American Journal of Translational Research
·
2025
·Vol. 17
·期 10
·8060
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IF 1.6
Xia Tian,Zheng Han,Ye Yu,Jie Tan,Qingxi Zhu,Wei Chen,Shasha Huang,Xiaoli Chen,Meng Liu
Objective: To investigate the role of CDH17 in cisplatin (DDP) resistance in gastric cancer (GC) and to elucidate the potential molecular mechanisms. Methods: DDP-resistant GC cell lines were established, and CDH17 expression was silenced in these cells. Cell proliferation was assessed using the MTT assay. Cellular glycolytic activity was quantified, and apoptosis was assessed using flow cytometry. The expression of CDH17, β-catenin, key Warburg-related effector proteins, and Cleaved-caspase-3 was determined through molecular experiments. The Warburg effect inhibitor 2-DG and the Wnt/β-catenin signaling pathway agonist CP21R7 were applied to investigate the underlying molecular mechanism. Results: CDH17 was significantly upregulated in the DDP-resistant GC cells. CDH17 knockdown increased the sensitivity of GC cells to DDP, suppressed the Warburg effect, and inhibited the activation of the Wnt/β-catenin signaling pathway. Treatment with 2-DG reduced the chemoresistance in resistant GC cells. However, CP21R7 treatment promoted the Warburg effect in the DDP-resistant GC cells and partially attenuated the effects of CDH17 silencing on both the Warburg effect and DDP sensitivity. Conclusion: CDH17 silencing reversed DDP resistance in GC cells, primarily through inhibition of the Warburg effect mediated by the Wnt/β-catenin signaling pathway.
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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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Bioactive Materials
·
2022
·
IF 16.874
Yi Xiao,Haomin Yi,Jingzhi Zhu,Suhua Chen,Guofang Wang,Yilong Liao,Yuanyuan Lei,Liyin Chen,Xingcai Zhang,Fangfu Ye
Toxicity assessment is a major problem in pharmaceutical candidates and industry chemicals development. However, due to the lack of practical analytical methods for DNA adduct analysis, the safety evaluation of drug and industry chemicals was severely limited. Here, we develop a DNAzyme-based method to detect DNA adduct damage for toxicity assessment of drugs and chemicals. Among 18 structural variants of G4 DNAzyme, EA2 DNAzyme exhibits an obvious DNA damaging effect of styrene oxide (SO) due to its unstable structure. The covalent binding of SO to DNAzyme disrupts the Hoogsteen hydrogen bonding sites of G-plane guanines and affects the formation of the G4 quadruplex. DNA damage chemicals reduce the peroxidase activity of the G4 DNAzyme to monitor the DNA adduct damage by disrupting the structural integrity of the G4 DNAzyme. Our method for genotoxic assessment of pharmaceutical candidates and industrial chemicals can elucidate the complex chemical pathways leading to toxicity, predict toxic effects of chemicals, and evaluate possible risks to human health.
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CELLS TISSUES ORGANS
·
2022
·
IF 2.208
Zhou Yafu,Yan Jianhua,Chen Huiguo,Zhou Wenwu,Yang Jinsong
GINS subunit complex 4 (GINS4) is fundamental to DNA replication and G1/S phase transition of the cell cycle in eukaryotes. Further, recent studies implied that GINS4 can mediate the progression of several tumors, but its mechanism in lung adenocarcinoma (LUAD) is not clarified. Therefore, the role of GINS4 in LUAD was explored. miR-133a-3p and GINS4 mRNA expression were tested through qRT-PCR. Protein levels of the two genes were assayed by Western blot. Their targeting relationship was predicted and verified by bioinformatics prediction and dual-luciferase analysis. The functions of miR-133a-3p and GINS4 in LUAD were evaluated by Transwell, wound healing, CCK-8, and flow cytometry assays. MTT assay and caspase-3 activity detection were utilized to measure the regulation of miR-133a-3p/GINS4 in the cisplatin sensitivity of LUAD cells. The results showed that GINS4 was highly expressed in LUAD cells (p < 0.05). miR-133a-3p, the upstream gene of GINS4 in LUAD, negatively mediated GINS4 expression. Moreover, overexpressing GINS4 enhanced the proliferative, migratory, and invasive abilities of LUAD cells and inhibited cell apoptosis and the sensitivity to cisplatin, while overexpressing miR-133a-3p caused the contrary results. However, the promoting effects of GINS4 overexpression on LUAD could be offset by miR-133a-3p overexpression. miR-133a-3p could regulate malignant behaviors and cisplatin sensitivity of LUAD cells through negatively regulating GINS4. In conclusion, our findings demonstrated that GINS4 was overexpressed in LUAD and promoted the malignant behavior of LUAD cells. Moreover, miR-133a-3p could negatively regulate GINS4, thereby suppressing the malignant progression and increasing the cisplatin sensitivity of LUAD
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INTERNATIONAL IMMUNOPHARMACOLOGY
·
2022
·
IF 5.714
Xue-qi Liu,Ming-ming Liu,Ling Jiang,Li Gao,Yao Zhang,Yue-bo Huang,Xian Wang,Wei Zhu,Han-xu Zeng,Xiao-ming Meng,Yong-gui Wu
Acute kidney injury (AKI) is marked by a fast deterioration of the kidney function that may be caused by a variety of factors. Recently, although our group found that PPBICA alleviated programmed cell death in AKI, poor water solubility limited its bioavailability. In this research, we screened a series of derivatives and found that C-316-1 had the best suppressive effect on preventing necroptosis and inflammation in cisplatin- and ischemia/reperfusion-induced AKI in vitro and in vivo with lower toxicity and better water solubility. Mass spectrometry results showed that C-316-1 bound to heat shock protein 90 (Hsp90), which was further confirmed by molecular docking and surface plasmon resonance. Additionally, the Hsp90 expression was upregulated in the blood and tissues of AKI patients. We discovered that C-316-1 decreased the RIPK1 protein level without affecting its mRNA expression. The proteasome inhibitor, MG132 restored the level of RIPK1 reduced by C-316-1, suggesting that C-316-1 limits necroptosis by promoting the degradation of RIPK1 rather than by reducing its production. Immunoprecipitation further showed that pretreatment with C-316-1 disrupted the Hsp90-Cdc37 protein–protein Interactions (PPIs). Thereby, C-316-1 inhibited the Hsp90-Cdc37 complex formation and led to a significant decrease in RIPK1, which in turn reduced necroptosis. Moreover, C-316-1 treatment did not protect against kidney injury in vivo and in vitro when Hsp90 was knocked down and R46, E47, and S50 in Cdc37 binding site of Hsp90 might form an important active pocket with C-316-1. These findings suggest that C-316-1 is a potential therapeutic agent against RIPK1-Mediated Necroptosis in AKI.
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ACS Applied Materials & Interfaces
·
2023
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IF 9.5
Leyi Fang,Xiao-Tong Pan,Kang Liu,Dechen Jiang,Deju Ye,Li-Na Ji,Kang Wang,Xing-Hua Xia
The simultaneous and accurate detection of intracellular pH (pHi) and extracellular pH (pHe) is essential for studying the complex physiological activities of cancer cells and exploring pH-related therapeutic mechanisms. Here, we developed a super-long silver nanowire-based surface-enhanced Raman scattering (SERS) detection strategy for simultaneous sensing of pHi and pHe. A surface-roughened silver nanowire (AgNW) with a high aspect ratio is prepared at a nanoelectrode tip using a Cu-mediated oxidation process, which is then modified by pH-sensitive 4-mercaptobenzoic acid (4-MBA) to form 4-MBA@AgNW as a pH sensing probe. With the assistance of a 4D microcontroller, 4-MBA@AgNW is efficient in simultaneously detecting pHi and pHe in both 2D and 3D culture cancer cells by SERS, with minimal invasiveness, high sensitivity, and spatial resolution. Further investigation proves that the surface-roughened single AgNW can also be used in monitoring the dynamic variation of pHi and pHe of cancer cells upon stimulation with anticancer drugs or under a hypoxic environment.
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ANALYTICAL CHEMISTRY
·
2026
·
IF 7.3
Fei Zhang,Yingyu Zhang,Xianwei Zhang,Qionglin Wang,Na Zhao,Jianying Ren,Man Zhang,Peng Wang,Mengxin Zhang,Wancun Zhang
Abstract Mitochondrial apurinic/apyrimidinic endonuclease 1 (APE1) mislocalization is closely linked to tumor progression and prognosis. Yet, its ubiquitous distribution across mitochondria, cytoplasm, and nucleus makes specific in situ imaging of mitochondrial APE1 highly challenging. Herein, we fabricate a sequentially activated biosensor (C-12S-tFNA) with 12S rRNA-gated spatial regulation of APE1 cleavage site (apurinic/apyrimidinic site, AP site) accessibility, where cytochrome c (cyt c) acts as the targeting motif to drive precise mitochondrial enrichment. In the initial state, the AP site is structurally locked to prevent nonspecific cleavage by extramitochondrial APE1. After entering the mitochondria, mitochondrial 12S rRNA, which is consistently expressed across diverse cell types, hybridizes with the AP-site-containing strand via base complementarity, leading to AP site unlocking. The exposed AP site is subsequently cleaved by mitochondrial APE1, separating the fluorophore-quencher pair and generating a fluorescent signal. Benefiting from the 12S rRNA-gated design, false-positive signals can be effectively suppressed. Experimental findings demonstrate that C-12S-tFNA exhibits high sensitivity (LOD: 0.002 U/mL) and exceptional specificity for mitochondrial APE1. Notably, it distinguishes high-risk from low-risk neuroblastoma (NB) in vivo without the need for surgically resected or biopsied tissue, while exhibiting favorable biocompatibility. Collectively, C-12S-tFNA enables noninvasive, activity-based mitochondrial APE1 imaging and holds promise for improving precision risk stratification in NB.
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Biomaterials Research
·
2023
·Vol. 27
·期 1
·1-20
·
IF 11.3
Jiang Hao,Tian Hailong,Wang Zhihan,Li Bowen,Chen Rui,Luo Kangjia,Lu Shuaijun,Nice Edouard C.,Zhang Wei,Huang Canhua,Zhou Yuping,Zheng Shaojiang,Gao Feng
Background Colorectal cancer (CRC) is the second most deadly cancer worldwide, with chemo-resistance remaining a major obstacle in CRC treatment. Notably, the imbalance of redox homeostasis-mediated ferroptosis and the modulation of hypoxic tumor microenvironment are regarded as new entry points for overcoming the chemo-resistance of CRC.
Methods Inspired by this, we rationally designed a light-activatable oxygen self-supplying chemo-photothermal nanoplatform by co-assembling cisplatin (CDDP) and linoleic acid (LA)-tailored IR820 via enhanced ferroptosis against colorectal cancer chemo-resistance. In this nanoplatform, CDDP can produce hydrogen peroxide in CRC cells through a series of enzymatic reactions and subsequently release oxygen under laser-triggered photothermal to alleviate hypoxia. Additionally, the introduced LA can add exogenous unsaturated fatty acids into CRC cells, triggering ferroptosis via oxidative stress-related peroxidized lipid accumulation. Meanwhile, photothermal can efficiently boost the rate of enzymatic response and local blood flow, hence increasing the oxygen supply and oxidizing LA for enhanced ferroptosis.
Results This nanoplatform exhibited excellent anti-tumor efficacy in chemo-resistant cell lines and showed potent inhibitory capability in nude mice xenograft models.Conclusion sTaken together, this nanoplatform provides a promising paradigm via enhanced ferroptosis and alleviated hypoxia tumor microenvironment against CRC chemo-resistance.Graphical Abstract
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ACS Applied Materials & Interfaces
·
2021
·
IF 9.229
Liuwei Zhang,Ming Qian,Hongyan Cui,Shuang Zeng,Jingyun Wang,Qixian Chen
Nanomedicine developed to date by means of directly encapsulating cytotoxins suffers from crucial drawbacks, including premature release and detoxification prior to arrival at pharmaceutics targets. To these respects, redox-responsive polymeric prodrugs of platinum (Pt) and camptothecin (CPT), selectively and concomitantly activated in the cytoplasm, were elaborated in manufacture of dual prodrug nanomedicine. Herein, multiple CPTs were conjugated to poly(lysine) (PLys) segments of block copolymeric poly(ethylene glycol) (PEG)-PLys through the redox responsive disulfide linkage [PEG-PLys(ss-CPT)] followed by reversible conversion of amino groups from PLys into carboxyl groups based on their reaction with cis-aconitic anhydride [PEG-PLys(ss-CPT&CAA)]. On the other hand, Pt(IV) in conjugation with dendritic polyamindoamine [(G3-PAMAM-Pt(IV)] was synthesized for electrostatic complexation with PEG-PLys(ss-CPT&CAA) into dual prodrug nanomedicine. Subsequent investigations proved that the elaborated nanomedicine could sequentially respond to intracellular chemical potentials to overcome a string of predefined biological barriers and facilitate intracellular trafficking. Notably, PEG-PLys(ss-CPT&CAA) capable of responding to the acidic endosomal microenvironment for transformation into endosome-disruptive PEG-PLys(ss-CPT), as well as release of G3-PAMAM-Pt(IV) from nanomedicine, prompted transclocation of therapeutic payloads from endosomes into cytosols. Moreover, concurrent activation and liberation of cytotoxic CPT and Pt(II) owing to their facile responsiveness to the cytoplasmic reducing microenvironment have demonstrated overwhelming cytotoxic potencies. Eventually, systemic administration of the dual prodrug construct exerted potent tumor suppression efficacy in treatment of intractable solid breast adenocarcinoma, as well as an appreciable safety profile. The present study illustrated the first example of nanomedicine with a dual prodrug motif, precisely and concomitantly activated by the same subcellular stimuli before approaching pharmaceutic action targets, thus shedding important implication in development of advanced nanomedicine to seek maximized pharmaceutic outcomes.
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BIOCHEMICAL PHARMACOLOGY
·
2020
·
IF 4.96
Cui Li,Liping Li,Yaodong Yi,Wei Wang,Jingqun Yuan,Fuqing Tan,Danbo Fang,Su Zeng,Hui Zhou,Huidi Jiang
Cisplatin is a first-line chemotherapeutic agent that is widely used for treatment of various solid tumors. However, cisplatin-induced adverse effects, particularly severe nephrotoxicity, preclude its application. In this study, we showed that L-tetrahydropalmatine ( L-THP) could selectively inhibit organic cation transporter 2 (OCT2), which plays a crucial role in renal cisplatin uptake from the circulation. Additionally, we demonstrated that L-THP attenuated cisplatin-induced toxicity in mouse primary renal tubular cells. Subsequently, we verified that L-THP reduced the renal accumulation of cisplatin and alleviated cisplatin-induced renal injury in healthy and tumor-bearing nude mice. In healthy mice, co-treatment of L-THP at 5–40 mg/kg reduced cisplatin renal accumulation to 75.0%-49.9% of that in cisplatin alone group (10 mg/kg), and alleviated cisplatin-induced nephrotoxicity. Additionally, it did not alter Pt concentration in the tumor tissue and did not impair its antitumor efficacy in tumor bearing nude mice. The tumor inhibitory rates of cisplatin (10 mg/kg) co-treated with L-THP at 10, 20 and 40 mg/kg were 71.4%, 70.4% and 69.4%, respectively, in H460 tumor bearing nude mice, higher than that of in cisplatin alone group (60.6%), while in HCT116 tumor bearing nude mice, the tumor inhibitory rates in co-treated with 20 mg/kg L-THP was 34.7% ( vs 26.3% in cisplatin alone group). Moreover, L-THP reduced cisplatin accumulation and alleviated cisplatin-induced cytotoxicity in human primary renal tubular cells. Therefore, our findings suggested that concomitant administration of L-THP could attenuate cisplatin-induced renal injury via selective inhibition of OCT2 without impairing its antitumor efficacy.
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Nature Biomedical Engineering
·
2020
·Vol. 4
·期 9
·853-862
·
IF 18.952
Zheng Di-Wei,Pan Pei,Chen Ke-Wei,Fan Jin-Xuan,Li Chu-Xin,Cheng Han,Zhang Xian-Zheng
Patients with kidney failure commonly require dialysis to remove nitrogenous wastes and to reduce burden to the kidney. Here, we show that a bacterial cocktail orally delivered in animals with kidney injury can metabolize blood nitrogenous waste products before they diffuse through the intestinal mucosal barrier. The microbial cocktail consists of three strains of bacteria isolated from faecal microbiota that metabolize urea and creatinine into amino acids, and is encapsulated in calcium alginate microspheres coated with a polydopamine layer that is selectively permeable to small-molecule nitrogenous wastes. In murine models of acute kidney injury and chronic kidney failure, and in porcine kidney failure models, the encapsulated microbial cocktail significantly reduced urea and creatinine concentrations in blood, and did not lead to any adverse effects.
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TOXICOLOGY
·
2021
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IF 4.221
Yaodong Yi,Liping Li,Feifeng Song,Ping Li,Mingyang Chen,Shixin Ni,Hengbin Zhang,Hui Zhou,Su Zeng,Huidi Jiang
Oxaliplatin (OXA) is a third-generation platinum drug; however, its application is greatly limited due to the severe peripheral neurotoxicity. This study aims to confirm the transport mechanism of OXA and to explore whether L-tetrahydropalmatine (L-THP) would alleviate OXA-induced peripheral neurotoxicity by selectively inhibiting these uptake transporters in vitro and in vivo . Our results revealed that organic cation transporter 2 (OCT2), organic cation/carnitine transporter 1 (OCTN1) and organic cation/carnitine transporter 2 (OCTN2) were involved in the uptake of OXA in dorsal root ganglion (DRG) neurons and mitochondria, respectively. L-THP (1−100 μM) reduced OXA (40 μM) induced cytotoxicity in MDCK-hOCT2 (Madin–Darby canine kidney, MDCK), MDCK-hOCTN1, MDCK-hOCTN2, and rat primary DRG cells, and decreased the accumulation of OXA in above cells and rat DRG mitochondria, but did not affect its efflux from MDCK-hMRP2 cells. Furthermore, Co-administration of L-THP (5–20 mg/kg for mice, 10–40 mg/kg for rats; twice a week, iv or ig ) attenuated OXA (8 mg/kg for mice, 4 mg/kg for rats; twice a week, iv ) induced peripheral neurotoxicity and reduced the platinum concentration in the DRG. Whereas, L-THP (1−100 μM for cells; 10–20 mg/kg for mice) did not impair the antitumour efficacy of OXA (40 μM for cells; 8 mg/kg for mice) in HT29 tumour-bearing nude mice nor in tumour cells (HT29 and SW620 cells). In conclusion, OCT2, OCTN1 and OCTN2 contribute to OXA uptake in the DRG and mitochondria. L-THP attenuates OXA-induced peripheral neurotoxicity via inhibiting OXA uptake but without impairing the antitumour efficacy of OXA. L-THP is a potential candidate drug to attenuate OXA-induced peripheral neurotoxicity.
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