Scientific Reports
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2025
·Vol. 15
·期 1
·1-14
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IF 3.9
Zhang Yuxi,Zhan Junbiao,Qiu Zhen,Tian Hao,Lei Shaoqing,Huang Qin,Xue Rui,Sun Qian,Xia Zhongyuan
Myocardial cold ischemia/reperfusion (I/R) injury is an inevitable consequence of heart transplantation, significantly affecting survival rates and therapeutic outcomes. Growth Differentiation Factor 15 (GDF15) has been shown to regulate GPX4-mediated ferroptosis, playing a critical role in mitigating I/R injury. Meanwhile, verbascoside (VB), an active compound extracted from the herbaceous plant, has demonstrated myocardial protective effects. In this study, heart transplantation was performed using a modified non-suture cuff technique, with VB administered at a dose of 20 mg/kg/day via intraperitoneal injection for 3 days in vivo. In vitro, cardiomyocytes were pretreated with 50 µg/ml VB for 24 h. VB treatment significantly reduced histopathological injury, decreased myocardial injury markers, and inhibited ferroptosis and oxidative stress during myocardial cold I/R injury in vivo. In vitro experiments further demonstrated that GDF15 alleviates ferroptosis induced by hypoxic reoxygenation by upregulating GPX4. Therefore, it is concluded that VB preconditioning can effectively reduce ferroptosis induced by myocardial cold I/R after heterotopic heart transplantation, possibly through up-regulation of GDF15/GPX4/SLC7A11 pathway.
研究领域:
心血管病学
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药理学
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移植学
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DOI
PubMed
高影响因子
Cellular and Molecular Gastroenterology and Hepatology
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2023
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IF 7.2
Xiaolei Li,Qian Huai,Cheng Zhu,Xu Zhang,Wentao Xu,Hanren Dai,Hua Wang
Background & Aims Liver fibrosis/cirrhosis is significant health burden worldwide, resulting in liver failure or cancer and accounting for many deaths each year. The pathogenesis of liver fibrosis is very complex, which makes treatment challenging. Growth differentiation factor 15 (GDF15), a cysteine knot protein belonging to the transforming growth factor β (TGF-β) superfamily, has been shown to play a protective role after tissue injury and to promote a negative energy balance during obesity and diabetes. However, paucity of literature is available about GDF15 function in liver fibrosis. This study aimed to investigate the immunomodulatory role and therapeutic potential of GDF15 in progression of hepatic fibrosis. Methods GDF15 expression was studied in patients with fibrosis/cirrhosis and in 2 murine models of liver fibrosis, including mice treated with CCl 4 or DDC diet. GDF15 involvement in the pathogenesis of liver fibrosis was assessed in Gdf15 knockout mouse using both CCl 4 and DDC diet experimental models. We used the CCl 4 and/or DDC diet–induced liver fibrosis model to examine the antifibrotic and anti-inflammatory effects of AAV8-mediated GDF15 overexpression in hepatocytes or recombinant mouse GDF15. Results GDF15 expression is decreased in the liver of animal models and patients with liver fibrosis/cirrhosis compared with those without liver disease. In vivo studies showed that GDF15 deficiency aggravated CCl 4 and DDC diet–induced liver fibrosis, while GDF15 overexpression mediated by AAV8 or its recombinant protein alleviated CCl 4 and/or DDC diet–induced liver fibrosis. In Gdf15 knockout mice, the intrahepatic microenvironment that developed during fibrosis showed relatively more inflammation, as demonstrated by enhanced infiltration of monocytes and neutrophils and increased expression of proinflammatory factors, which could be diminished by AAV8-mediated GDF15 overexpression in hepatocytes. Intriguingly, GDF15 exerts its effects by metabolic reprogramming macrophages to acquire an oxidative phosphorylation–dependent anti-inflammatory functional fate. Furthermore, adoptive transfer of GDF15-preprogrammed macrophages to mouse models of liver fibrosis induced by CCl 4 attenuated inflammation and alleviated the progression of liver fibrosis. Conclusion GDF15 ameliorates liver fibrosis via modulation of liver macrophages. Our data implicate the importance of the liver microenvironment in macrophage programming during liver fibrosis and suggest GDF15 that is a potentially attractive therapeutic target for the treatment of patients with liver fibrosis.
研究领域:
肝病学
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免疫学
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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
Human Cell
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2024
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IF 3.4
Zhang Ke,Zhang Hailing,Wang Bing,Gao Shanshan,Sun Caiping,Jia Cong,Cui Jinquan
Abnormal functions of trophoblast cells are associated with the pathogenesis of preeclampsia (PE). Nuclear receptor subfamily 2 group F member 1 (NR2F1) acts as a transcriptionally regulator in many diseases, but its role in PE remains unknown. Hypoxia/reoxygenation (H/R)-stimulated HTR-8/SVneo cells were used to mimic PE injury in vitro. NR2F1 overexpression alleviated trophoblast apoptosis, as evidenced by the decreased number of TUNEL-positive cells and the downregulation of caspase 3 and caspase 9 expression in cells. NR2F1 overexpression increased the invasion and migration ability of HTR-8/SVneo cells, accompanied by increased protein levels of matrix metalloproteinase (MMP)-2 and MMP-9. mRNA-seq was applied to explore the underlying mechanism of NR2F1, identifying growth differentiation factor 15 (GDF15) as the possible downstream effector. Dual-luciferase reporter, ChIP-qPCR, and DNA pull-down assays confirmed that NR2F1 bound to the promoter of GDF15 and transcriptionally inhibited its expression. GDF15 overexpression increased apoptosis and decreased the ability of invasion and migration in HTR-8/SVneo cells expressing NR2F1. MAPK pathway was involved in the regulation of PE. Administration of p38 inhibitor, ERK inhibitor, and JNK inhibitor reversed the effect of simultaneous overexpression NR2F1 and GDF15 on trophoblast apoptosis, invasion, and migration. Our findings demonstrated that NR2F1 overexpression inhibited trophoblast apoptosis and promoted trophoblast invasion and migration. NR2F1 might negatively regulate GDF15 expression by binding to its promoter region, which further inhibited MAPK signaling pathway in PE. Our study highlights that NR2F1 might sever as a potential target in PE. Graphical abstract
研究领域:
妇产科学
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分子生物学
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细胞生物学
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转录调控
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信号传导
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DOI
PubMed
高影响因子
PHARMACOLOGICAL RESEARCH
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2025
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IF 10.5
Rongfang Guo,Shuying Zhang,Anyao Li,Ping Zhang,Xin Peng,Xiaoyan Lu,Xiaohui Fan
Type 2 diabetes mellitus (T2DM) is a significant public health issue with high morbidity and mortality. Ginsenoside Rb1 (Rb1) and berberine (BBR), the main bioactive compounds of Panax ginseng and Coptis chinensis , respectively, are known for their hypoglycemic effects. Nevertheless, the synergistic effects and underlying mechanism of Rb1 and BBR on T2DM remain unclear. In this study, we utilized a leptin receptor-deficient (db/db) mouse model to investigate the protective effects of their combination treatment. Our findings demonstrated that the combined use of Rb1 and BBR at a 1:4 ratio had more pronounced effects than the first-line anti-diabetic drug metformin on reducing the weight ratio of white adipose tissue, ameliorating insulin resistance, and improving glucose and lipid metabolism. Using spatial transcriptomics, we revealed that metformin treatment improved gluconeogenesis and lipogenesis only in the periportal zone, while the combination treatment induced improvements throughout the liver lobule, with distinct key targets across different zones, thus underscoring a more comprehensive modulation of hepatic metabolism. This may be the key reason why this combination therapy demonstrated superior protective effects against T2DM. Additionally, the reversed expression of the key callback gene hepcidin (HAMP) and its regulator growth differentiation factor 15 (GDF15) following the combination therapy across all zones, along with validation experiments, further suggested that GDF15/HAMP pathway might be a key mechanism underlying the beneficial effects of Rb1 and BBR against T2DM. This study also indicates a path toward innovative drug cocktails for treating T2DM, offering a holistic approach to regulate the entire liver lobule metabolism.
研究领域:
医学
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分子生物学
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PubMed
高影响因子
MOLECULAR AND CELLULAR ENDOCRINOLOGY
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2025
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IF 3.6
Lanlan Cheng,Jie Zhang,Yungai Xiang,Li Tan
Spontaneous abortion (SA) refers to the loss of a pregnancy without external intervention. The runt-related transcription factor 3 (RUNX3) is associated with gestational disorders in view of previous studies. However, RUNX3 has not been reported in SA. RUNX3 is significantly upregulated in the placental villi of abortion patients based on the GSE123719 microarray data. Herein, we further validated and found that the expression of RUNX3 in placental villi of SA women was higher than those of induced abortion (IA) women. In vitro , we constructed human RUNX3 overexpression or interference adenovirus vectors to modulate RUNX3 expression in trophoblast cells. Our findings revealed that RUNX3 overexpression accelerated trophoblast cell ferroptosis, while RUNX3 knockdown alleviated erastin-induced ferroptosis. Subsequently, the dual luciferase reporter assay was performed to confirm that RUNX3 bound to the GDF15 promoter to transcriptionally repress GDF15 transcriptional activity. Importantly, GDF15 attenuated the pro-ferroptosis effects of RUNX3 on HTR-8/SVneo cells. In vivo , mouse RUNX3 interference adenovirus vectors were used to silence RUNX3 in mice. The results presented that the reduction of RUNX3 inhibited embryo adsorption rate in SA mice, involving ferroptosis and the interaction between RUNX3 and GDF15. Taken together, this study established that RUNX3 advanced SA progression by enhancing trophoblast ferroptosis via transcriptionally repressing GDF15. These findings may provide novel therapeutic strategies for SA management.
研究领域:
分子生物学
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细胞生物学
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生殖医学
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遗传学
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生物化学
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PubMed
高影响因子
Nature Communications
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2024
·Vol. 15
·期 1
·1-14
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IF 14.7
Guo Xuanming,Asthana Pallavi,Zhai Lixiang,Cheng Ka Wing,Gurung Susma,Huang Jiangang,Wu Jiayan,Zhang Yijing,Mahato Arun Kumar,Saarma Mart,Ustav Mart,Kwan Hiu Yee,Lyu Aiping,Chan Kui Ming,Xu Pingyi,Bian Zhao-Xiang,Wong Hoi Leong Xavier
Obesity, a global health challenge, is a major risk factor for multiple life-threatening diseases, including diabetes, fatty liver, and cancer. There is an ongoing need to identify safe and tolerable therapeutics for obesity management. Herein, we show that treatment with artesunate, an artemisinin derivative approved by the FDA for the treatment of severe malaria, effectively reduces body weight and improves metabolic profiles in preclinical models of obesity, including male mice with overnutrition-induced obesity and male cynomolgus macaques with spontaneous obesity, without inducing nausea and malaise. Artesunate promotes weight loss and reduces food intake in obese mice and cynomolgus macaques by increasing circulating levels of Growth Differentiation Factor 15 (GDF15), an appetite-regulating hormone with a brainstem-restricted receptor, the GDNF family receptor α-like (GFRAL). Mechanistically, artesunate induces the expression of GDF15 in multiple organs, especially the liver, in mice through a C/EBP homologous protein (CHOP)-directed integrated stress response. Inhibition of GDF15/GFRAL signalling by genetic ablation of GFRAL or tissue-specific knockdown of GDF15 abrogates the anti-obesity effect of artesunate in mice with diet-induced obesity, suggesting that artesunate controls bodyweight and appetite in a GDF15/GFRAL signalling-dependent manner. These data highlight the therapeutic benefits of artesunate in the treatment of obesity and related comorbidities.
研究领域:
药理学
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内分泌学
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代谢学
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分子生物学
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动物模型
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DOI
高影响因子
Frontiers in Pharmacology
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2026
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IF 5.4
Liang Zhang,Huan Liu,Si Jiang,Desheng Li,Xin Li,Maolei Xu,Jianwen Fei,Ling Zhou
Background The natural compound morusin (Mor) acts as a potent tumor suppressor in non-small cell lung cancer (NSCLC), but its potential to sensitize DDP and its direct targets are less understood. This work aims to investigate the DDP-sensitizing effects of Mor and the underlying mechanisms. Methods Cell viability and drug synergy were assessed in NSCLC cells. Ferroptosis was evaluated by measuring lipid reactive oxygen species (ROS), iron accumulation, and the expression of ferroptosis markers. GDF15 was identified as a target via transcriptome sequencing. Its direct binding with Mor was confirmed by molecular docking. The ubiquitin-mediated degradation mechanism and its functional role in ferroptosis were validated using the proteasome inhibitor MG132, alongside GDF15 overexpression and knockdown models. Clinical relevance was assessed using TCGA database analysis. Results Mor induces ferroptosis and significantly augments DDP sensitivity in both NSCLC and cisplatin-resistant A549 cells (A549/DDP). Mechanistically, Mor directly binds to GDF15 and promotes its ubiquitin-mediated degradation. Consequently, GDF15 overexpression reversed Mor-induced cytotoxicity and DDP sensitization. Furthermore, DDP exposure impairs intracellular GDF15 protein levels, and the Mor/DDP combination synergistically suppresses GDF15 in A549 cells. Notably, GDF15 expression is elevated in NSCLC cells compared to normal lung epithelial cells. However, A549/DDP cells exhibit diminished intracellular GDF15 protein relative to parental cells, while GDF15 transcription is upregulated. Knockdown of GDF15 augmented DDP sensitivity in resistant cells. Conclusion Mor reverses DDP resistance by inducing GDF15 degradation and ferroptosis, suggesting that Mor-based combination therapy holds promise in treating NSCLC.
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PubMed
高影响因子
FREE RADICAL BIOLOGY AND MEDICINE
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2025
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IF 8.2
Sichan Li,Shunzi Shao,Zhaokun Zhang,Zhuo Wang,Xiaolei Han,Xiaoqian Jia,Hongxin Zhang,Yuan Gao,Xiaobo Zhang
Metabolic dysfunction-associated steatotic liver disease (MASLD) has become a global epidemic, leading to an unmet medical need for pharmacological interventions. This study aims to investigate the protective effect and mechanism of a synthetic wogonin derivate V8 against hepatic steatosis. Herein, we report that V8 attenuates lipid accumulation and prevents mitochondrial dysfunction in hepatocytes. Growth differentiation factor 15 (GDF15), a well-known cytokine with powerful metabolic action, mediates the effect of V8 on lipid metabolic disorders. Mechanistically, due to its lysosomotropic property, V8 promotes nuclear translocation of transcription factor EB (TFEB) and subsequent GDF15 gene transcription through activating adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK). Further analysis demonstrates GDF15 mainly improves mitochondrial homeostasis under stressful condition. Consistently, Gdf15 ablation in mice results in aggravated hepatic lipid deposition and liver injury upon high-fat diet feeding. Moreover, V8 alleviates diet-induced hepatic steatosis in a GDF15-dependent manner, and improves toxins-induced hepatic pathological phenotypes accompanying with upregulation of GDF15. Collectively, these data demonstrate the beneficial metabolic effect of V8 and highlight its utility in treating hepatic steatosis and its associated metabolic complications.
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PubMed
高影响因子
Communications Biology
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2026
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IF 5.8
Gu Qingqing,Chen Qianwen,Deng Ye,Deng Li,Huang Jianya,Wang Jingyi,Ji Yuan,Wang Ruxing,Wang Qingjie,Sun Ling
Doxorubicin (DOX) is a highly effective chemotherapeutic agent, but its clinical application is limited by cardiotoxicity. Mitochondrial dysfunction and apoptosis are key mechanisms underlying DOX-induced cardiomyopathy (DIC), while the role of telomerase reverse transcriptase (TERT) and its specific regulatory mechanisms remain unclear. An in vitro DOX-induced H9C2 cardiomyocyte injury model was established. TERT was overexpressed via adenoviral transfection or inhibited using BIBR1532. An in vivo mouse model of DOX-induced acute myocardial injury was constructed, with TERT expression regulated via intramyocardial adenoviral injection. Cardiac function was evaluated by echocardiography, and myocardial pathology was observed via staining. Additionally, exosome-encapsulated growth differentiation factor 15 (EXO-GDF15) was extracted and identified. Its regulatory mechanism on TERT was explored using DNA pull-down and luciferase reporter gene assays. Metabolomics was used to analyze the effect of TERT on mitochondrial metabolites in cardiomyocytes. TERT overexpression reduced DOX-induced apoptosis, increased mitochondrial membrane potential, and promoted autophagy in cardiomyocyte. In mice, TERT overexpression improved cardiac function and alleviated myocardial fibrosis, inflammation, and cardiomyocyte hypertrophy. Conversely, TERT inhibition exacerbated these injuries. EXO-GDF15 could be endocytosed by cardiomyocytes and alleviated DOX-induced myocardial injury by downregulating SUB1 to promote TERT transcription. Luciferase reporter assays showed that SUB1 binds to the BS4 site of the TERT promoter. Metabolomics showed that TERT increased the mitochondrial metabolite thiamine pyrophosphate (TPP) in cardiomyocytes, which alleviated myocardial injury by participating in the tricarboxylic acid cycle. EXO-GDF15 alleviates doxorubicin-induced cardiotoxicity via the SUB1/TERT/TPP signaling axis, thereby providing advanced insights for future DIC treatment.
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DOI
高影响因子
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