Pharmaceutics
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2026
·Vol. 18
·期 1
·102
·
IF 5.5
Yujing Huangfu,Wei Chen,Dandan Guo,Peiyao Wang,Aifang Li,Yi Yang,Shuxuan Li,Qianfang Wang,Baiyan Wang,Shuying Feng
Background: As a widely used chemotherapeutic agent, cisplatin frequently induces acute kidney injury (AKI), which severely compromises patient survival and limits its clinical use. While the natural flavonoid diosmetin (Dio) shows promise in mitigating cisplatin-induced nephrotoxicity, its clinical translation is challenged by poor solubility, low bioavailability, and incompletely elucidated mechanisms. This study aimed to overcome these limitations by developing a novel drug delivery system using the microalgae Dunaliella salina ( D. salina , Ds ) to load Dio ( Ds -Dio), thereby enhancing its efficacy and exploring its therapeutic potential. Methods: We first characterized the physicochemical properties of Ds and Dio, and then Ds -Dio complex was synthesized via co-incubation. Its nephroprotective efficacy and safety were systematically evaluated in a cisplatin-induced mouse AKI model by assessing renal function (serum creatinine, blood urea nitrogen), injury biomarkers, histopathology, body weight, and organ index. The underlying mechanism was predicted by network pharmacology and subsequently validated experimentally. Results: The novel Ds -Dio delivery system has been successfully established. In the AKI model, Ds -Dio significantly improved renal function and exhibited a superior protective effect over Dio alone; this benefit is attributed to the enhanced bioavailability provided by Ds carrier. In addition, Ds -Dio also demonstrated safety performance, with no evidence of toxicity to major organs. Network pharmacology analysis predicted the involvement of PI3K/AKT pathway, which was experimentally verified. Specifically, we confirmed that Ds -Dio alleviates AKI by modulating the PI3K/AKT pathway, resulting in concurrent suppression of NF-κB-mediated inflammation and activation of NRF2-dependent antioxidant responses. Conclusions: This study successfully developed a microalgae-based drug delivery system, Ds -Dio, which significantly enhances the nephroprotective efficacy of Dio against cisplatin-induced AKI. The nephroprotective mechanism is associated with modulation of the PI3K/AKT pathway, resulting in the simultaneous attenuation of oxidative stress and inflammation.
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JOURNAL OF MEDICINAL CHEMISTRY
·
2024
·
IF 6.8
Xinlin Lin,Mengsi Zheng,Kai Xiong,Fa Wang,Yu Chen,Liangnian Ji,Hui Chao
Using photodynamic therapy (PDT) to trigger nonconventional cell death pathways has provided a new scheme for highly efficient and non-side effects to drug-resistant cancer therapies. Nonetheless, the unclear targets of available photosensitizers leave the manner of PDT-induced tumor cell death relatively unpredictable. Herein, we developed a novel Ru(II)-based photosensitizer, Ru-Poma. Possessing the E3 ubiquitin ligase CRBN-targeting moiety and high singlet oxygen yield of 0.96, Ru-Poma was demonstrated to specifically photodegrade endogenous CRBN, increase lipid peroxide, downregulate GPX4 and GAPDH expression, and consequently induce ferroptosis in cisplatin-resistant cancerous cells. Furthermore, with the deep penetration of two-photon excitation, Ru-Poma achieved drug-resistant circumvention in a 3D tumor cell model. Thus, we describe the first sample of the CRBN-targeting Ru(II) complex active in PDT.
研究领域:
癌症治疗
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光化学
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细胞生物学
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分子生物学
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药物化学
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EUROPEAN JOURNAL OF PHARMACOLOGY
·
2026
·
IF 4.7
Wenying Fu,Ying Yan,Chongchong Shu,Chenxin Xu,Yinghua Chen,Yiqun Xia,Jundixia Chen,Yunzhi Chen,Ri Cui,Peng Zou,Daoyong Ni
6-Methoxydihydrosanguinarine is a natural alkaloid derived from medicinal plants that exhibits significant antitumor activity, making it a promising candidate for cancer therapy. However, the exact molecular mechanisms underlying its effects require further investigation. In this study, we investigated the cytotoxicity and underlying mechanisms of 6-Methoxydihydrosanguinarine in human non-small cell lung cancer (NSCLC) cells. Our findings reveal that reactive oxygen species (ROS) accumulation is the key driver of its antitumor activity. Mechanistically, 6-Methoxydihydrosanguinarine activates the JNK signaling pathway and induces endoplasmic reticulum (ER) stress, both of which can be reversed by the ROS scavenger N-acetylcysteine (NAC). Interestingly, 6-Methoxydihydrosanguinarine also activates autophagy, and inhibition of autophagy reverses the JNK and ER stress pathway activation induced by 6-Methoxydihydrosanguinarine. Notably, 6-Methoxydihydrosanguinarine synergistically enhances cisplatin-induced NSCLC cell death, and this synergistic effect is abolished by NAC, highlighting the critical role of ROS accumulation in their combined efficacy. This study systematically elucidates the molecular mechanisms of 6-Methoxydihydrosanguinarine against NSCLC, revealing that, in addition to the JNK and autophagy pathways, ER stress also mediates its antitumor effects. Moreover, our data establish a rationale for exploring 6-Methoxydihydrosanguinarine in NSCLC therapy and highlight its combination with cisplatin as a potentially effective strategy.
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CELLULAR ONCOLOGY
·
2026
·Vol. 49
·期 4
·94
·
IF 5.6
Wang Benlin,Zheng Xianchong,Hua Qingsheng,Zou Feng,Huang Tao,Chen Jiawei
Background Cisplatin-based chemotherapy is first-line for muscle-invasive bladder cancer (BLCA), but chemoresistance remains the primary barrier to clinical efficacy. RNA-binding proteins (RBPs) orchestrate post-transcriptional gene regulation and are increasingly implicated in cancer chemoresistance; however, the role and regulatory mechanism of the splicing factor RBP SLU7 in BLCA cisplatin resistance remain completely unknown. Methods We analyzed SLU7 expression and clinical prognosis in two independent cisplatin-treated BLCA cohorts (GSE87304, GSE169455). Cisplatin-resistant BLCA cell lines (T24-CIS, UMUC3-CIS) were established for functional assays (CCK-8, qRT-PCR, western blotting). Molecular interactions were validated by RIP-qPCR, immunofluorescence(IF), RNA-FISH, nucleocytoplasmic fractionation, co-immunoprecipitation (co-IP), and mass spectrometry (MS). In vivo therapeutic efficacy was assessed in BLCA xenograft models. Results SLU7 was significantly upregulated in cisplatin-resistant BLCA cells, and high SLU7 expression independently predicted poor cancer-specific survival (CSS) and recurrence-free survival (RFS) in cisplatin-treated patients. SLU7 knockdown suppressed MAP3K3 expression, inhibited p38 MAPK pathway, and restored cisplatin sensitivity. Mechanistically, SLU7 directly bound MAP3K3 mRNA and promoted its nuclear export—a non-canonical function independent of its canonical splicing activity. MS and Co-IP identified NAA50 as the upstream regulator that catalyzes N-terminal acetylation of SLU7 to prevent its ubiquitin-proteasomal degradation, thereby sustaining SLU7 stability. Pharmacological inhibition of NAA50 with Naa50-IN-1 destabilized SLU7, blocked the MAP3K3-p38 axis, and reversed cisplatin resistance in vitro and in vivo. Conclusions We uncover a novel NAA50–SLU7–MAP3K3-p38 MAPK regulatory axis that drives cisplatin resistance in BLCA. NAA50-mediated N-terminal acetylation stabilizes SLU7, which in turn facilitates MAP3K3 mRNA nuclear export to activate p38 MAPK signaling. Targeting NAA50 represents a promising therapeutic strategy to overcome cisplatin resistance in BLCA, and SLU7 serves as a predictive biomarker for cisplatin response.
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Nanoscale
·
2026
·
IF 5.2
MarMar Tuohan,Geng Hu,Di Zhu,Bo Hu,Mengyue Ni,Liujia Chan,Yu Lu,Yuji Wang
Triple-negative breast cancer (TNBC) remains challenging to treat because of its aggressiveness and poor response to chemotherapy. Although cisplatin is clinically used for TNBC, its therapeutic window is narrow due to severe systemic toxicity and rapid development of drug resistance, underscoring the need for new strategies. To address this, we developed LMCDPS, a molecular language-model platform that learns the structural grammar of natural compounds, predicts their compatibility for co-assembly with cisplatin, and uniquely traces active small molecules back to their botanical origins. Using LMCDPS, we identified persimmon leaf-derived flavonoids as optimal cisplatin partners and confirmed their ability to spontaneously form stable, excipient-free nanoparticles (PLF-Cis NPs) via π–π interaction and hydrogen bonding. These nanoparticles eliminate synthetic carriers, reduce impurities in crude extracts, and substantially enhance tumor delivery, achieving an 11.3-fold increase in intracellular platinum accumulation. PLF-Cis NPs exert potent anti-TNBC activity by coordinating cisplatin-induced apoptosis, flavonoid-mediated ferroptosis, and immunogenic cell death, thereby promoting dendritic-cell maturation and robust CD8+ T-cell infiltration. In an orthotopic 4T1 model, they achieved a 71.5% reduction in tumor growth. This study establishes a language-model-driven framework for designing natural product-based, excipient-free nanomedicines, offering a scalable path to enhance chemotherapy while mitigating systemic toxicity.
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Animal Models and Experimental Medicine
·
2026
·
IF 3.3
Lu Chen,Shu Sun,Yujia Liu,Liehao Jiang,Cuiyun Wu,Ting Liu,Yujiao Zhao,Yuwei Liu,Lu Liu,Qi Wang,Xiaowei Zheng,Ping Huang
A zebrafish xenograft model accurately distinguishes metastatic from non‐metastatic HNSCC and recapitulates cisplatin sensitivity/resistance patterns. Using patient‐derived tumors, it predicts individual therapeutic responses, offering a rapid, clinically applicable platform for guiding personalized treatment.
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CURRENT MEDICINAL CHEMISTRY
·
2024
·
IF 3.5
Liu Wei,Zheng Yi-nan,Jiang Shuang,Ren Shen,Tang Shan,Zhang Jing,Wang Zi,Li Wei
Background: Based on the Maillard reaction principle of red ginseng, this
study innovatively synthesized a new amino acid derivative by combining arginine with
lactose through simulated synthesis and was separated and purified through repeated silica
gel and polyacrylamide gel (Bio-gel P-II) column chromatography.
Purpose: The work was aimed at elucidating the synthesis of a novel amino acid derivative
and investigating the intestinal protective activity of the novel amino acid derivative
and possible molecular mechanism by establishing the intestinal injury model induced
by cisplatin in mice.
Methods: The purity and molecular weight of the amino acid derivatives were determined
to be by electrospray ionization mass spectrometry (ESI-MS). Subsequently, by
establishing cisplatin (20 mg/kg)-induced intestinal injury in vivo for 10 days and IEC-6
cell model. The biochemical indexes and histopathological analysis were used to evaluate
the oxidative stress and inflammatory and pathological changes of intestinal tissue in
mice. The protein expression levels of p-Nuclear transcription factor-κB (p-NF-κB),
cleaved caspase 3/caspase 3, cleaved caspase 9/caspase-9, Bcl-2, Bax, cytochrome C,
phosphatidylinositol 3-kinase (PI3K), Protein Kinase B (Akt), p-PI3K, p-Akt were quantified
through immunofluorescence staining and western blot analysis.
Results: The new amino acid derivatives of chemical structure were identified to be 1-
(arginine-Nαgroup)-1-deoxy-4-O-(β-D-galactopyranosyl)-D-fructose, named Argininylfructosyl-
galactose (AFGA, C18H34N4O12). The results showed that pretreatment with a
single AFGA dose remarkably alleviated cisplatin-evoked intestinal oxidative stress injury,
and the levels of reactive oxygen species (ROS) were lessening in IEC-6 cells
(p<0.05, p<0.01) and could effectively reduce the secretion of TNF-α and IL-1β in
serum and the expression level of NF-κB protein in intestinal tissues (p<0.01). Meantime,
AFGA also significantly suppressed the caspase 3, caspase 9, cytochrome C and
Bax protein expression in intestinal tissue in mice (p<0.01), and regulated the PI3K/Akt
pathway (p<0.05, p<0.01). Importantly, the molecular docking results of AFGA also
suggested a better binding ability with the above-mentioned related target proteins.
Conclusion: The results clearly revealed AFGA as a potential multifunctional therapeutic
agent with a clear protective effect against cisplatin-induced intestinal injury may be
related to the PI3K/Akt signaling pathway.
研究领域:
药理学
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毒理学
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分子生物学
·
生物化学
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MOLECULAR PHARMACEUTICS
·
2025
·
IF 4.5
Jieming Zhang,Fangfang Zhou,Xin Du,Meiru Zhang,Suxiao Li,Songtao Niu,Qungang Chang,Yongju He
Cisplatin-based chemotherapy is widely used to combat cancers through an apoptosis pathway. However, drug resistance induced by upregulated glutathione (GSH) in tumor cells and systemic side effects significantly compromise its therapeutic efficacy. The application of nanocarriers with a GSH-scavenging ability is a promising strategy to overcome these obstacles. In addition, ferroptosis has shown great potential in eliminating the limitation of apoptosis-mediated chemotherapeutics. Herein, a multifunctional nanoplatform (S4MON-Cis@TA-Fe3+), loaded with cisplatin in tetrasulfide bonds-bridged mesoporous organosilica nanoparticles (S4MON) and then coated with tannic acid (TA)-Fe3+ metal-phenolic network, is developed for apoptosis–ferroptosis synergistic therapy. In the acidic tumor cells, the outer TA-Fe3+ network is disassembled into Fe3+ and TA, and the internal S4MON-Cis network is exposed. The released TA and endogenous GSH reduce Fe3+ to Fe2+, which significantly increases cellular oxidative stress through the Fenton reaction and GSH consumption. Moreover, S4MON-Cis decreases the intracellular GSH content through redox reaction between tetrasulfide bonds and GSH, which further augments cellular oxidative stress and triggers nanoparticle degradation to release cisplatin. Subsequently, cisplatin induces apoptosis and elevates the cellular hydrogen peroxide level to improve the Fenton reaction efficiency. The multiple oxidative stress amplification greatly promotes lipid peroxidation and glutathione peroxidase 4 downregulation, boosting tumor ferroptosis. Meanwhile, the dual GSH elimination significantly improves the antitumor effect of cisplatin. As a result, S4MON-Cis@TA-Fe3+ exhibits effective tumor growth inhibition through self-enhanced apoptosis–ferroptosis synergistic therapy, which holds great promise for cancer therapy.
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Redox Biology
·
2026
·
IF 16.2
Zitong Zhao,Ge Ge,Menghan Gong,Yi Liu,Liying Ma,Dongdong Zhang,Li Sun,Yongmei Song
Background Cisplatin resistance is a primary cause of treatment failure in ovarian cancer (OC), partly due to enhanced antioxidant defenses that counteract cisplatin-induced DNA damage and reactive oxygen species (ROS). Beyond the classic Glutathione Peroxidase 4 (GPX4) pathway, evidence suggests that non-canonical pathways like those mediated by Ferroptosis Suppressor Protein 1 (FSP1) may drive resistance. This study aims to elucidate how such alternative pathways facilitate resistance under cisplatin-induced ROS stress. Methods Ubiquitin Specific Peptidase 18 (USP18) was identified from a deubiquitination library. Protein/RNA interaction and m 6 A analyses revealed its regulation of downstream effectors Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) and FSP1. The combination of cisplatin with the FSP1 inhibitor (iFSP1) was evaluated in vitro and in vivo models. Results Cisplatin-induced ROS upregulates the expression of the USP18 through the transcription factor c-JUN, establishing the ROS-c-JUN-USP18 signaling axis. This axis stabilizes the IGF2BP2 protein via USP18-mediated deubiquitination, which in turn enhances the stability of FSP1 mRNA in an m6A methylation-dependent manner, thereby driving the selective activation of the FSP1-mediated pathway over the canonical GPX4 pathway. The predictive efficacy of models derived from the ROS-c-JUN-USP18-IGF2BP2-FSP1 axis was demonstrated by ROC curves and nomograms, confirming their utility in identifying patients with cisplatin-resistant OC. Importantly, the combination of iFSP1 with cisplatin produces a significant synergistic effect, effectively overcoming drug resistance in USP18-high tumors. Conclusion This study elucidates the mechanism by which the ROS-c-JUN-USP18-IGF2BP2-FSP1 axis regulates cisplatin resistance and proposes a novel iFSP1-cisplatin combination therapy, offering a promising new strategy for OC treatment.
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Journal of Materials Chemistry B
·
2022
·Vol. 11
·期 3
·667-674
·
IF 7.571
Zheng Zhang,Weichen Yan,Yuanhui Ji
Cisplatin (CDDP) is one of the most frequently used chemotherapeutic drugs due to its broad-spectrum and potent antitumor activity. Unfortunately, inactivation due to glutathione (GSH) substances and insufficient cellular uptake of CDDP greatly hinder its clinical applications. Herein, manganese dioxide (MnO2) was reported as an efficient glutathione (GSH) consumption material for promoting the accumulation and preventing premature leakage of CDDP in tumor cells. In this work, γ-polyglutamic acid/cisplatin (PGA/CDDP) conjugates and PGA/CDDP nanoparticles (NPs) were respectively constructed via the ligand exchange reaction and electrostatic interaction. Furthermore, PGA/CDDP NPs were in situ coated with MnO2 (PGA/CDDP@MnO2 NPs) through the redox reaction of the residual carboxyl group (–COOH) and potassium permanganate (KMnO4). As a result, the PGA/CDDP@MnO2 NPs achieved a satisfactory drug-loading efficiency (ca. 37.26%) and multi-responsive controlled drug release. Remarkably, the MnO2 shells exhibited excellent performance for efficient glutathione (GSH) consumption and significantly enhanced the killing effect (ca. 2–3 times) in human lung cancer cells (A549) compared with pure CDDP. Moreover, it was observed that PGA/CDDP@MnO2 NPs could also inhibit the migration and invasion of A549 cells. Overall, these remarkable performances of PGA/CDDP@MnO2 NPs make MnO2 promising for controlled drug release and intelligent anticancer therapy.
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Microbiology Spectrum
·
2022
·Vol. 10
·期 3
·
IF 9.043
Ye-Ting Zou,Jing Zhou,Jin-Hao Zhu,Cheng-Ying Wu,Hong Shen,Wei Zhang,Shan-Shan Zhou,Jin-Di Xu,Qian Mao,Ye-Qing Zhang,Fang Long,Song-Lin Li
Our previous study found that Qiong-Yu-Gao (QYG), a traditional Chinese medicine formula derived from Rehmanniae Radix, Poria, and Ginseng Radix, has protective effects against cisplatin-induced acute kidney injury (AKI), but the underlying mechanisms remain unknown. In the present study, the potential role of gut microbiota in the nephroprotective effects of QYG was investigated. We found that QYG treatment significantly attenuated cisplatin-induced AKI and gut dysbiosis, altered the levels of bacterial metabolites, with short-chain fatty acids (SCFAs) such as acetic acid and butyric acid increasing and uremic toxins such as indoxyl sulfate and p-cresyl sulfate reducing, and suppressed histone deacetylase expression and activity. Spearman’s correlation analysis found that QYG-enriched fecal bacterial genera Akkermansia, Faecalibaculum, Bifidobacterium, and Lachnospiraceae_NK4A136_group were correlated with the altered metabolites, and these metabolites were also correlated with the biomarkers of AKI, as well as the indicators of fibrosis and inflammation. The essential role of gut microbiota was further verified by both the diminished protective effects with antibiotics-induced gut microbiota depletion and the transferable renal protection with fecal microbiota transplantation. All these results suggested that gut microbiota mediates the nephroprotective effects of QYG against cisplatin-induced AKI, potentially via increasing the production of SCFAs, thus suppressing histone deacetylase expression and activity, and reducing the accumulation of uremic toxins, thereby alleviating fibrosis, inflammation, and apoptosis in renal tissue.IMPORTANCE Cisplatin-induced acute kidney injury is the main limiting factor restricting cisplatin’s clinical application. Accumulating evidence indicated the important role of gut microbiota in pathogenesis of acute kidney injury. In the present study, we have demonstrated that gut microbiota mediates the protective effects of traditional Chinese medicine formula Qiong-Yu-Gao against cisplatin-induced acute kidney injury. The outputs of this study would provide scientific basis for future clinical applications of QYG as prebiotics to treat cisplatin-induced acute kidney injury, and gut microbiota may be a promising therapeutic target for chemotherapy-induced nephrotoxicity.
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Evidence-based Complementary and Alternative Medicine
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2021
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IF 2.63
Jian Zhao,Hewei Li,Wanying Li,Zixian Wang,Zhewen Dong,Huan Lan,Chengqiang Wang,Jia-Le Song
Sinapic acid (Sa) is a small-molecule phenolic acid compound predominant in fruits, vegetables, and grains. This study investigated the antitumor effects of cisplatin (DDP) combined with Sa (Sa/DDP) on the hepatic cancer cells (HCC), HepG2 and SMMC-7721. The HepG2 and SMMC-7721 cells were treated with Sa or Sa/DDP, and the cell proliferation and cell cycle were detected using the MTT assay. The cell migration was detected using the transwell and scratch assays, while apoptosis and autophagy were detected using Hoechst, MDC, and Annexin V-FITC/PI staining. The protein expression was quantitated using the western blot. Sa/DDP was found to not only inhibit cancer cell proliferation and migration but also induce cell apoptosis. Simultaneously, the Sa/DDP combination was found to activate autophagy, and the HCQ autophagy inhibitor enhanced the apoptosis in the Sa/DDP-induced liver cancer cells. The combined use of Sa and DDP makes it an attractive adjuvant therapy strategy for tumors, establishing the prospect of phenolic acid compounds for the adjuvant treatment of hepatocellular carcinoma.
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