EUROPEAN JOURNAL OF PHARMACOLOGY
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2025
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IF 4.7
Yanmin Zhang,Jianqiang Hu,Yan Zhang,Xiaolin Yang,Weihua Tong,Xinxin Ci
Background The transition from acute kidney injury (AKI) to chronic kidney disease (CKD) is a significant cause of kidney failure. Although the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) has been demonstrated to inhibit ferroptosis and alleviate cisplatin-induced AKI, the specific roles of Nrf2 and the alkaloid leonurine in modulating the AKI-CKD transition remain incompletely elucidated. Methods Murine and human proximal tubular epithelial cell models of the AKI-CKD transition were established using repeated low-dose cisplatin (RLDC) to investigate the roles of Nrf2 and leonurine in ferroptosis regulation and disease progression. Key results In mice, RLDC administration induced persistent tubular injury, ferroptosis, and progressive renal fibrosis. In HK-2 cells, RLDC triggered oxidative stress and ferroptosis. Although Nrf2 expression was transiently upregulated during the acute phase (4 weeks post-RLDC), it was downregulated by the chronic phase (8 weeks post-RLDC), correlating with impaired antioxidant capacity and exacerbated ferroptosis. Nrf2 knockout mice exhibited more severe oxidative damage, ferroptosis, and renal dysfunction following RLDC challenge. Pharmacological activation of Nrf2 by leonurine attenuated oxidative injury and ferroptosis and promoted tubular repair. Leonurine also suppressed the epithelial–mesenchymal transition and aberrant extracellular matrix deposition, ultimately mitigating renal fibrosis. The protective effects of leonurine were abolished in Nrf2 knockout mice. Conclusion These findings demonstrate that Nrf2 activation mitigates cisplatin-induced AKI-CKD transition by counteracting oxidative stress and ferroptosis, thereby attenuating renal fibrosis. Leonurine, as a potent Nrf2 activator, represents a promising therapeutic agent for preventing AKI-CKD transition.
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高影响因子
ACS Applied Materials & Interfaces
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2025
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IF 8.2
Jianxu Zhou,Taotao Huo,Junxian Miu,Ziyi Wang,Xiaoyu Shan,Jiaqi Song,Yuquan Bai,Shuichu Hao,Chun Zhang,Shichang Liu,Biao Wang,Guanying Li
The inhibition of residual tumor recurrence while repairing bone defects poses a challenging issue for postoperative osteosarcoma treatment. Here, we develop a self-assembling peptide hydrogel (GelA) for the targeted delivery of cisplatin (CDDP), aiming to integrate postoperative tumor inhibition with bone defect repair. GelA exhibits exceptional biocompatibility, high loading capacity for CDDP, and superior bone adhesion. After in situ injection to bone defects, CDDP-loaded hydrogel GelA-CDDP demonstrates a strong affinity for hydroxyapatite, thereby facilitating optimal bone adhesion and prolonging the retention time of CDDP in a postoperative wound. Furthermore, GelA-CDDP can regulate the distribution and release behavior of CDDP, minimizing off-target effects and optimizing the therapeutic outcomes of chemotherapy and osteogenesis. Finally, in the orthotopic osteosarcoma transplantation model in mice, postoperative treatment with GelA-CDDP significantly inhibits residual osteosarcoma recurrence as well as repair of bone defects through synergistic osteogenesis promotion and osteoclastic inhibition. We believe that this hydrogel-based therapy strategy holds great promise in achieving simultaneous tumor inhibition and bone defect repair for postoperative osteosarcoma treatment.
研究领域:
肿瘤学
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生物材料
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药剂学
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组织工程
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高影响因子
PHYTOMEDICINE
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2024
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IF 6.7
Shanshan Guo,Lang Zhou,Xueqi Liu,Li Gao,Yuanyuan Li,Yonggui Wu
Background In acute kidney injury (AKI), ferroptosis is the main mechanism of cell death in the renal tubular epithelium. Baicalein, a traditional Chinese medicine monomer, plays a protective role in various kidney diseases; however, the effect of baicalein on ferroptosis in AKI still needs further exploration. Purpose In this study, we explored the role of baicalein and its specific mechanism in mediating ferroptosis in cisplatin-induced AKI. Methods We used a cisplatin-induced AKI model to study the effects of baicalein on renal tissue and tubular epithelial cell injury. The effects of baicalein on tubular epithelial cell ferroptosis were detected in cisplatin-induced AKI and further verified by folic acid-induced AKI. The Swiss Target Prediction online database was used to predict the possible mechanism by which baicalein regulates ferroptosis, and the specific target proteins were further verified. Molecular docking and SPR were used to further determine the binding potential of baicalein to the target protein. Finally, RNA interference (RNAi) technology and enzymatic inhibition were used to determine whether baicalein regulates ferroptosis through target proteins. Results Baicalein alleviated cisplatin- and folic acid-induced renal dysfunction and pathological damage and improved cisplatin-induced HK2 cell injury. Mechanistically, baicalein reduced the expression of 12-lipoxygenase (ALOX12), which inhibits phospholipid peroxidation and ferroptosis in AKI. Molecular docking and SPR demonstrated direct binding between baicalein and ALOX12. Finally, we found that silencing ALOX12 had a regulatory effect similar to that of baicalein. Comparable results were also obtained with the ALOX12 inhibitor ML355. Conclusion This was the first study to confirm that baicalein regulates ferroptosis both in vitro and in vivo in cisplatin-induced AKI and to verify the regulatory effect of baicalein in folic acid-induced AKI. Our results reveal the critical role of ALOX12 in kidney damage and ferroptosis caused by cisplatin and emphasize the regulatory effect of baicalein on renal tubular epithelial cell ferroptosis mediated by ALOX12. Baicalein is an effective drug for treating AKI, and ALOX12 is a potential drug target.
研究领域:
药理学
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肾病学
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细胞生物学
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分子生物学
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药物发现
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PubMed
高影响因子
Frontiers in Pharmacology
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2025
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IF 4.8
Jie Li,Xiujuan Yang,Xiaolong Lian,Baojian Li,Quhuan Ma,Lingling Yang,Guangmiao Gao,Yi Deng,Zhijun Yang
Cisplatin (CP), a widely used antineoplastic drug, could induce hepatotoxicity and is also one of the most common reasons for drug-induced liver injury (DILI). Licorice (Chinese name GanCao, GC) is a commonly used herbal drug in traditional Chinese medicine (TCM) that has been shown to treat liver diseases and DILI. CP has been documented to induce apoptosis through the promotion of endoplasmic reticulum (ER) stress. However, the exact role of ER stress in the pathogenesis of CP-induced hepatotoxicity remains unclear. A rat DILI model was constructed through intraperitoneal injection of CP, and the anti-DILI effect of GC was detected by liver coefficients, liver function tests, pathological staining, and oxidative stress indices. Additionally, the ER stress and apoptosis indices were investigated by quantitative real-time PCR (qRT-PCR), Western blotting, and immunofluorescence (IF) on CP-induced toxicity in rat liver tissues and LO2 cells. In the model group, liver function indicators significantly elevated, liver lesions more pronounced, and the reactive oxygen species (ROS) level in the liver increased, the expression of ER stress markers, apoptosis factors, and indicators related to the protein kinase RNA-like ER kinase/activating transcription factor 4/C/EBP homologous protein (PERK/ATF4/CHOP) pathway significantly elevated. Treatment of the CP-induced toxicity in the rat model with GC significantly improved liver function, reduced liver lesions, decreased liver ROS. In addition, GC significantly inhibited the expression of ER stress markers, apoptosis factors, and indicators related to PERK/ATF4/CHOP pathway, demonstrating the anti-CP-induced hepatotoxicity effect of GC. In this study, we verified the protective effect of GC in CP-induced hepatotoxicity in rats and clarified its mechanisms related to ER stress and apoptosis.
研究领域:
药理学
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毒理学
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肝脏病学
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PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
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2013
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IF 3.458
Qing Lv,Li-Min Li,Min Han,Xin-Jiang Tang,Jin-Na Yao,Xiao-Ying Ying,Fan-Zhu Li,Jian-Qing Gao
Methods on how to improve the sequential targeting of glioma subsequent to passing of drug through the blood–brain barrier (BBB) have been occasionally reported. However, the characteristics involved are poorly understood. In the present study, cisplatin (Cis) liposome (lipo) was modified with transferrin (Tf) to investigate the characteristics of potential sequential targeting to glioma. In bEnd3/C6 co-culture BBB models, higher transport efficiency across the BBB and cytotoxicity in basal C6 cells induced by Cis-lipo(Tf) than Cis-lipo and Cis-solution, suggest its sequential targeting effect. Interestingly, similar liposomal morphology as that of donor compartment was first demonstrated in the receptor solution of BBB models. Meanwhile, a greater acquisition in the lysosome of bEnd3, distributed sequentially into the nucleus of C6 cells were found for the Cis-lipo(Tf). Pre-incubation of chlorpromazine and Tf inhibited this process, indicating that a clathrin-dependent endocytosis is involved in the transport of Cis-lipo(Tf) across the BBB.
研究领域:
药学
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神经科学
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癌症研究
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高影响因子
TOXICOLOGY LETTERS
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2021
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IF 4.374
Jiayi Gu,Ling Tong,Xin Lin,Yuming Chen,Hao Wu,Xueling Wang,Dehong Yu
The ototoxic mechanisms of cisplatin on the organ of Corti and spiral ganglion neurons have been extensively studied, while few studies have been focused on the stria vascularis (SV). Herein, we verified the functional and morphological impairment in SV induced by a single injection of cisplatin (12 mg/kg, I.P.), represented by a reduction in Endocochlear Potentials (EP) and strial atrophy, and explored underlying mechanisms. Our results revealed increased extravasation of chromatic tracers (Evans blue dye and FITC-dextran) around microvessels after cisplatin exposure. The increased vascular permeability could be attributed to changes of pericytes (PCs) and perivascular-resident macrophage-like melanocytes (PVM/Ms) in number or morphology, as well as the enhanced level of HIF-1α and downstream VEGF. This capillary leakage led to a high accumulation of cisplatin in the perivascular space in SV, and disrupted the integrity of blood-labyrinth barrier (BLB). Also, tight junction (ZO-1) loosening and Na + , K + -ATPase damage was considered to be other critical contributors of BLB breakdown, which resulted in EP drop and consequent hearing loss. This study explored the role of stria vascularis in cisplatin-induced ototoxicity in terms of BLB hyperpermeability and pointed to a novel therapeutic target for the prevention of cisplatin-related hearing loss.
研究领域:
耳鼻喉科学
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药理学
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毒理学
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PubMed
高影响因子
PATHOLOGY RESEARCH AND PRACTICE
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2022
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IF 3.309
Jianfa Wu,Xiaohong Ni,Zhen Yu,Suqin Wu,Zhou Liu
Background CRNDE is known to be an important predictive factor of prognosis in many tumors; however, its role in cisplatin resistance is still unknown in ovarian cancer. The aim of the current research was to investigate the association between CRNDE and cisplatin resistance. Materials and methods QRT-PCR and in situ hybridization assay were employed to detect the expression of CRNDE in ovarian cancer cells and tissues; CCK8 assay, AnnexinV-FITC apoptosis assay and Trans-well assay, to determine the cell proliferation , apoptosis and invasion; and RNA-pull down assay, mass spectrometry analysis, gene microarray to search the targeted gene of CRNDE and SRSF1 . Association of CRNDE with SRSF1 was determined in ovarian cancer cells and nude mice . Results It was found that CRNDE and SRSF1 expression were higher in the cisplatin resistant ovarian cancer cells than their control cells. High expression of CRNDE and SRSF1 led to cisplatin resistance. While inhibition of CRNDE or SRSF1 sensitized ovarian cancer to cisplatin in vitro and in vivo. Moreover, as indicated in RIP assay, SRSF1 was potentially the targeted gene of CRNDE, and CRNDE promoting SRSF1 expression to induce cisplatin resistance; as indicated in gene microassay, there was significantly positive correlation between SRSF1 and TIA1 , and SRSF1 promoting TIA1 expression. Conclusion In conclusion, CRNDE induced cisplatin resistance in ovarian cancer through SRSF1/TIA1 signaling pathway ; thus, CRNDE inhibitor or SRSF1 inhibitor combined with cisplatin might act as a novel promising approach to ovarian cancer.
研究领域:
肿瘤学
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分子生物学
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遗传学
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高影响因子
OncoTargets and Therapy
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2021
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IF 4.147
Jian-Hong An,Chun-Yan Li,Chun-Ya Chen,Jian-Bin Wu,Hong Shen
Purpose Cisplatin is one of the most widely used antineoplastic drugs but has limited therapeutic effects due to nephrotoxicity. The aim of this study was to determine the possible renoprotective effect of the antioxidant raloxifene on cisplatin-induced nephrotoxicity in mice. Materials and Methods Cisplatin-induced acute renal injury was established in female C57 mice that were treated with saline (normal control) or raloxifene over a 7-day period. The body weight of the mice was recorded. Histopathological examinations of the kidney tissues were performed using H&E, PAS staining and TEM. The histomorphology of liver and other organs was observed by H&E staining. The serum levels of creatinine, blood urea nitrogen (BUN), alanine transaminase (ALT) and glutamic oxalacetic transaminase (AST) were analyzed by specific kits. Superoxide dismutase (SOD) and glutathione (GSH) activity, and the content of malondialdehyde (MDA) in the kidney, liver homogenates and HK-2 cells were measured by WST-8 and thiobarbituric acid colorimetric methods. Moreover, the mitochondrial structures of HK-2 cells were performed using TEM. The viability and proliferation of HK-2 cells were examined by CCK-8 and EdU incorporation assays. The mitochondrial membrane potential was measured by JC-1 fluorescence. Results Raloxifene significantly reduced the levels of serum creatinine, urea, ALT and AST in the cisplatin-treated mice, and alleviated cisplatin-induced renal and hepatic tissue injury. Furthermore, raloxifene also increased the activity of GSH and SOD in the renal tissues and HK-2 cells, and reduced MDA levels, thereby limiting oxidative stress in the kidney. Conclusion Raloxifene protected against cisplatin-induced nephrotoxicity by activating the antioxidant system, along with alleviating liver damage. It should be considered as a potential adjuvant in cisplatin-based chemotherapeutic protocols.
研究领域:
药理学
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毒理学
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肾病学
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细胞生物学
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高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
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2022
·Vol. 20
·期 1
·1-17
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IF 9.429
Xu Lihua,Zhang Kaixiang,Ma Xing,Li Yingying,Jin Yajie,Liang Chenglin,Wang Yong,Duan Wendi,Zhang Hongling,Zhang Zhenzhong,Shi Jinjin,Liu Junjie,Wang Yunlong,Li Wentao
Despite many nano-based strategies devoted to delivering cisplatin for tumor therapy, its clinical benefits are compromised by poor tissue penetration and limited DNA adducts formation of the drug. Herein, a cisplatin loading nanomotor based janus structured Ag-polymer is developed for cisplatin delivery of deeper tissue and increased DNA adducts formation. The nanomotor displayed a self‐propelled tumor penetration fueled by hydrogen peroxide (H2O2) in tumor tissues, which is catalytically decomposed into a large amount of oxygen bubbles by Ag nanoparticles (NPs). Notably, cisplatin could elevate the intracellular H2O2 level through cascade reactions, further promote the degradation of Ag NPs accompanied with the Ag+ release, which could downregulate intracellular Cl− through the formation of AgCl precipitate, thereby enhancing cisplatin dechlorination and Pt–DNA formation. Moreover, polymer can also inhibit the activity of ALKBH2 (a Fe2+-dependent DNA repair enzyme) by chelating intracellular Fe2+ to increase the proportion of irreparable Pt–DNA cross-links. It is found that deep tissue penetration, as well as the increased formation and maintenance of Pt–DNA adducts induced by the nanomotor afford 80% of tumor growth inhibition with negligible toxicity. This work provides an important perspective of resolving chemotherapeutic barriers for boosting cisplatin therapy.Graphical Abstract
研究领域:
癌症治疗
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纳米技术
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化疗
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药物递送系统
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高影响因子
PROTEIN AND PEPTIDE LETTERS
·
2025
·Vol. 32
·期 8
·597-609
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IF 1.1
Qixiang Fang,Chengyu You,Xi Xiao,Yang Liu,Weiguang Yang,Qingchao Li,Liangliang Qing,Zhilong Dong
Introduction Dysregulation of mevalonate metabolism is a hallmark of tumorigenesis and therapy resistance across malignancies, though its role in bladder cancer remains unclear. This study aimed to elucidate its impact on prognosis and cisplatin chemosensitivity in bladder cancer. Methods Transcriptomic data and clinical information of bladder cancer patients were obtained from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. Non-negative matrix factorization (NMF) was used to cluster mevalonate metabolism-related genes into distinct metabolic subtypes (C1 and C2). Associations between mevalonate metabolism, clinical characteristics, immune infiltration, and cisplatin resistance were analyzed using Gene Set Variation Analysis (GSVA), Kaplan-Meier survival analysis, single-sample Gene Set Enrichment Analysis (ssGSEA), and in vitro experiments. Results NMF clustering classified bladder cancer patients into two metabolic subtypes (C1/C2). The C1, characterized by higher mevalonate metabolism (MVAscore), was associated with a poorer prognosis, shorter overall survival (OS), and higher T-stage and pathological grades. Immune analysis showed lower immune cell infiltration in C1. Immune infiltration analysis revealed significantly lower immune infiltration levels in the C1. Further analysis revealed a positive correlation between mevalonate metabolism and platinum resistance, with a notable increase in mevalonate metabolism observed in cisplatin-resistant bladder cancer cells. In vitro, simvastatin inhibited the proliferation of bladder cancer cells and enhanced their sensitivity to cisplatin. Discussion Mevalonate metabolism drives BCa heterogeneity and chemoresistance while suppressing anti-tumor immunity. Its dysregulation serves as both a prognostic biomarker and a target for therapeutic intervention. Conclusion Mevalonate metabolism contributes to cisplatin resistance in bladder cancer and represents a potential therapeutic target. Simvastatin targeting this pathway enhances the efficacy of cisplatin, providing a novel personalized chemotherapy strategy.
研究领域:
肿瘤学
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癌症代谢
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药理学
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分子生物学
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生物信息学
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Oncology Letters
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2026
·Vol. 31
·期 3
·1-11
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IF 2.2
Cairong Zhang,Jie Ma,Wenling Wang,Min Guo,Cuiliu Han,Madinamu Sadike,Kaichun Zhu
Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.
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高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2026
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IF 2.5
Pengcheng Rao,Tairan Zhang,Ju Li,Weideng Wei,Xiaoqiang Xia,Qianming Chen,Xiaoping Xu,Xiaodong Feng
Cisplatin-based chemotherapy responses are highly heterogeneous across cancers, with the mechanisms governing drug sensitivity remaining incompletely understood. Using genome-wide CRISPR-Cas9 knockout screening, we systematically characterized regulators of cisplatin response and uncovered a counterintuitive finding: mTOR inhibition promotes cisplatin tolerance, contradicting the canonical view that PI3K-AKT-mTOR activation confers chemoresistance. Mechanistically, both mTOR suppression and cisplatin treatment converge to activate cytoprotective autophagy, which enhances cancer cell survival under therapeutic stress. The amino acid transporter SLC7A5 was identified and validated as a key integrator of the mTOR-autophagy axis that modulates cisplatin sensitivity. SLC7A5 expression positively correlates with cisplatin sensitivity across cancer cell lines, and its downregulation is associated with cisplatin resistance in multiple cancer types, supporting its potential as a mechanistically grounded predictive biomarker. Translationally, leucine supplementation sensitizes cancer cells to cisplatin in an SLC7A5-mTOR-autophagy-dependent manner. Collectively, our study defines a novel mTOR-autophagy adaptive loop governing cisplatin tolerance, positions SLC7A5 as a central regulatory node with both biomarker and therapeutic target value, and proposes leucine supplementation as a simple, translatable strategy to improve cisplatin efficacy in SLC7A5-expressing tumors.
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