Oxidative Medicine and Cellular Longevity
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2021
·
IF 6.543
Xiao-lu Wang,Liang Wang,Fo-lan Lin,Si-si Li,Ting-xuan Lin,Ren-wang Jiang
Copper/zinc superoxide dismutase (SOD1) can clear cisplatin- (CP-) induced excessive reactive oxygen species (ROS), but exogenous SOD1 cannot enter cells because of its low biomembrane permeability. Cell-penetrating peptides (CPPs) can rapidly cross plasma membranes. This study is aimed at identifying an efficient and stable CPP-SOD1 and investigating its effects on CP-induced nephrotoxicity. We recombined SOD1 with 14 different CPPs and purified them using an NTA-Ni2+ column. In in vitro experiments, CPPs-SOD1 cell membrane penetration ability and JNK/p38 MAPK signaling pathway were evaluated using Western blotting. ROS production, mitochondrial membrane potential (MMP), and cell apoptosis were determined using flow cytometry and immunofluorescence staining in VERO and HK-2 cells. For in vivo experiments, mice were administered PSF-SOD1 for 2 h before cotreatment with a single CP injection for an additional 4 days. Blood and kidney samples were collected for renal function assessment (creatinine, urea nitrogen, histopathology, TUNEL assay, and JNK/p38 MAPK signaling pathway). Compared with TAT-SOD1, we found that PSF-SOD1 is more efficient at crossing the cell membrane and is stable after transduction into cells. Pretreatment with PSF-SOD1 inhibited CP-induced apoptosis, ROS generation, and JNK/p38 MAPK activation and restored CP-induced MMP loss in VERO and HK-2 kidney cells. Treatment of mice with PSF-SOD1 inhibited CP-induced serum creatinine, blood urea nitrogen elevation, and JNK/p38 MAPK activation. H&E staining and TUNEL assay indicated that kidney tissue damage was alleviated following PSF-SOD1 pretreatment. Overall, PSF-SOD1 ameliorated CP-induced renal damage by partially reducing oxidative stress and cell apoptosis by regulating JNK/p38 MAPK signaling pathway and might be a better cytoprotective agent than TAT-SOD1.
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Frontiers in Pharmacology
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2022
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IF 5.988
Shi Le,Shu Yang,Hu Xiangdong,Akram Waheed,Wang Jun,Dong Shuang,Luo Biaobiao,Zhang Jiuliang,Hu Sheng,Li Xiaohua,Hu Xuebo
Chemotherapy is considered a most effective way to treat cancer. However, it is very common that chemotherapy causes unbearable mental and physical side effects to cancer patients, which ultimately reduces the patients’ confidence of overcoming diseases and compromises the treatment of chemotherapy. Cisplatin (DDP), a widely used anticancer agent for various types of cancers, also damages nontumor cells and tissues, which are mostly related to the activation of the inflammation pathway. Previously, we have discovered a few rational formulas of food as medicine materials that reduced systemic inflammation in in vitro and in vivo models. Hence, this study reports the ability of an optimized traditional Chinese anti-inflammatory formulation capable of synergizing the antitumor effect of DDP in vitro and in vivo. More significantly, by formulation of two anti-inflammatory herbal medicine, the Chrysanthemum × morifolium (Ramat.) Hemsl [Asteraceae] and Lonicera japonica Thunb [Caprifoliaceae] with a mediator Glycyrrhiza uralensis Fisch. ex DC [Fabaceae], a best formula relieved the kidney damage imposed by DDP. Treatments of various combinations of major chemical components of the three herbs also exhibited a similar trend for lowering the DDP-induced nephrotoxicity; however, contrary to that of the formula of herbal extracts, all chemical formulas could not recover the body weight and food intake of the tumor-bearing mice treated by DDP. Our findings suggested that the therapeutic index of DDP-based chemotherapy was able to be improved by minimizing toxicities from the two-herb formula to inhibit the inflammation in mouse tumor models and DDP-induced acute kidney injury mouse models.
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JOURNAL OF BIOMATERIALS APPLICATIONS
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2026
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IF 2.5
Yakun Ge,Pengcheng Li,Jiatong Zhang,Ruolan Wang,Renwen Zhang,Hongyu Xu,Zhenming Hao,Yuanxin Zhang
Tumor-associated macrophages (TAMs) play a pivotal role in establishing a tumor immunosuppressive microenvironment (TIME) by inducing a phenotypic shift in macrophage from the pro-inflammatory M1 to the anti-inflammatory M2 phenotype. This polarization facilitates tumor growth, progression, metastasis, immune evasion, and chemoresistance. Consequently, reprogramming the TIME by repolarizing TAMs has emerged as a promising approach in cancer therapy. In this study, we synthesized core-shell structured nanoparticles (UCNPs@CB-Zol-Pt) utilizing host-guest interactions between NaYF4:Yb/Er (UCNPs) and cucurbit[7]uril (CB). These nanoparticles were designed to polarize M2-like macrophages into M1-like macrophages and release tumor-associated antigens (TAAs), thereby potentially inducing the release of immunogenic cell death (ICD). Furthermore, the M1-type macrophages could ingest, process, and present TAAs generated from platinum-based chemotherapy through MHC class II molecules. This process simultaneously enhances the infiltration of helper and effector T cells into the TIME, thereby potentiating the efficacy of checkpoint blockade immunotherapy.
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Frontiers in Pharmacology
·
2026
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IF 5.4
Xiuye Huang,Yuxian Li,Yongan Liao,Xiaotong Lin,Xipan Zhao,Xiaojie Li,Shengliang Yuan,Jiuyao Zhou
Introduction The calcium-sensing receptor (CaSR), a G protein-coupled receptor (GPCR), plays a critical role in kidney injury by promoting inflammation and apoptosis when activated. Whether Wulingsan (WLS), a traditional Chinese herbal formula used for kidney disorders, exerts its protective effects against acute kidney injury (AKI) via modulation of the CaSR pathway remains unclear. Methods WLS’s chemical profile was characterized by ultra-high performance liquid chromatography coupled with Q-Exactive mass spectrometry (UHPLC-QE-MS). C57BL/6J mice were divided into Control, cisplatin (CP)-induced AKI, WLS (2.34/4.68/9.36 g/kg), and CaSR inhibitor NPS2143 (4.5 mg/kg) groups. Mice were pretreated with WLS/NPS2143 before CP injection (20 mg/kg, i. p.). Renal function, histopathology, inflammation, oxidative stress, and apoptosis were evaluated. Cisplatin-induced mouse renal tubular epithelial cells (mRTECs) were treated with WLS-containing serum (5%–10%) for in vitro validation. Molecular docking predicted the binding affinity of WLS components to CaSR. Results UHPLC-QE-MS identified 15 major WLS components, with 13 binding to CaSR (Polyporusterone E: binding energy of −10.4 kcal/mol). WLS pretreatment significantly improved renal function (reduced serum creatinine (SCr)/blood urea nitrogen (BUN)), attenuated tubular injury, suppressed inflammation (downregulated monocyte chemoattractant protein-1 (MCP-1)/tumor necrosis factor-α (TNF-α)/interleukin-1β (IL-1β)), alleviated oxidative stress (restored glutathione (GSH)/superoxide dismutase (SOD), reduced malondialdehyde (MDA)), and inhibited apoptosis (decreased terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells, modulated Bcl-2-associated X protein (Bax)/B-cell lymphoma-2 (Bcl-2) ratio, downregulated cleaved Caspase 3). Mechanistically, WLS inhibited renal CaSR/calmodulin-dependent protein kinase β (CaMKKβ)/adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK) pathway activation (reduced CaSR/CaMKKβ/p-AMPK expression). In vitro , WLS-containing serum reduced cisplatin-induced reactive oxygen species (ROS) production, intracellular Ca 2+ overload, and apoptosis in mRTECs, effects reversed by the CaSR agonist cinacalcet. Conclusion This study demonstrates that WLS protects against CP-induced kidney injury and inhibits apoptosis in renal tubular epithelial cells in association with the CaSR/CaMKKβ/AMPK pathway.
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JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY
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2026
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IF 5.2
Xiali Yin,Ming Jiang,Nandie Wu,Yuncheng Bei,Shuxian Zhang,Lanqi Cen,Wenmei Rao,Sen Hong,Xiaoping Gu
A hydrogel system DDP-Pa@Gel was developed without altering the microstructure. • The in vivo retention times of the drugs were assessed over a period of five days. • DDP-Pa@Gel markedly improved the antitumor efficacy and overall survival duration. • DCs increased from 13.3% to 33.1%, while a 5.1-fold increase in IFN-γ + CD8 + T cells. • DDP-Pa@Gel demonstrated an 18.0% reduction in Tregs with statistical significance. Triple-negative breast cancer is getting more attention due to its unfavorable prognosis. Although the surgical resection is the first-line option in the treatment of breast cancer. But due to the poor efficacy and prognosis, now Cisplatin (DDP) based preoperative Neo-adjuvant therapy becomes the mainstay of triple-negative breast cancer. Immune cells in the tumor environment have significant impacts on the effectiveness of treatment. In this study, we observed an anti-tumor effect of combining Parecoxib with DDP in a 4T1 mouse model. Then we designed a co-delivery system based on a thermo-sensitive injectable hydrogel for preoperative Neo-adjuvant combination chemotherapy of the triple-negative breast cancer. The hydrogel system co-loaded with Parecoxib and DDP characterized by a special sol-gel transition in response to temperature and presented a sustained release in vitro and in vivo. In the tumor microenvironment (TME), we observed a synergistic anti-tumor effect and inhibition of cell proliferation, as well as a significant increase in mature Dendritic cells (mDCs) and IFN-γ + CD8 + T cells. Hydrogel loaded with Parecoxib and DDP also reduced the need for frequent administration. These findings demonstrate that the co-delivery hydrogel system DDP-Pa@Gel has great potential in the preoperative Neo-adjuvant chemotherapy of triple-negative breast cancer, that will promote the efficacy and reduce the frequency of administration as a valuable option. Triple-negative breast cancer is getting more attention due to its unfavorable prognosis. Surgical resection is the major option in the treatment of breast cancer. But due to the poor efficacy and prognosis, now preoperative neoadjuvant therapy becomes the mainstay of triple-negative breast cancer. Cisplatin (DDP) based neoadjuvant chemotherapy is the fundamental aspect of treatment. Immune cells in the tumor environment have significant impacts on the effectiveness of treatment. In this study, we observed an anti-tumor effect of combining Parecoxib with DDP in a 4T1 mouse model. Then we designed co-delivery system based on a thermo-sensitive injectable hydrogel for preoperative neoadjuvant combination chemotherapy of the triple-negative breast cancer. The hydrogel system co-loaded with Parecoxib and DDP characterized by a special sol-gel transition in response to temperature and presented a sustained release in vitro and in vivo. A synergistic anti-tumor effect and cell proliferation inhibition were observed, so as a significant increase in mature Dendritic cells (mDCs) and IFN-γ + CD8 + T cells in the tumor microenvironment (TME). The use of hydrogel co-loaded with Parecoxib and DDP benefited to fewer administration as well. These findings demonstrate that the co-delivery hydrogel system DDP-Pa@Gel has great potential in the preoperative neoadjuvant chemotherapy of triple-negative breast cancer, that will promote the efficacy and reduce the frequency of administration as a valuable option. Download: Download high-res image (286KB) Download: Download full-size image
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JOURNAL OF NANOBIOTECHNOLOGY
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2022
·Vol. 20
·期 1
·1-14
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IF 9.429
Li Xing,Zhang Lingpu,Li Tuo,Li Shumu,Wu Wenjing,Zhao Lingyu,Xie Peng,Yang Jinqi,Li Peipei,Zhang Yangyang,Xiao Haihua,Yu Yingjie,Zhao Zhenwen
Background Cisplatin, the alkylating agent of platinum(II) (Pt(II)), is the most common antitumor drug in clinic; however, it has many side effects, therefore it is higly desired to develop low toxicity platinum(IV) (Pt(IV)) drugs. Multi-omics analysis, as a powerful tool, has been frequently employed for the mechanism study of a certain therapy at the molecular level, which might be helpful for elucidating the mechanism of platinum drugs and facilitating their clinical application.Methods Strating form cisplatin, a hydrophobic Pt(IV) prodrug (CisPt(IV)) with two hydrophobic aliphatic chains was synthesized, and further encapsulated with a drug carrier, human serum albumin (HSA), to form nanoparticles, namely AbPlatin(IV). The anticancer effect of AbPlatin(IV) was investigated in vitro and in vivo. Moreover, transcriptomics, metabolomics and lipidomics were performed to explore the mechanism of AbPlatin(IV).Results Compared with cisplatin, Abplatin(IV) exhibited better tumor-targeting effect and greater tumor inhibition rate. Lipidomics study showed that Abplatin(IV) might induce the changes of BEL-7404 cell membrane, and cause the disorder of glycerophospholipids and sphingolipids. In addition, transcriptomics and metabolomics study showed that Abplatin(IV) significantly disturbed the purine metabolism pathway.Conclusion sThis research highlighted the development of Abplatin(IV) and the use of multi-omics for the mechanism elucidation of prodrug, which is the key to the clinical translation of prodrug.Graphical Abstract
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高影响因子
BIOORGANIC CHEMISTRY
·
2021
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IF 5.275
Lanmei Chen,Jie Wang,Xianhong Cai,Suxiang Chen,Jingjing Zhang,Baojun Li,Weigang Chen,Xinhua Guo,Hui Luo,Jincan Chen
Both ruthenium (Ru) and isoquinoline (IQ) compounds are regarded as potential anticancer drug candidates. Here, we report the synthesis and characterization of three novel cyclometalated Ru(II)-isoquinoline complexes: RuIQ-3 , RuIQ-4 , and RuIQ-5, and evaluation of their in vitro cytotoxicities against a panel of cell lines including A549/DDP, a cisplatin-resistant human lung cancer cell line. A549/DDP 3D multicellular tumor spheroids (MCTSs) were also used to detect the drug resistance reversal effect of Ru(II)-IQ complexes. Our results indicated that the cytotoxic activities against cancer cells of Ru(II)-IQ complexes, especially RuIQ-5 , were superior compared with cisplatin. In addition, RuIQ-5 exhibited low toxicity towards both normal HBE cells in vitro and zebrafish embryos in vivo . Further investigation on cellular mechanism of action indicated that after absorption by A549/DDP cells, RuIQ-5 was mainly distributed in the nucleus, which is different from cisplatin. Besides, RuIQ-5 could induce apoptosis through mitochondrial dysfunction, reactive oxygen species (ROS) accumulation, ROS-mediated DNA damage, and cycle arrest at both S and G2/M phases. Moreover, RuIQ-5 could inhibit the overexpression of Nrf2 through regulation of Akt/GSK-3β/Fyn signaling pathway and hindering the nuclear translocation of Nrf2. Based on these findings, we firmly believe that the studied Ru(II)-IQ complexes hold great promise as anticancer therapeutics with high effectiveness and low toxicity.
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Acta Pharmaceutica Sinica B
·
2021
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IF 11.614
Boyi Niu,Yixian Zhou,Kaixin Liao,Ting Wen,Sixian Lao,Guilan Quan,Xin Pan,Chuanbin Wu
The therapeutic efficacy of cisplatin has been restricted by drug resistance of cancers. Intracellular glutathione (GSH) detoxification of cisplatin under the catalysis of glutathione S -transferases (GST) plays important roles in the development of cisplatin resistance. Herein, a strategy of “pincer movement” based on simultaneous GSH depletion and GST inhibition is proposed to enhance cisplatin-based chemotherapy. Specifically, a redox-responsive nanomedicine based on disulfide-bridged degradable organosilica hybrid nanoparticles is developed and loaded with cisplatin and ethacrynic acid (EA), a GST inhibitor. Responding to high level of intracellular GSH, the hybrid nanoparticles can be gradually degraded due to the break of disulfide bonds, which further promotes drug release. Meanwhile, the disulfide-mediated GSH depletion and EA-induced GST inhibition cooperatively prevent cellular detoxification of cisplatin and reverse drug resistance. Moreover, the nanomedicine is integrated into microneedles for intralesional drug delivery against cisplatin-resistant melanoma. The in vivo results show that the nanomedicine-loaded microneedles can achieve significant GSH depletion, GST inhibition, and consequent tumor growth suppression. Overall, this research provides a promising strategy for the construction of new-type nanomedicines to overcome cisplatin resistance, which extends the biomedical application of organosilica hybrid nanomaterials and enables more efficient chemotherapy against drug-resistant cancers.
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JOURNAL OF ETHNOPHARMACOLOGY
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2020
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IF 3.69
Diao Hui,Tan Rui-Zhi,Li Jian-Chun,Zhong Xia,Wen Dan,Fan Jun-Ming,Wang Li
Ethnopharmacological relevance Acute kidney injury (AKI) is a common disease in hospitalized patients, especially in critically ill patients. It is characterised with high morbidity and mortality, and is also an important cause of chronic kidney disease and chronic renal failure. Astragalus propinquus Schischkin and Panax notoginseng (A&P) compound, a famous traditional Chinese medicine , consists of Astragalus propinquus Schischkin, Panax notoginseng, Angelica sinensis , Achyranthes bidentata , and Ecklonia kurome, has been widely used for the treatment of various kidney diseases in the southwest of China. However, the effects of A&P on treatment of AKI and its underlying mechanism are needed to be uncovered. Aim of the study Recent researches reported that Mincle (Macrophage-inducible C-type lectin) plays a key role in renal injury of AKI by regulating the expression and secretion of inflammatory cytokines on macrophage through modulating NF-κB signaling pathway. Here, we aimed to investigate the renoprotective effect of A&P on AKI and whether by inhibiting Mincle. Materials and methods We established a lipopolysaccharide (LPS)-induced Bone Marrow-Derived Macrophage (BMDM) inflammatory cell model and a cisplatin-induced mouse AKI model in vitro and in vivo . Renal histopathology staining was performed to observe kidney morphology. The expression and secretion of inflammatory cytokines were detected by real-time PCR and Enzyme-linked immunosorbent assay. Western blotting was used to detect the protein levels and Flow cytometry performed to detect polarization of macrophage. Results The results showed that A&P significantly reduced the mRNA expression of IL-1β, IL-6, TNFα and MCP-1 in LPS-stimulated BMDM cells, and secretion of IL-1β and IL-6 in supernatant. The same results were found in Cisplatin-induced AKI kidney and serum after treatment with A&P. The data also showed that A&P strongly reduced the mRNA and protein levels of Mincle in vitro and vivo , and also inhibited the activation of Syk and NF-κB. Notably, A&P down-regulated the M1 macrophage marker iNOS, which may relate to the inhibition of Mincle. Interestingly, both overexpression of Mincle by transfection of pcDNA3.1-Mincle plasmid and administration of TDB (a ligand of Mincle) can significantly abolished the A&P-inhibited inflammation in BMDM, suggesting Mincle pathway play a key role in macrophage inflammation in AKI. Conclusion Our findings indicated that A&P protected kidney from inhibiting inflammation through down-regulating of Mincle pathway in macrophage in AKI. It provides a potential medicine compound for the treatment of AKI.
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JOURNAL OF DRUG TARGETING
·
2023
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IF 4.5
Wenhui Ye,Huaiyou Lv,Qinxiu Zhang,Jianxiong Zhao,Xin Zhao,Guozhi Zhao,Chongzheng Yan,Fengqin Sun,Zhongxi Zhao,Xiumei Jia
Non-small cell lung cancer (NSCLC) accounting for about 80-85% of all lung cancer cases is one of the fastest-growing malignancies in terms of incidence and mortality worldwide and is commonly treated with cisplatin (DDP). Although treatment may initially be effective, the DDP therapy often leads to the development of chemoresistance and treatment failure. Disulfiram (DSF), an old alcohol-aversion drug, has been revealed to help reverse drug resistance in several cancers. In addition, several studies have shown a close relationship between drug resistance and cancer cell stemness. In this study, DDP and DSF were embedded in hydroxypropyl-β-cyclodextrin (CD) to prepare a co-loaded inclusion complex of DDP and DSF (DDP-DSF/CD) with enhanced solubility and therapeutic effects. The effects and mechanism of DSF on the DDP resistance from the perspective of cancer cell stemness were determined. Our data show that DDP-DSF/CD increased cytotoxicity and apoptosis of DDP-resistant A549 (A549/DDP) cells, inhibited stem cell transcriptional regulatory genes and drug resistance-associated proteins and reversed the DDP resistance in vitro and in vivo. Overall, DDP-DSF/CD could be a promising formulation for the reversal of DDP resistance in NSCLC by inhibiting cancer cell stemness.
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高影响因子
BIOMATERIALS
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2017
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IF 8.402
Feng Li,Tianyu Li,Wei Cao,Lu Wang,Huaping Xu
Cisplatin (CDDP) has received worldwide approval for clinical use in the past decades. However, its development in cancer chemotherapy was overshadowed by severe side effects and drug resistance. Herein, we developed a CDDP drug delivery system with high encapsulation efficiency and near-infrared light stimuli-responsive drug release properties based on the coordination of novel tellurium-containing block polymer (PEG-PUTe-PEG) and CDDP. The nanocarriers made from PEG-PUTe-PEG were loaded with CDDP and indocyanine green (ICG) simultaneously. The coordination chemistry between CDDP and tellurium guaranteed the nanocarrier a high stability in plasma and prolonged circulation time in vivo by reducing possible penetration of water molecule into the nanoparticles . Under the stimuli of a near-infrared laser, an amount of ROS can be generated by irradiation of ICG. The tellurium is easily oxidized by ROS because of the low electronegativity of tellurium. The CDDP could be rapidly released from the nanocarriers along with the oxidation of the tellurium at the tumor sites as the oxidized tellurium will weaken the coordination interaction with CDDP. In addition, the encapsulated ICG played a synergistic antitumor effect through photothermal effect with mild laser irradiation . The integrated strategy achieved higher antitumor efficacy and showed minimal side effects compared with the CDDP alone.
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Discover Oncology
·
2024
·Vol. 15
·期 1
·1-13
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IF 2.8
Yin Xiaoyan,Zhang Haizhong,Wang Jingmiao,Bian Yanrui,Jia Qiaojing,Yang Zhichao,Shan Chunguang
In this study, we investigated the role of the newly discovered lncRNA FLJ20021 in laryngeal cancer (LC) and its resistance to cisplatin treatment. We initially observed elevated lncRNA FLJ20021 levels in cisplatin-resistant LC cells (Hep-2/R). To explore its function, we transfected lncRNA FLJ20021 and cyclin-dependent kinase 1 (CDK1) into Hep-2/R cells, assessing their impact on cisplatin sensitivity and PANoptosis. Silencing lncRNA FLJ20021 effectively reduced cisplatin resistance and induced PANoptosis in Hep-2/R cells. Mechanistically, lncRNA FLJ20021 primarily localized in the nucleus and interacted with CDK1 mRNA, thereby enhancing its transcriptional stability. CDK1, in turn, promoted panapoptosis in a ZBP1-dependent manner, which helped overcome cisplatin resistance in Hep-2/R cells. This study suggests that targeting lncRNA FLJ20021 can be a promising approach to combat cisplatin resistance in laryngeal cancer by regulating CDK1 and promoting PANoptosis via the ZBP1 pathway. These findings open up possibilities for lncRNA-based therapies in the context of laryngeal cancer.
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