
·Vol. 12
·期 3
·2202009
·
IF 11.092
Yi Zhang,Liyi Peng,Ke Hu,Ning Gu
Ferroptosis has recently become a research hotspot, and the induction of tumor cell ferroptosis has emerged as a powerful method for tumor therapy. However, the efficiency of tumor cell ferroptosis induction remains unmet for clinical use, which may be attributed to the large discrepancies between in vitro and in vivo models. To address this issue, in this study, a hydrogel platform with stress relaxation is utilized to develop a multicellular spheroid model of the DLD1 colon cancer cell line through cancer cell self-organization. The spheroids are highly similar to real tumor tissue, and ferroptosis resistance at the transcriptional, protein, and cellular levels. Collaboration of the ferroptosis induction reagent erastin and the nanoenzyme MnZnFe 2 O 4 @PEG-COOH to overcome the ferroptosis resistance of the spheroids is also demonstrated. Taken together, this study demonstrates the effectiveness of the model developed using this hydrogel platform for further mechanistic studies, and for the assessment of novel cancer treatment strategies based on ferroptosis.
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Biomed Research International
·
2022
·
IF 3.246
Hongwei Shi,Yue Yan,Hong Yang,Peng Pu,Heng Tang
Objective. Pirarubicin (THP) is one of anthracycline anticancer drugs. It is widely used in the treatment of various cancers, but its hepatotoxicity cannot be ignored. Schisandrin B (SchB) is a traditional liver-protecting drug, which has the ability to promote mitochondrial function and upregulate cellular antioxidant defense mechanism. However, whether it can resist THP-induced hepatotoxicity has not been reported. The purpose of this study was to observe and explore the effect of SchB on THP-induced hepatotoxicity and its potential mechanism by adding SchB to the diet of rats with THP-induced hepatotoxicity. Methods. The rat model of THP-induced hepatotoxicity was established and partly treated with SchB diet. The changes of serum liver function indexes ALT and AST were observed. The histomorphological changes of liver were observed by HE staining. The biomarker levels of oxidative stress in rat serum and liver were measured to observe oxidative stress state. The expressions of ferroptosis-related protein GPX4 and oxidative stress-related protein were detected by Western blot. Primary hepatocytes were prepared and cocultured with THP, SchB, and Fer-1 to detect the production of reactive oxygen species (ROS) and verify the above signal pathways. Results. THP rats showed a series of THP-induced hepatotoxicity changes, such as liver function damage, oxidative stress, and ferroptosis. SchB diet effectively alleviated these adverse reactions. Further studies showed that SchB had strong antioxidant and antiferroptosis abilities in THP-induced hepatotoxicity. Conclusion. SchB has obvious protective effect on THP-induced hepatotoxicity. The mechanism may be closely related to inhibiting oxidative stress and ferroptosis in the liver.
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高影响因子
eLife
·
2024
·
IF 6.4
Fangyan Wang,Xiujie Liu,Furong Huang,Yan Zhou,Xinyu Wang,Zhengyang Song,Sisi Wang,Xiaoting Wang,Dibang Shi,Gaoyi Ruan,Xiawei Ji,Eryao Zhang,Zenglin Tan,Yuqing Ye,Chuang Wang,Jesse Zhu,Wantie Wang
Hepatic ischemia/reperfusion injury (HIRI) is a common and inevitable factor leading to poor prognosis in various liver diseases, making the outcomes of current treatments in clinic unsatisfactory. Metformin has been demonstrated to be beneficial to alleviate HIRI in recent studies, however, the underpinning mechanism remains unclear. In this study, we found metformin mitigates HIRI-induced ferroptosis through reshaped gut microbiota in mice, which was confirmed by the results of fecal microbiota transplantation treatment but showed the elimination of the beneficial effects when gut bacteria were depleted using antibiotics. Detailedly, through 16S rRNA and metagenomic sequencing, we identified that the metformin-reshaped microbiota was characterized by the increase of gamma-aminobutyric acid (GABA) producing bacteria. This increase was further confirmed by the elevation of GABA synthesis key enzymes, glutamic acid decarboxylase and putrescine aminotransferase, in gut microbes of metformin-treated mice and healthy volunteers. Furthermore, the benefit of GABA against HIRI-induced ferroptosis was demonstrated in GABA-treated mice. Collectively, our data indicate that metformin can mitigate HIRI-induced ferroptosis by reshaped gut microbiota, with GABA identified as a key metabolite.
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高影响因子
Redox Biology
·
2024
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IF 10.7
Xin Zhong,Kangwei Wang,Yonghua Wang,Luya Wang,Sudan Wang,Weijian Huang,Zhuyin Jia,Shan-Shan Dai,Zhouqing Huang
Continuous remodeling of the heart can result in adverse events such as reduced myocardial function and heart failure. Available evidence indicates that ferroptosis is a key process in the emergence of cardiac disease. P2 family purinergic receptor P2X7 receptor (P2X7R) activation plays a crucial role in numerous aspects of cardiovascular disease. The aim of this study was to elucidate any potential interactions between P2X7R and ferroptosis in cardiac remodeling stimulated by angiotensin II (Ang II), and P2X7R knockout mice were utilized to explore the role of P2X7R and elucidate its underlying mechanism through molecular biological methods. Ferroptosis is involved in cardiac remodeling, and P2X7R deficiency significantly alleviates cardiac dysfunction, remodeling, and ferroptosis induced by Ang II. Mechanistically, Ang II interacts with P2X7R directly, and LYS-66 and MET-212 in the C-type domain form a binding complex with Ang II. P2X7R blockade influences HuR-targeted GPX4 and HO-1 mRNA stability by affecting the shuttling of HuR from the nucleus to the cytoplasm and its expression. These results suggest that focusing on P2X7R could be a possible therapeutic approach for the management of hypertensive heart failure.
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高影响因子
Biomolecules
·
2026
·Vol. 16
·期 10
·1507
·
IF 5.6
Ting Ge,Yifan Wen,Jiale Zhao,Wenjia Wang,Wenwen Xu,Bo Li,Yibing Wang,Weihua Zhang,Enping Zhang
Litter size is a critical trait determining the economic efficiency of sheep production. Ferritin heavy chain 1 (FTH1), a key iron-storage protein, plays an important role in regulating cellular susceptibility to ferroptosis. Based on our previous observation that ferroptosis-related pathways differ between ovaries from single-lamb and multi-lamb Hu ewes, this study investigated the role ofFTH1in regulating ferroptosis and granulosa cell (GC) function in sheep.FTH1expression was examined in ovarian tissues and GCs from Hu sheep with different reproductive phenotypes and follicular developmental stages using RT-qPCR. An erastin-induced ferroptosis model was established in sheep GCs, andFTH1function was evaluated through overexpression and interference experiments. Ferroptosis-related indicators, including ROS, C11-BODIPY 581/591, Fe2+, malondialdehyde (MDA), reduced glutathione (GSH), ferroptosis-associated genes, and GPX4 protein expression, were analyzed. Steroidogenic function was assessed by measuring the expression ofSTAR,CYP11A1,HSD17B1, and3β-HSD, as well as estradiol (E2) and progesterone (P4) secretion. RNA sequencing was performed to identify transcriptional changes associated withFTH1overexpression in erastin-treated GCs.FTH1expression was higher in ovaries from multiparous sheep and healthy follicles.FTH1overexpression alleviated erastin-induced ferroptosis by enhancing GPX4 expression and reducing Fe2+accumulation, ROS production, and lipid peroxidation, whereasFTH1knockdown aggravated ferroptosis damage. Furthermore,FTH1maintained steroidogenic function by promotingSTARexpression and preserving E2and P4synthesis under ferroptosis stress. Ferrostatin-1 (Fer-1) partially rescued GC viability and steroidogenic capacity, and attenuated erastin-induced apoptosis. Under erastin treatment, transcriptome analysis identified 297 differentially expressed mRNAs and 92 lncRNAs betweenFTH1-overexpressing GCs and the corresponding vector control. These differentially expressed transcripts represent candidate regulatory relationships that require further functional validation. Enrichment analysis highlighted cytokine signaling and ROS-related pathways, suggesting potential processes associated with the effects ofFTH1under these conditions. Collectively, these findings support thatFTH1protects sheep GCs against ferroptosis-induced injury and supports steroidogenic function, providing new insights into the role of iron homeostasis in follicular development.
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高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2024
·
IF 4.8
Xiaocui Jiang,Xiaoming Yu,Zhongyi Zhu,Yinjuan Lyu,Xinyu Jiang,Zihao Liu,Jigang Cao,Min Xiao
Ethnopharmacological relevance The effect of hyperuricemia (HUA) on testicular spermatogenesis cannot be ignored. The classical Chinese medicine compound Shenling Baizhu San (SLBZS) can reduce uric acid and improve testicular spermatogenesis, while researchers have not well explored the related pathology and pharmacodynamic mechanism have. Aims of study To investigate whether the dysfunction of testicular spermatogenesis caused by HUA and the therapeutic effect of SLBZS are related to testicular cell ferroptosis. Materials and methods C57BL/6 mice and C57BL/6 background Sirt3 -/- mice were induced by oxazinate potassium (OXO), and HUA spermatogenic dysfunction mice model were constructed and treated with SLBZS. Sperm quality detection and testicular histopathology served for evaluating the protective mechanism of SLBZS against testicular spermatogenesis in HUA mice. Biochemical detection, transmission electron microscopy, immunohistochemistry and immunofluorescence were used to evaluate ferroptosis level of testicular cells. Western blot analysis assisted in verifying the expression of the corresponding pathway proteins. Results The testes of mice with HUA spermatogenic dysfunction were subjected to OXO-induced oxidative stress and ferroptosis, and the Sirt3/Nrf2 pathway-related protein expressions were changed. SLBZS improved the testes of mice with HUA spermatogenic dysfunction in terms of their spermatogenic function, oxidative stress and ferroptosis, and promoted Sirt3/Nrf2 antioxidant pathway-related proteins to be expressed. The analysis of Sirt3 -/- mice was modeled and dosed, and it was found that SLBZS could not improve the spermatogenic function, oxidative stress and ferroptosis of Sirt3-deficient model mice’ testes. Conclusions OXO-induced spermatogenic dysfunction in HUA is associated with ferroptosis of testicular cells. SLBZS can be used for treating spermatogenic dysfunction in HUA possibly by activating Sirt3/Nrf2 signaling pathway, which inhibits ferroptosis due to oxidative stress.
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高影响因子
ACS Biomaterials Science & Engineering
·
2024
·
IF 5.4
Beibei Zhang,Hao Liu,Yifei Wang,Yong Zhang
Ferroptosis is an appealing cancer therapy strategy based on the H2O2-involved Fenton reaction to produce toxic •OH for lipid peroxidation. However, intracellular H2O2 is easily consumed and results in a deficient Fenton reaction. This obstacle can be overcome by traditional chemotherapeutic drugs for H2O2 supplements. Moreover, a recent work illustrated that dihydroartemisinin (DHA) could promote ferroptosis against tumoral cells, particularly in the presence of ferrous compounds. To achieve combined chemotherapy and ferroptosis, a nanocarrier (TKNPDHA-Fc) was constructed by using thioketal (TK)-bridged paclitaxel prodrug (PEG-TK-PTX) and ferrocene (Fc)-conjugated PEG-Fc, where DHA was encapsulated by a hydrophobic–hydrophobic interaction. Upon cellular uptake, TKNPDHA-Fc could facilitate PTX release through TK breakage under an excess H2O2 microenvironment. Owing to the loss of the hydrophobic PTX component, TKNPDHA-Fc underwent a rapid dissociation for improving DHA to act as a ferroptotic inducer along with Fe supplied from Fc. Moreover, both the chemotherapy-induced reactive oxygen species and the •OH produced from reinforced ferroptosis further stimulated the TK cleavage. The “self-catalytic” loop of TKNPDHA-Fc remarkably improved the antitumor performance in vivo via combined mechanisms, and its tumor inhibition rate reached 78.3%. This work highlights the contribution of ROS-responsive and self-catalytic nanoplatforms for enhancing the potential of combined chemotherapy and ferroptosis for cancer therapy in the future.
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高影响因子
PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY
·
2024
·
IF 4.2
Xinyu Wu,Jiawei Chen,Kaixin Ping,Yan Xia,Mengxin Li,Yannan Xiang,Huimao Feng,Jingquan Dong
Long-term residue of difenoconazole (DFZ) in the environment caused multiple organ damage to aquatic organisms. Due to the potential hepatoprotective and neuroprotective properties of silybin (SIL), we hypothesized that SIL could alleviate growth inhibition, liver, and brain damage in carp induced by DFZ exposure. The in vivo experiments were divided into the Control group, the SIL group, the DFZ group and the DFZ + SIL group. The exposure concentration of DFZ was 0.39 mg/L, and the therapeutic dose of SIL was 400 mg/kg. The whole experiment lasted for 30 days. SIL was also found to reduce hepatic injury and lipid metabolism based on H&E staining, oil red O staining, and measurement of serum and liver tissue levels of ALT, AST, LDH, TG, and TC. Similarly, SIL reduced brain damage after DFZ exposure, according to H&E staining and detection transcription level of the ZO-1, ZO-2, occludin, and Claudin7 in carp brain. In terms of mechanism, the results showed that SIL inhibited the excessive production of ROS in liver and brain tissues, increased the activity of antioxidant enzymes (T-AOC, SOD, CAT) and resist oxidative stress. Also, SIL promoted the production of anti-inflammatory factors (TGF-β1 and IL-10) and inhibited the expression of pro-inflammatory factors (TNF-α and IL-6) to reduce the inflammatory response in liver and brain tissues caused by DFZ. ln terms of ferroptosis, by lowering iron levels, upregulating ferroptosis-related genes (GPX4, SIC7A11, GCLC), and downregulating the expression of NCOA4, STEAP3, COX2, and P53, SIL was able to inhibit ferroptosis of liver and brain tissues of carp. In addition, SIL restored the reduced mitochondrial membrane potential (MMP) level and inhibited apoptosis as measured by MMP level detection, TUNEL staining, and apoptosis gene transcript levels. In this study, we analyzed the interactions between genes and proteins associated with oxidative stress, inflammation, ferroptosis and apoptosis using the String database and ranked the nodes in the network using the Cytoscape plugin Cytohubba, and found that P53, Caspase3, TNF-α, IL-6 and Bcl-2 were the key hub genes. Our study not only revealed the multiple pharmacological activities of SIL, but also provided a reference for the prevention and reduction pesticide hazards to aquatic organisms.
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高影响因子
Pharmaceutics
·
2024
·Vol. 16
·期 5
·639
·
IF 4.9
Junming Cui,Xinxi Cai,Rui Qian,Lin Wu,Xueyong Qi,Jin Cao,Song Shen
Artemisinin has an endoperoxide bridge structure, which can be cleaved by ferrous ions to generate various carbonyl radicals in an oxygen-independent manner, highlighting its potential for treating hypoxic tumors. In our study, we fabricated Tween 80 micelles loaded with Fe3O4nanoparticles and artemisinin for cancer therapy. The synthesized Fe3O4nanoparticles and drug-loaded micelles have particle sizes of about 5 nm and 80 nm, respectively, both exhibiting excellent dispersibility and stability. After uptake by MCF-7 cells, drug-loaded micelles release Fe2+and ART into the cytoplasm, effectively inducing the generation of reactive oxygen species (ROS) in hypoxic conditions, thereby enhancing toxicity against cancer cells. In vitro and in vivo studies have demonstrated that ART and Fe3O4nanoparticles are encapsulated in Tween 80 to form micelles, which effectively prevent premature release during circulation in the body. Although free ART and Fe3O4nanoparticles can inhibit tumor growth, TW80-Fe3O4-ART micelles demonstrate a more pronounced inhibitory effect, with a tumor suppression rate of up to 85%. A novel strategy based on artemisinin and ferroptosis is thus offered, holding a favorable prospect for hypoxic cancer therapy.
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