FASEB JOURNAL
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2026
·Vol. 40
·期 4
·e71580
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IF 4.3
Liujie Zheng,Yinhua Ni,Suyao Xie,Yitian Ji,Jiahong Dong,Lanjun Fu,Zhengwei Fu,Juan Jin,Qiang He
Acute kidney injury (AKI) is a serious complication of cisplatin chemotherapy, requiring new preventive therapies. Germacrone, a sesquiterpenoid derived from Rhizoma Curcuma , has multiple pharmacological effects, including anti-inflammatory, antiapoptotic, and antioxidant effects. The current study aimed to investigate the effect and mechanism of germacrone on AKI. Single high-dose and multiple low-dose cisplatin-induced AKI and AKI-chronic kidney disease (CKD) transition mouse models were used to determine the preventive effect of germacrone, with the mechanism explored in HK-2 and Raw264.7 cells. A breast cancer tumor-bearing model was developed to determine whether the nephron-protective effects of germacrone affect the anticancer properties of cisplatin. Here, we found that germacrone significantly alleviated AKI and fibrosis in cisplatin-treated mice, as demonstrated by decreased serum creatinine and blood urea nitrogen (BUN) levels and improved renal pathology. Germacrone attenuated cisplatin-induced apoptosis and inflammation in vivo and in vitro. RNA sequencing revealed that germacrone restored cisplatin-induced gene dysregulation and regulated inflammation and apoptosis through the PI3K/AKT and Ras/MAPK pathways. Inhibition of these pathways abrogated the renoprotective effect of germacrone in vitro. Moreover, germacrone reduced macrophage activation and induced an M2-dominant shift in macrophage polarization in the kidneys and Raw264.7 cells via similar pathways. Furthermore, germacrone protected the kidneys without affecting the chemotherapeutic effects of cisplatin on a mouse model of breast cancer. Therefore, germacrone is expected to have universal renoprotective effects across different AKI models and a tumor-bearing model through similar signaling pathways, suggesting its potential as a clinical adjuvant therapy for reducing nephrotoxicity in patients receiving cisplatin chemotherapy. Graphical Germacrone alleviates inflammation and apoptosis in cisplatin-injured kidneys by activating PI3K/AKT and suppressing Ras/MAPK signaling, thereby protecting against acute kidney injury (AKI) in mice. This renoprotection is reinforced by its ability to drive an M2-dominant macrophage shift both in vivo and in vitro, ultimately restoring tubular integrity and renal function.
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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2026
·
IF 8.5
Qixiang Fang,Chengyu You,Xi Xiao,Weiguang Yang,Longtu Ma,Qingchao Li,Yan Tao,Zhilong Dong
Cisplatin resistance remains a major challenge in bladder cancer. Although the tumor suppressor ASPP2 is a critical co-factor for TP53-mediated apoptosis, its role in metabolic reprogramming and cisplatin response remains unclear. This study aimed to delineate the mechanism by which ASPP2 regulates cisplatin sensitivity through metabolic reprogramming. We first assessed the clinical significance of ASPP2 using patient tissues and public databases, finding that its downregulation in bladder cancer is associated with poor patient survival. Through gain- and loss-of-function studies in vitro and in vivo, we further demonstrated that ASPP2 inhibits the mevalonate (MVA) pathway independently of TP53 status, thereby sensitizing cells to cisplatin-induced DNA damage and apoptosis. This chemosensitizing effect was specifically reversed by the addition of MVA pathway metabolites. Moreover, WWP2 was identified as the E3 ubiquitin ligase responsible for ASPP2 degradation via K48-linked ubiquitination. Finally, WWP2 silencing was shown to stabilize ASPP2, suppress the MVA pathway, and synergize with cisplatin to impede tumor growth in mouse models. Overall, the WWP2-ASPP2-MVA pathway axis is identified as a novel driver of cisplatin resistance in bladder cancer. These results establish a mechanistic basis for targeting this axis to restore chemosensitivity, offering a promising therapeutic strategy for recalcitrant disease.
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MICROCHEMICAL JOURNAL
·
2026
·
IF 5.1
Sai-Nan Qin,Yi-Xue Zhang,Yi-Jie Cao,Ting Wan,Yi-Yang Zhou,Shan-Shan Su,Yu-Qiong Guo,Jian-Jun Sun,Kalle Salminen
Cisplatin (DDP), as a broad-spectrum anticancer drug, requires dynamic monitoring of its blood concentration and intervention in its dosage administration to balance efficacy and safety due to significant individual differences in its metabolism, side effects, and resistance in different patients. However, rapid and robust methods for monitoring and quantifying DDP in complex biological fluids are still lacking. This work presents an electrochemical aptamer-based ( E -AB) sensor for rapid measurement of DDP concentration in blood. In which capture probe aptamers were designed constructed by visualizing and analyzing their binding pockets, followed by molecular docking and circular dichroism to screen the aptamer Apt25, which has a small binding energy and a large conformational change, for use in the construction of the sensor. In the presence of DDP, the aptamer undergoes a conformational change at the electrode interface, altering the electron transfer rate of the electroactive label to detect DDP concentration variations. After systematically using electrochemical techniques to optimize the sensor testing conditions, the sensor can directly analyze and detect DDP in urine and blood with a measurement range of 0.001–2 mM and a detection limit of 1 μM, which satisfies the needs of clinical testing. The spiked recoveries in different biological samples were 80.8–110% and 79–115.2%, respectively. In addition, the sensor has sufficient selectivity and stability, which is expected to enable real-time monitoring of DDP concentration for dosage adjustment and improvement of drug bioavailability at the clinical site.
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MOLECULAR NUTRITION & FOOD RESEARCH
·
2026
·Vol. 70
·期 16
·e70582
·
IF 4.5
Xianjie Li,Zhaoming Liu,Yi Chen,Jieping Luo,Zi Xie,Yirui Yang,Ziqi Zhou,Lin Fu,Xiaoya Yang,Caixia Wu
Cisplatin-induced acute kidney injury (AKI) is a dose-limiting chemotherapy complication laking effective clinical interventions. This study investigated the protective mechanisms of proanthocyanidins (PACs), a promising food-derived polyphenol, against cisplatin-induced systemic toxicity in C57BL/6 mice. Multi-omics integration combining 16S rRNA sequencing and renal transcriptomics, was employed to identify microbial-metabolic signaling nodes. Notably, 7-day PAC pretreatment (25 or 50 mg/kg/day) significantly alleviated renal dysfunction, normalized serum creatinine, blood urea nitrogen, reinforced renal antioxidant defenses, and suppressed kidney inflammation. Transcriptomic profiling revealed that cisplatin-induced renal damage was associated with the dysregulation of the cAMP signaling pathway, which was effectively reversed by PACs. Furthermore, 16S rRNA sequencing revealed that PACs restructured the gut microbiota by suppressing the pathogenic taxa ( Alistipes and CAG_485 ) and enriching beneficial taxa ( Muribaculaceae ). Integrated network analysis further linked these microbial shifts to the stabilization of renal cAMP signaling and redox homeostasis, suggesting a coordinated gut-kidney crosstalk. In conclusion, PACs function as a multifaceted food-derived adjuvant that potentially attenuates cisplatin-induced AKI, providing a molecular framework for gut-targeted nutritional intervention in chemotherapy-induced systemic toxicity.
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ACS Applied Materials & Interfaces
·
2026
·
IF 7.8
Shupeng Shi,Haicong Liu,Qingping Peng,Shenao Nan,Shuyan Liu,Linna Wei,Haoyu Wang,Kai Wang,Xiaohong Zhong,Xin Chen,Wenzhe Gao
The development of next-generation nanotheranostics is increasingly challenged by the dual imperatives of environmental sustainability and the urgent need to overcome complex biological barriers, particularly multidrug resistance (MDR) in hepatocellular carcinoma (HCC). Herein, we bridge the gap between circular economy principles and precision nanomedicine by upcycling discarded eggshell membranes (ESM) into a hierarchical metabolic therapeutic platform. Utilizing the protein fiber network of ESM as a natural biotemplate, we orchestrated the anisotropic growth of calcium carbonate (CaCO3) into unique yolk–shell nanostructures (YSNs) via interfacial molecular recognition. This bioinspired architecture features a high specific surface area, enabling the efficient coloading of the chemotherapeutic cisplatin (CDDP) and ultrathin vanadium carbide (V4C3) MXene nanozymes, stabilized by a biotinylated carboxymethyl chitosan (Biotin-CMCS) targeting shell. Mechanistically, this “Trojan Horse” system exploits the acidic tumor microenvironment (TME) to trigger a rapid cascade of disassembly, releasing a surge of Ca2+ ions and MXene-driven reactive oxygen species (ROS). Crucially, we demonstrate that the resulting mitochondrial calcium overload instigates a catastrophic “bioenergetic crisis,” characterized by the irreversible opening of mitochondrial permeability transition pores (mPTP) and the precipitous depletion of intracellular adenosine triphosphate (ATP). This metabolic collapse effectively deactivates ATP-dependent DNA repair machineries (e.g.,poly(ADP-ribose) polymerase 1 (PARP1) and excision repair cross-complementation group 1 (ERCC1)), thereby reversing cisplatin resistance and sensitizing tumor cells to DNA damage. In vivo evaluations in HCC xenografts confirm potent tumor regression with minimal systemic toxicity, facilitated by the renal clearance of biodegradable calcium metabolites. This work presents a paradigm shift in material design, transforming biowaste into a metabolic reprogramming weapon for sustainable and effective cancer therapy.
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Discover Nano
·
2026
·Vol. 21
·期 1
·415
·
IF 6.7
Long Lin,Zhang Yexi,Xiao Jun,Zang Jianhua
Purpose To fabricate hesperetin-loaded fucoidan-selenium (Hes/Fu-Se) nanoparticles (NPs) for alleviating cisplatin-induced acute kidney injury (AKI), overcoming hesperetin’s low solubility and bioavailability and boosting antioxidant and anti-inflammatory efficacy. Methods Hes/Fu-Se NPs were prepared by encapsulating hesperetin within fucoidan, and then functionalized selenium (Se) NPs. Nanoparticle physicochemical properties and antioxidant activity (FRAP, ABTS) were characterized. Cisplatin-stimulated HK-2 cells were used for in vitro detection of cell viability, apoptosis, ROS accumulation, mitochondrial function and cGAS-STING signaling. A cisplatin-induced AKI mouse model was adopted to test renal biochemical indexes, renal histopathology and renal injury-related protein expression. Results Synthesized Hes/Fu-Se NPs exhibited uniform particle size, superior aqueous solubility and potent antioxidant activity. In vitro, the NPs restored HK-2 cell viability, mitigated apoptosis and ROS overproduction, and inhibited DNA damage and cGAS-STING cascade activation. In vivo, Hes/Fu-Se markedly reduced serum BUN and CRE, alleviated renal histological lesions and inflammatory infiltration, and downregulated the expression of cGAS, STING, γH2AX and TNF-α in kidney tissues. Conclusions Hes/Fu-Se NPs relieve cisplatin-triggered AKI via amplified antioxidation, DNA damage restoration and cGAS-STING pathway suppression. This nanoformulation provides a promising nephroprotective strategy against chemotherapy-related renal toxicity for clinical translation. Graphical abstract
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Bioactive Materials
·
2021
·
IF 14.593
Zhongyu Jiang,Xiangru Feng,Haoyang Zou,Weiguo Xu,Xiuli Zhuang
PEGylation has been widely applied to prolong the circulation times of nanomedicines via the steric shielding effect, which consequently improves the intratumoral accumulation. However, cell uptake of PEGylated nanoformulations is always blocked by the steric repulsion of PEG, which limits their therapeutic effect. To this end, we designed and prepared two kinds of poly( l -glutamic acid)-cisplatin (PLG-CDDP) nanoformulations with detachable PEG, which is responsive to specific tumor tissue microenvironments for prolonged circulation time and enhanced cell internalization. The extracellular pH (pH e )-responsive cleavage 2-propionic-3-methylmaleic anhydride (CDM)-derived amide bond and matrix metalloproteinases-2/9 (MMP-2/9)-sensitive degradable peptide PLGLAG were utilized to link PLG and PEG, yielding pH e -responsive PEG- pH e -PLG and MMP-sensitive PEG- MMP -PLG. The corresponding smart nanoformulations PEG- pH e -PLG-Pt and PEG- MMP -PLG-Pt were then prepared by the complexation of polypeptides and cisplatin (CDDP). The circulation half-lives of PEG- pH e -PLG-Pt and PEG- MMP -PLG-Pt were about 4.6 and 4.2 times higher than that of the control PLG-Pt, respectively. Upon reaching tumor tissue, PEG on the surface of nanomedicines was detached as triggered by pH e or MMP, which increased intratumoral CDDP retention, enhanced cell uptake, and improved antitumor efficacy toward a fatal high-grade serous ovarian cancer (HGSOC) mouse model, indicating the promising prospects for clinical application of detachable PEGylated nanoformulations.
研究领域:
药剂学
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肿瘤学
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纳米医学
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FOOD SCIENCE AND TECHNOLOGY RESEARCH
·
2023
·
IF 0.6
Yunfan Liu,Jiazhou Zhai,Fei Qin,Liping Gao,Yongxin She,Mengqiang Wang
The aim of this study was to investigate the protective effect of polyphenol extract from Highland barley (HBPE) on cisplatin (CDDP)-induced oxidative damage and mitochondrial damage in rat kidney. The experimental rats were divided into control group, CDDP group, HBPE (600 mg/kg) group, CDDP+HBPE (150 mg/kg) group, CDDP+HBPE (300 mg/kg) group and CDDP+HBPE (600 mg/kg) group. Rats in each group were intragastrically fed with normal saline and corresponding dose of HBPE for 21 d. On the 16th day, CDDP group and CDDP+HBPE group were injected intraperitoneally with CDDP (7.5 mg/kg), and the other groups were injected with the same amount of normal saline. On the 22nd day, the rats were killed and blood samples were taken to detect the contents of blood urea nitrogen (BUN) and creatinine (CrE) in serum, and calculate the kidney index. The kidney samples were used for the measurement of malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), lactate dehydrogenase (LDH), malate dehydrogenase (MDH), hexokinase (HK), and processed for histopathological examinations. The results showed that HBPE improved the abnormalities of serum CrE, BUN, antioxidant and carbohydrate metabolic enzymes in kidney induced by CDDP. HBPE can also reduce the degeneration of renal tubules and glomerular atrophy. Therefore, HBPE has a significant protective effect on oxidative stress injury and mitochondrial damage induced by CDDP in rats.
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ARCHIVES OF TOXICOLOGY
·
2022
·Vol. 97
·期 2
·441-456
·
IF 6.168
Xu Chi,Jiang Shuyun,Ma Xingyu,Jiang Zeyong,Pan Youguang,Li Xiang,Zhang Liying,Zhou Hao,Chen Shen,Xing Xiumei,Chen Liping,Fu Wenfan,Wang Qing,Chen Wen,Li Daochuan
Cisplatin is recommended as a first-line chemotherapeutic agent against advanced non-small cell lung cancer (NSCLC), but acquired resistance substantially limits its clinical efficacy. Recently, DNA methylation has been identified as an essential contributor to chemoresistance. However, the precise DNA methylation regulatory mechanism of cisplatin resistance remains unclear. Here, we found that nicotinamide nucleotide transhydrogenase ( NNT ) was silenced by DNA hypermethylation in cisplatin resistance A549 (A549/DDP) cells. Also, the DNA hypermethylation of NNT was positively correlated to poor prognosis in NSCLC patients. Overexpression of NNT in A549/DDP cells could reduce their cisplatin resistance, and also suppressed their tumor malignancy such as cell proliferation and clone formation. However, NNT enhanced sensitivity of A549/DDP cells to cisplatin had little to do with its function in mediating NADPH and ROS level, but was mainly because NNT could inhibit protective autophagy in A549/DDP cells. Further investigation revealed that NNT could decrease NAD + level, thereby inactivate SIRT1 and block the autophagy pathway, while re-activation of SIRT1 through NAD + precursor supplementation could antagonize this effect. In addition, targeted demethylation of NNT CpG island via CRISPR/dCas9-Tet1 system significantly reduced its DNA methylation level and inhibited the autophagy and cisplatin resistance in A549/DDP cells. Thus, our study found a novel chemoresistance target gene NNT , which played important roles in cisplatin resistance of lung cancer cells. Our findings also suggested that CRISPR-based DNA methylation editing of NNT could be a potential therapeutics method in cisplatin resistance of lung cancer.
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JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY
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2022
·
IF 5.062
Shentao Zhang,Erjing Li,Zhao Liu,Haitao Shang,Yichi Chen,Hui Jing
Purpose Ultrasound-mediated nanobubbles destruction (UTND) technology could enhance drug transport efficiency and increase the local drug concentration. We structured a novel Olaparib-loaded nanobubbles (Ola-NBs). Then investigated its ability to inhibit triple negative breast cancer (TNBC) cell growth in vitro. Additionally, we observed the change of cisplatin sensitivity before and after Olaparib treatment. Methods The Ola-NBs were prepared using extrusion and thin-film hydration combination methods. Cell viability was checked by CCK-8 assay, and calculated the 50% inhibition concentration (IC 50 ) of Olaparib and cisplatin. Next, Jc-1 staining was used to observe mitochondrial membrane depolarization, and an apoptosis assay was applied to assess the apoptosis in different groups. Finally, a Western blot assay was used to evaluate the inhibition effect of Olaparib on TNBC at the molecular level. Results Ola-NBs were prepared successfully. The zeta potential was −0.617 ± 0.197 mV, and the average diameter was 473.52 ± 17.33 nm. The IC 50 of Olaparib had not significant difference in TNBC cells. However, the IC 95 was higher in cisplatin-resistant MDA-MB-231 cells (MDA-MB-231/CDDP). The cell viability decreased following Olaparib treatment and was more obvious in the Ola-NBs group ( P < 0.05). In addition, the IC 50 of cisplatin was lower in the post-Olaparib treatment group. Jc-1 results revealed that the mitochondrial membrane decreased more strongly in the Ola-NBs and combination therapy groups. And the results of Jc-1 corroborated the apoptosis assay results. Moreover, Bax protein expression level increased, while Bcl-2 protein expression decreased in the treatment groups. Conclusion Olaparib not only inhibited TNBC cell growth, but it also improved the sensitivity of cisplatin in TNBC cells. And nanobubbles (NBs) might be an effective supporter, because it can enhance the drug efficacy under ultrasound irradiation.
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Applied Materials Today
·
2021
·
IF 10.041
Xiang-Fu Du,Yi Li,Jing Long,Wei Zhang,Dou Wang,Cai-Rong Li,Mei-Xia Zhao,Yuxiao Lai
Nanoscale drug delivery system (nDDS) mediated combinatorial therapy shows great promise in cancer treatment to circumvent the drawbacks of conventional monotherapy. In this study, we reported the development of a supramolecular self-assembly strategy to construct multifunctional nDDS. Cisplatin prodrug (Pt-CD) was successfully loaded onto polydopamine nanoparticles (PDA NPs) through the host-guest supramolecular self-assembly between β-cyclodextrins (β-CD) and adamantyl groups. Two cancer therapeutic modalities, photothermal therapy (PTT) and chemotherapy, were integrated into the as-designed nanoplatform (PDA-Pt NPs) to endow combinatorial anticancer capacity. The excellent photothermal performance and redox responsive cisplatin release behavior of PDA-Pt NPs was fully validated. Moreover, PDA-Pt NPs exhibited photoacoustic imaging capacity for real-time in vivo monitoring of the accumulation of the nanodrug in the tumor site and facilitated the imaging-guided PTT at the optimal treatment window. Ultimately, the combinatorial chemo-photothermal therapy mediated by PDA-Pt NPs exhibited very potent anticancer activity against osteosarcoma 143B cells in vitro and complete ablation of the subcutaneous tumor xenograft in vivo . In conclusion, this study represents an innovative and facile supramolecular self-assembly strategy for fabrication of multifunctional nanotheranostics for efficient combined anticancer therapy, which could further inspire the development of other combinatorial nanotherapeutics.
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CHEMICAL RESEARCH IN TOXICOLOGY
·
2021
·
IF 3.739
Bei Tan,Jie Chen,Siyuan Qin,Chuyao Liao,Ying Zhang,Di Wang,Siqi Li,Zunjian Zhang,Pei Zhang,Fengguo Xu
Cisplatin is a chemotherapeutic agent widely employed in the treatment of various solid tumors. However, its use is often restricted by acute kidney injury (AKI) which is the dose-limiting adverse effect of cisplatin. While numerous studies aiming to alleviate the AKI have been conducted, there are no effective remedies in clinical practice. In this paper, a targeted metabolomics study was performed to reveal the potential relationship between tryptophan metabolism and cisplatin-induced AKI. A chemical derivatization integrated liquid chromatography coupled tandem mass spectrometry (LC-MS/MS) approach was utilized to quantify 29 metabolites in the tryptophan pathway in rat kidney medulla and cortex after cisplatin administration. Results showed that tryptophan metabolism was remarkably disturbed both in the medulla and cortex after cisplatin administration. We also found that the tryptophan pathway in the medulla was more sensitive to cisplatin exposure compared with the cortex. Among these metabolites, indoxyl sulfate was focused for further study because it accumulated most significantly in the kidney cortex and medulla in a dose-dependent manner. A function verification study proved that chlormethiazole, a widely used CYP2E1 inhibitor, could reduce the production of indoxyl sulfate in the liver and attenuate cisplatin-induced AKI in rats. In conclusion, our study depicted the tryptophan pathway in cisplatin-induced AKI for the first time and demonstrated tryptophan metabolism is closely associated with the renal toxicity caused by cisplatin, which can be of great use for the discovery of renal toxicity attenuating remedies.
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