PHYTOMEDICINE
·
2024
·
IF 6.7
Ji Liu,Ying Han,Zhiyun Wu,Manli Chen,Wenwen Wu,Zijun Zhao,Jinjin Yuan,Zhijian Zheng,Qiang Lin,Nan Liu,Hongbin Chen
Background Perilladehyde, an extract of perillae in the Labiatae family, can produce significant anti-inflammatory and antioxidant effects. Although literature evidences the favorable effect of perillaldehyde on ischemic stroke, the exact mechanism remains blurred. Purpose This study attempted to explore the impact of perillaldehyde on cerebral ischemia-reperfusion injury and the related action mechanism. Methods The rat tMCAO and neuronal OGD/R models were established to simulate cerebral ischemia-reperfusion injury. Lentiviruses were used to interfere with the expression of Nrf2 and Trx2 in neurons. The effects and action mechanisms of perillaldehyde were explored by various experimental methods, including chromatin immunoprecipitation assay, Western Blot, flow cytometry, dual-luciferase reporter gene assay, transmission electron microscopy, MRI, RNA-seq, and immunofluorescence staining. Results Perillaldehyde pretreatment effectively mitigated the tMCAO-induced brain injury in rats by reducing cerebral infarction, improving neuromotor function, and attenuating cell apoptosis in the ischemic penumbra. In vitro, perillaldehyde pretreatment alleviated cell death and excessive oxidative stress, preserved the mitochondrial membrane integrity, enhanced mitochondrial energy metabolism, and facilitated the restoration of mitochondrial ultrastructure after OGD/R. The mechanism probe revealed that perillaldehyde activated the Nrf2/Keap1/Trx2 signaling axis, thus promoting the transcription of Trx2 and improving mitochondrial structure and function. The aforementioned impacts of perillaldehyde were somewhat counteracted by disrupting the expression of Nrf2 and Trx2, suggesting that the neuroprotection of perillaldehyde partially involves the activation of the Nrf2/Keap1/Trx2 axis. Conclusions This study firstly demonstrates the existence of the Nrf2/Keap1/Trx2 signaling axis in cerebral ischemia-reperfusion injury and evidences that perillaldehyde pretreatment can promote the restoration of neuronal mitochondrial structure and function by activating the Nrf2/Keap1/Trx2 axis after cerebral ischemia-reperfusion injury. These findings signify that perillaldehyde holds great promises for clinical management of ischemic stroke.
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INTERNATIONAL IMMUNOPHARMACOLOGY
·
2024
·
IF 4.8
Qiang Li,Yanbin Zheng,Jianyu Zhao,Xinyi Wei,Zongxin Shi,Haonan Fan,Chenxu Ge,Minxuan Xu,Jun Tan
Chronic kidney disease (CKD) presents a significant public health concern, with obesity being a prominent contributing factor to kidney disorders by inducing oxidative stress, lipotoxicity, and tubular cell injury. Natural anthocyanins extracted from red radishes ( Raphanus sativus L.) exert antioxidant and anti-apoptotic functions. This study aims to employ a novel natural pigment anthocyanin, referred to as radish red (RR) isolated from red radishes, to alleviate obesity-related metabolic disturbances and kidney impairment in a CKD mouse model induced by high-fat and high-fructose diets (HFFD). The in vitro study initially demonstrated that RR treatment significantly mitigated the palmitate acid (PA)-induced injury and cytotoxicity in human tubular epithelial HK2 cells. Subsequently, RR supplementation notably improved obesity and associated metabolic dysfunctions in mice caused by HFFD . Abnormal renal function indices including serum creatinine, blood urea nitrogen (BUN), uric acid (UA), urine protein, albuminuria and urine albumin-to-creatinine ratio (UACR) were detected in HFFD-fed mice, which were effectively alleviated by RR treatment. Histologically, renal tubular cell injury, lipid deposition, tubular dilatation, and renal fibrosis induced by HFFD were markedly improved after RR administration in mice. Furthermore, RR treatment significantly alleviated oxidative stress in HFFD-fed mice, as evidenced by the decreased renal reactive oxygen species (ROS) production, 4-HNE, and NOX4 expression levels. Anti-oxidants such as superoxide dismutase-1 (SOD1), NAD (P) H: quinone oxidoreductase (NQO1), heme oxygenase-1 (HO-1) and glutamate cysteine ligase (GCLC) were highly upregulated in kidney of HFFD-fed mice with RR consumption through improving NFE2-related factor 2 (Nrf2) signaling activation. Furthermore, ferroptosis was identified in the kidneys of HFFD-fed mice, evidenced by the elevated levels of malondialdehyde (MDA), iron content, and lipid peroxidation, along with the decreased expression of glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11). These occurrences were significantly mitigated following RR treatment. Mechanistically, we further discovered that the suppressive effects of RR in restricting oxidative stress, ferroptosis, lipid accumulation, and injury of tubular epithelial cells induced by PA were significantly counteracted by Nrf2 knockdown. Collectively, our results demonstrated that dietary supplementation with RR could potentially serve as an efficacious therapeutic modality for the management of obesity-related CKD progression by enhancing Nrf2 activation to impede oxidative stress and ferroptosis.
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BMC Nephrology
·
2025
·Vol. 26
·期 1
·1-14
·
IF 2.4
Lou Yunpeng,Shi Hongguang,Sha Ning,Li Feifei,Gu Xiaofeng,Lin Huiyan
Background Ursodeoxycholic acid (UDCA), traditionally recognized for its hepatoprotective effects, has also shown potential in protecting kidney injury. This study aimed to evaluate the protective effects of UDCA against sepsis-induced acute kidney injury (AKI) and to elucidate the underlying mechanisms.Methods Sixty male C57BL/6 N mice were utilized to establish a sepsis-induced AKI model through intravenous injection of lipopolysaccharides (LPS, 10 mg/kg). UDCA (15, 30, and 60 mg/kg) was administered intraperitoneally once daily for 7 days before LPS injection. Kidney injury was evaluated by HE staining and biochemical markers, including serum creatinine (Cr), blood urea nitrogen (BUN), urinary protein, neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), N-acetyl-β-D-glucosaminidase (NAG), and retinol binding protein (RBP). Oxidative stress parameters and nuclear factor erythroid 2-related factor 2 (Nrf2)/ heme oxygenase-1 (HO-1) pathway, pro-inflammatory cytokines and nuclear factor-kappa B (NF-κB) pathway were also evaluated. Additionally, HK-2 cells were treated with LPS in vitro, and cell viability and apoptosis were detected using CCK-8 kit and flow cytometer, respectively.Results UDCA significantly attenuated LPS-induced renal histopathological damage and improved renal function, as evidenced by reduction in serum Cr, BUN, and urinary protein levels. UDCA also up-regulated the protein expression of zonula occludens-1 (ZO-1) and Ezrin in the kidney, and reduced the urinary levels of NGAL, KIM-1, NAG, and RBP. Moreover, UDCA inhibited NF-κB p65 phosphorylation and reduced pro-inflammatory cytokines levels (TNF-α, IL-1β, and IL-6) in both serum and kidney. UDCA alleviated oxidative stress by activating the Nrf2/HO-1 pathway in the kidney. In vitro, UDCA reduced LPS-induced cell injury and apoptosis in HK-2 cells, with these protective effects being blocked by the Nrf2 inhibitor ML385.Conclusion sOur present study demonstrated that UDCA exerts protective effects against sepsis-induced AKI by attenuating oxidative stress and inflammation, primarily through the activation of the Nrf2/HO-1 pathway and inhibition of the NF-κB pathway. These findings highlight the therapeutic potential of UDCA in preventing sepsis-induced AKI.
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Pharmaceutics
·
2025
·Vol. 17
·期 2
·268
·
IF 5.5
Yunhua Teng,Jiaojiao Ma,Junxia Zhang,Bohan Liang,Aijie Zhang,Yanjie Li,Shiqi Dong,Huirong Fan
Background:It has been documented that radiation can influence the pharmacokinetics of chemotherapy drugs, yet the underlying mechanisms remain poorly understood. In clinical practice, a considerable number of cancer patients undergo radiotherapy, and those with comorbid hypertension required antihypertensive drugs, including valsartan, an angiotensin II receptor blocker. However, there is no research investigating whether radiotherapy poses a risk of altering the pharmacokinetics.Objective:The objective of this study is to investigate the impact of X-ray abdominal irradiation on the pharmacokinetics of valsartan and to preliminarily elucidate the underlying mechanism.Methods:The pharmacokinetics of valsartan after X-ray irradiation was investigated in rats and in vitro by detecting the concentration of valsartan in biological samples by LC-MS/MS. The oxidative stress in the intestine and the mRNA expression of partial transporters and Nrf2 in the liver and small intestine were detected by biochemical reagent kit or RT-qPCR.Results: In vivo studies showed that X-ray irradiation resulted in a significant decrease in the AUC and Cmaxof valsartan, and the cumulative fractional excretion of valsartan in bile and urine, although there was no significant change in fecal excretion. In vitro studies showed that the uptake of valsartan by both intestine and Caco-2 cells decreased after irradiation, and the cellular uptake could be restored by Mrp2 inhibitor MK571. The levels of GSH, SOD, and CAT in the intestine decreased after irradiation. The mRNA expressions of Mrp2 and P-gp in the intestine or Caco-2 cells were significantly upregulated after irradiation while there was a downregulation of Mrp2 and oatp1b2 in liver. Nrf2 and HO-1 in the intestine were also significantly upregulated, which clarified the involvement of Mrp2 and the possible molecular mechanism.Conclusions:Abdominal X-ray irradiation can cause oxidative stress and upregulate intestinal Mrp2, which may be related to oxidative stress and upregulation of Nrf2, reducing intestinal absorption of valsartan and leading to a significant decrease in the blood concentration of valsartan.
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BIOCHEMICAL PHARMACOLOGY
·
2024
·
IF 5.3
Mingyue Tan,Yunfei Yin,Weixiang Chen,Jun Zhang,Yifeng Jin,Yue Zhang,Lei Zhang,Tingbo Jiang,Bin Jiang,Hongxia Li
Ferroptosis is a newly defined mode of cellular demise. The increasing investigation supports that ferroptosis is a crucial factor in the complex mechanisms of myocardial ischemia–reperfusion (I/R) injury. Hence, targeting ferroptosis is a novel strategy for treating myocardial injury. Although evidence suggests that trimetazidine (TMZ) is potentially efficacious against myocardial injury, the exact mechanism of this efficacy is yet to be fully elucidated. This study aimed to determine whether TMZ can act as a ferroptosis resistor and affect I/R-mediated myocardial injury. To this end, researchers have constructed in vitro and in vivo models of I/R using H9C2 cardiomyocytes, primary cardiomyocytes, and SD rats. Here, I/R mediated the onset of ferroptosis in vitro and in vivo, as reflected by excessive iron aggregation, GSH depletion, and the increase in lipid peroxidation. TMZ largely reversed this alteration and attenuated cardiomyocyte injury. Mechanistically, we found that TMZ upregulated the expression of Sirt3. Therefore, we used si-Sirt3 and 3-TYP to interfere with Sirt3 action in vitro and in vivo, respectively. Both si-Sirt3 and 3-TYP partly mitigated the inhibitory effect of TMZ on I/R-mediated ferroptosis and upregulated the expression of Nrf2 and its downstream target, GPX4-SLC7A11. These results indicate that TMZ attenuates I/R-mediated ferroptosis by activating the Sirt3-Nrf2/GPX4/SLC7A11 signaling pathway. Our study offers insights into the mechanism underlying the cardioprotective benefits of TMZ and establishes a groundwork for expanding its potential applications.
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BRITISH JOURNAL OF PHARMACOLOGY
·
2024
·
IF 6.8
Yun Zhao,Guobin Zheng,Shu Yang,Shangjing Liu,Yifan Wu,Yaodong Miao,Zhen Liang,Yunqing Hua,Jing Zhang,Jia Shi,Dan Li,Yanfei Cheng,Yunsha Zhang,Yuanli Chen,Guanwei Fan,Chuanrui Ma
Background and purpose Atherosclerosis is the basis of cardiovascular disease. Ferroptosis is a form of programmed cell death characterized by lipid peroxidation, which contributes to atherogenesis. The plant extract PNS ( Panax notoginseng saponins ), containing the main active ingredients of Panax notoginseng , exhibits anti-atherogenic properties. Herein, we determined whether PNS and its major components could attenuate atherosclerosis by suppressing ferroptosis and revealed the underlying mechanism(s). Experimental approach The anti-atherogenic effects of PNS and their association with inhibition of ferroptosis was determined in apoE −/− mice. In vitro, the anti-ferroptotic effect and mechanism(s) of PNS components were demonstrated in the presence of ferroptosis inducers. Expression of ferroptosis markers and the ubiquitination of Keap1 were evaluated in USP2 −/− macrophages. Finally, the anti-atherogenic effect of USP2 knockout was determined by using USP2 −/− mice treated with high-fat diet (HFD) and AAV-PCSK9. Key results PNS inhibited ferroptosis and atherosclerosis in vivo. PNS suppressed ferroptosis and ferroptosis-aggravated foam cell formation and inflammation in vitro. Mechanistically, PNS and its components activated Nrf2 by antagonizing Keap1, which was attributed to the inhibition of USP2 expression. USP2 knockout antagonized ferroptosis and ferroptosis-aggravated foam cell formation and inflammation, thus mitigating atherosclerosis. USP2 knockout abolished inhibitory effects of PNS on foam cell formation and inflammation in vitro. Conclusion and implications PNS reduced USP2-mediated Keap1 de-ubiquitination and promoted Keap1 degradation, thereby activating Nrf2, improving iron metabolism and reducing lipid peroxidation, thus contributing to an anti-atherosclerotic outcome. Our study revealed the mechanism(s) underlying inhibition of ferroptosis and atherosclerosis by PNS. Graphical
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ACS Omega
·
2025
·
IF 4.3
Suyun Rao,Ke Xiao,Xuhui Chen,Xufang Sun
Diabetic retinopathy (DR) is a major cause of vision impairment, with diabetic retinal neurodegeneration (DRN) identified as an early pathological feature. Although dopamine (DA) has demonstrated protective effects in various neurodegenerative diseases, its role in DRN is inadequately understood. This study provides evidence that DA can alleviate DRN impairment and elucidates the underlying mechanisms. Diabetes was induced in C57BL/6 mice through a single large dose injection of streptozotocin, and the dopamine precursor l-DOPA was administered via intraperitoneal injection daily for 2 weeks to therapeutically supplement dopamine levels. The results indicated that l-DOPA treatment significantly restored retinal thickness, enhanced the amplitude of oscillatory potentials, and alleviated retinal glial cell activation compared to diabetic mice. In vitro, DA treatment of SH-SY5Y cells under high-glucose stress led to a significant increase in superoxide dismutase activity, with a reduction in malondialdehyde levels, lipid peroxide, and iron ion concentration. Additionally, the expression of GPX4, SLC7A11, ferritin, Nrf2, and HO-1 proteins was upregulated, while the expression of NCOA4 was downregulated. Importantly, the protective effects of DA were significantly attenuated by the Nrf2 inhibitor ML385, confirming the involvement of the Nrf2/HO-1 pathway in DA’s protective mechanism. These findings suggest that DA alleviates oxidative stress, reduces ferroptosis, and improves the retinal function in DRN through the activation of the Nrf2/HO-1 pathway, indicating that DA may represent a novel therapeutic strategy for treating DRN.
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DRUG DEVELOPMENT RESEARCH
·
2025
·Vol. 86
·期 7
·e70174
·
IF 4.2
Zhenfei Yu,Xiaoling Qian,Weihua Wu,Meiqi Zhang,Ying Li
Intracerebral hemorrhage (ICH) is a serious acute cerebrovascular disease with a high death and disability rate. Baicalin plays a neuroprotective role in various diseases, but its regulatory mechanism on ICH remains unclear. In this study, we investigated the protective effects and mechanisms of baicalin in ICH using an ICH mouse model. ICH mouse model was established by injection of collagenase type IV into intracranial in C57BL/6 mice. Neurological function was evaluated by neurological severity scores and the rotarod test. Hemorrhagic foci of brain was evaluated by TTC and hematoxylin−eosin staining. Iron ion deposition in brain was detected by Prussian blue staining. Ferroptosis was evaluated by measuring expression of FTH-1, SLC7A11, GPX4, and TFRC, as well as detecting iron content and levels of glutathione (GSH) and malondialdehyde (MDA). GPX4 expression and apoptosis of brain were detected by immunofluorescence staining and TUNEL assay. Results showed that baicalin improved neurological function and reduced the area of hemorrhagic foci of brain in ICH mouse model. Baicalin decreased iron ion deposition, inhibited ferroptosis and apoptosis, and upregulated GPX4 in brain of ICH mouse model. Moreover, baicalin increased AKT1 phosphorylation and the protein level of Nrf2 in brain of ICH mouse model. Notably, AKT1 inhibitor LY294002 and Nrf2 inhibitor reversed the effects of baicalin on the activation of AKT1/Nrf2/GPX4 axis and the inhibition of ferroptosis in brain of ICH mouse model. Collectively, we demonstrated that baicalin promotes ICH recovery by inhibiting ferroptosis in brain tissue through activation of AKT/Nrf2/GPX4 axis. These results may provide new insights for the study of baicalin in the treatment of ICH.
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BMC Complementary Medicine and Therapies
·
2025
·Vol. 25
·期 1
·451
·
IF 3.4
Pan Sunfeng,Xiong Lie,Li Jiakun,Wang Zhenjun,Su Yujuan,Fang Gaofeng,Zhu Minda,Shi Hanqiang,Li Jiayan,Liu Zhaoyan,Han Chunmao,Shi Yanbo
Background Venous leg ulcer (VLU) is among the most severe clinical manifestations of chronic venous disease (CVD) and imposes substantial burdens on both patients and society. VLU pathogenesis is closely associated with the impairment of vascular endothelial cells. In this study, tissue samples from the patients’ s skins around wound at different stages of CVD were collected during operation and used to elucidate the involvement of ferroptosis in the pathogenesis of VLU. Also the potential mechanism through which Huoxue Shengji (HXSJ) decoction alleviates ferroptosis in human umbilical vein endothelial cells (HUVECs) was investigated. Methods During surgical procedure such as great saphenous vein high ligation and stripping surgery, matched skin tissues from the normal, hyperpigmentation (HPT), lipodermatosclerosis (LDS), and VLU regions were collected from 10 patients with VLU, and the levels of iron and glutathione peroxidase 4 (GPX4) were quantified to evaluate ferroptosis. In vitro, HUVECs were used to iron overload induction using exogenous 100 µM ferric ammonium citrate (FAC) or 100 µM hemin, or ferroptosis induction with 10 µM erastin, and treated with 10 µg/ml HXSJ decoction for 24 h. Subsequently, lipid peroxidation (LPO) damage, mitochondrial function, and key genes involved in ferroptosis were assessed. Results Iron deposition in the affected skin of patients with CVD gradually increased before progression to VLU and significantly decreased during the VLU stage. Moreover, GPX4 expression increased significantly in the HPT stage but was gradually suppressed with further deterioration of CVD. The in vitro results indicated that in both the iron overload and ferroptosis models, HXSJ decoction effectively upregulated the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), solute carrier family 7 member 11 (SLC7A11, xCT), and GPX4, which was accompanied by the inhibition of malondialdehyde and protein carbonylation production, the alleviation of ferrous ion accumulation, and the restoration of mitochondrial function. Conclusions This study demonstrated that iron accumulation-mediated inactivation of GPX4 serves as a crucial mechanism in VLU formation through ferroptosis induction. Notably, the therapeutic mechanism through which HXSJ decoction alleviates ferroptosis involves Nrf2/xCT/GPX4 pathway activation and a reduction in ferrous ion accumulation. These findings may provide novel insights into VLU pathogenesis and give possible reason for developing traditional Chinese medicine therapies targeting ferroptosis and VLUs. Graphical
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AQUATIC TOXICOLOGY
·
2025
·
IF 4.3
Hao Wu,Jinwei Gao,Dong Liu,Xiangrong Liu,Feiming Chen,Jiayuan Qin,Yunfei Ye,Zhenzhen Xiong,Jiayu Wu,Can Yang,Min Xie,Rui Song,Dongsheng Ou
In recent years, deltamethrin (DEL) pollution poses a significant threat to aquaculture; however, the protective role of vitamin C (VC) against acute toxicity in crucian carp has not been well understood. This study provides compelling evidence that exposure to 2.0 mg/L waterborne VC significantly mitigates DEL-induced 96-hour mortality in crucian carp ( p < 0.001). Importantly, this research represents the first documentation of the protective effects of waterborne VC in fish, which is mediated through the modulation of the aryl hydrocarbon receptor (AhR)/nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway—a mechanism not previously reported in crucian carp. The observed protective effect is attributed to the enhancement of antioxidant and anti-inflammatory responses via this signaling pathway. Exposure to DEL at 6.2 μg/L resulted in severe oxidative stress, characterized by significantly increased malondialdehyde (MDA) levels and depletion of catalase (CAT), glutathione (GSH), and superoxide dismutase (SOD) in the liver and intestine ( p < 0.01). Histopathological damage, including hepatic vacuolation, shortened villi, and inflammation, as well as elevated reactive oxygen species (ROS), was observed. Co-exposure to VC normalized antioxidant markers, reduced MDA and ROS levels, and alleviated tissue damage ( p < 0.05). Mechanistically, VC counteracted the suppression of AhR/Nrf2 by DEL, leading to the statistically significant upregulation of antioxidant genes ( gst, sod, cat ) and suppression of pro-inflammatory cytokines ( il1β, il6, tnfα ) ( p < 0.05). VC exhibited tissue-specific regulation by enhancing hepatic Nrf2 defenses and co-activating intestinal AhR/Nrf2, as confirmed by Western blot analysis. Our study shows that waterborne VC effectively protects against acute DEL toxicity under current experimental conditions, suggesting its potential as an eco-friendly emergency intervention in aquaculture during sudden pesticide exposure. Further research is needed to confirm its effectiveness in complex pond systems and various fish species.
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NEUROSCIENCE
·
2025
·
IF 2.8
Siqi Quan,Mengyuan Li,Zhouli Yue,Hui Liu,Shuaijun Peng,Roujia Guo,Xiaoyan Fang,Yucheng Li
Neuroinflammation and oxidative stress are major pathogenic drivers of depression, with the Keap1/Nrf2/HO-1 pathway serving as a key regulator of both processes. Formononetin (FMN) is a naturally occurring isoflavone with anti-inflammatory and antioxidant activities; however, its potential to exert antidepressant effects through activation of this pathway has not been investigated. In this study, lipopolysaccharide (LPS, 1 mg/kg, i.p.) was used to induce neuroinflammation and depressive-like behaviors in mice, and FMN (20 or 40 mg/kg) was administered for seven days prior to LPS challenge. FMN dose-dependently alleviated LPS-induced behavioral deficits, including reduced sucrose preference, decreased locomotor activity, and prolonged immobility in the tail suspension test. Hematoxylin-eosin (HE) and Nissl staining revealed that FMN markedly attenuated LPS-induced hippocampal neuronal damage. FMN also inhibited microglial activation, as evidenced by reduced Iba-1 expression, decreased NF-κB phosphorylation, and downregulation of both mRNA and protein levels of pro-inflammatory cytokines, including IL-1β, TNF-α, and IL-6. Furthermore, LPS-induced lipid peroxidation was significantly attenuated, as indicated by lower levels of 4-hydroxynonenal (4-HNE). Molecular docking suggested a potential direct interaction between FMN and Keap1, while Western blot analysis confirmed that FMN downregulated Keap1 and upregulated Nrf2 and HO-1 protein expression. Collectively, these findings demonstrate that FMN alleviates LPS-induced neuroinflammation and depressive-like behaviors, likely through activating the Keap1/Nrf2/HO-1 pathway, supporting its potential as a preventive candidate for inflammation-associated depression.
研究领域:
神经药理学
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分子生物学
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精神病学
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炎症研究
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氧化应激
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PHYTOMEDICINE
·
2025
·
IF 8.3
Shaowei Zheng,Ya Gao,Houkang Cao,Kai Guo,Wenxiu Wang,Guiying Lu,Shasha Wang,Mingli Zhong,Bo Li,Kefeng Zhang,Riming Wei,Jianzhao Wu
Background Acute liver failure (ALF) is associated with ferroptosis and currently lacks specific drugs and therapies. Previous studies have shown the hepatoprotective activity of Sophoricoside (SOP) in diverse models of hepatic injury. However, the role of SOP in ALF caused by lipopolysaccharide (LPS)/D-galactosamine (D-GalN) is still unknown. Purpose To investigate the therapeutic effects of SOP on ALF and its underlying mechanisms of action. Methods In vivo , an ALF mouse model was established using LPS and D-GalN. RNA sequencing was used to identify differentially expressed genes, which were subsequently confirmed by Western blot and qRT-PCR. In vitro , erastin was used to induce ferroptosis in HepG2 cells. Subsequently, the cells were treated with SOP, the nuclear factor erythroid 2-related factor 2 (Nrf2) inhibitor ML385, and the glutathione peroxidase 4 (GPX4) inhibitor RSL3. Additionally, siRNA was utilized for Nrf2 knockdown. Measurements of biochemical markers, reactive oxygen species (ROS) levels, alterations in mitochondrial membrane potential, qRT-PCR, and Western blot analysis were used to confirm the effectiveness and mechanism of SOP. Finally, the interaction between SOP and Nrf2 was verified through molecular docking, surface plasmon resonance (SPR), and cellular thermal shift assay (CETSA). Results In vivo , experimental analysis revealed that SOP ameliorated liver injury, hepatocyte Fe 2+ accumulation, and oxidative stress. RNA sequencing analysis indicated that SOP reversed the abnormal expression of genes related to Nrf2 and the ferroptosis pathway. In vitro , SOP ameliorated erastin-induced oxidative stress, ROS accumulation, and mitochondrial membrane potential loss. After the application of pharmacological inhibitors and siRNA knockdown, the SOP’s inhibitory effect on ferroptosis was antagonized. Conclusion SOP alleviated ALF by activating the Nrf2/GPX4 signaling pathway, thereby mitigating oxidative stress and ferroptosis.
研究领域:
药理学
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分子生物学
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肝病学
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细胞生物学
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生物化学
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