EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
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2018
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IF 4.816
Qun Wei,Jun-Ya Ning,Xi Dai,Yuan-Di Gao,Le Su,Bao-Xiang Zhao,Jun-Ying Miao
Heat shock protein 90 (HSP90) inhibition has aroused increasing enthusiasm in antitumor strategies in recent years. According to our previous studies, we synthesized a series of coumarin pyrazoline compounds HCP1-HCP6 that might be HSP90 inhibitors . Interactions between HCP1-HCP6 and HSP90 were examined and antitumor activities of them were investigated in A549 lung cancer cells. Results showed that all the six derivatives could interact with HSP90, in which HCP1 exhibited the best binding ability and inhibited the activity of HSP90. Meanwhile, HCP1-HCP6 reduced the cell viability of A549 cells and HCP1 possessed the lowest IC 50 value. Above all HCP1 exerted better HSP90 inhibitory and anticancer effects than our initially identified HSP90 inhibitor DPB . As to the underlying mechanism, HCP1-HCP6 not only induced apoptosis as DPB but also blocked autophagic flux in A549 cells. Therefore, we discovered a novel HSP90 inhibitor HCP1 that had better biological activity and provided us a useful tool to explore the underlying mechanism of lung cancer therapy.
CAS / MDL:
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高影响因子
TOXICOLOGY AND APPLIED PHARMACOLOGY
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2025
·
IF 3.4
Simiao Qiao,Fanshu Li,Jia Huang,Xiaoqian Wu,Xiaoying Cao,Xifeng Zhang,Zhifeng Wei
This study was designed to clarify the reason for PM 2.5 to induce the ferroptosis of bronchial epithelial cells and worsen asthma in detail, advancing the development of relevant drugs. Results displayed that PM 2.5 mainly induced ferroptosis but not apoptosis of bronchial epithelial cells, indicating by the changes of lipid reactive oxygen species (ROS), iron, malondialdehyde, lactic dehydrogenase, nuclear receptor coactivator 4, glutathione and glutathione peroxidase 4 levels, and further confirmed by using in combination with the ferroptosis and apoptosis inhibitors. It also caused the mitochondrial disturbance, reduced the level of mitochondrial membrane potential, up-regulated the level of mitochondrial ROS, and mechanisms were subsequently ascribed to dynamin-related protein 1 (DRP1)-related mitochondrial fission. Furthermore, the up-regulation on ubiquitination of pyruvate kinase M2 (PKM2) but not macrophage stimulating 1 or interferon regulatory factor 1, the transcriptional regulators locating at the upstream of DRP1, was showed by PM 2.5 via controlling “aryl hydrocarbon receptor (AHR)-heat shock protein 90 (HSP90)” axis. In addition, isoliquiritigenin (ISL), the main active ingredients in licorice, was demonstrated to prevent the PM 2.5 -induced activation of AHR-PKM2-ferroptosis in asthma. In conclusion, PM 2.5 activated “AHR-HSP90” axis to disturb DRP1-related mitochondrial fission, induced ferroptosis of bronchial epithelial cells, and worsened asthma. Conversely, ISL restored the above-mentioned signals, ferroptosis and asthma mediated by PM 2.5 , and was suggested as a potential compound to combat the exacerbation of asthma.
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高影响因子
ACS Applied Materials & Interfaces
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2020
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IF 8.758
Xiangyu Deng,Wei Guan,Xiangcheng Qing,Wenbo Yang,Yimei Que,Lei Tan,Hang Liang,Zhicai Zhang,Baichuan Wang,Xiangmei Liu,Yanli Zhao,Zengwu Shao
Conventional therapeutic approaches to treat malignant tumors such as surgery, chemotherapy, or radiotherapy often lead to poor therapeutic results, great pain, economic burden, and risk of recurrence and may even increase the difficulty in treating the patient. Long-term drug administration and systemic drug delivery for cancer chemotherapy would be accompanied by drug resistance or unpredictable side effects. Thus, the use of photothermal therapy, a relatively rapid tumor elimination technique that regulates autophagy and exerts an antitumor effect, represents a novel solution to these problems. Heat shock protein 90 (HSP90), a protein that reduces photothermal or hypothermic efficacy, is closely related to AKT (protein kinase B) and autophagy. Therefore, it was hypothesized that autophagy could be controlled to eliminate tumors by combining exogenous light with a selective HSP90 inhibitor, for example, SNX-2112. In this study, an efficient tumor-killing strategy using graphene oxide loaded with SNX-2112 and folic acid for ultrafast low-temperature photothermal therapy (LTPTT) is reported. A unique mechanism that achieves remarkable therapeutic performance was discovered, where overactivated autophagy induced by ultrafast LTPTT led to direct apoptosis of tumors and enabled functional recovery of T cells to promote natural immunity for actively participating in the attack against tumors. This LTPTT approach resulted in residual tumor cells being rendered in an “injured” state, opening up the possibility of concurrent antitumor and antirecurrence treatment.
研究领域:
肿瘤学
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治疗学
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免疫学
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生物医学工程
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DOI
PubMed
高影响因子
Nanoscale
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2020
·Vol. 12
·期 32
·17064-17073
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IF 6.895
Jinghua Li,Daoming Zhu,Weijie Ma,Yang Yang,Ganggang Wang,Xiaoling Wu,Kunlei Wang,Yiran Chen,Fubing Wang,Wei Liu,Yufeng Yuan
Hepatocellular carcinoma is the fourth leading cause of cancer-related deaths globally. Advanced nanomaterials have emerged as effective approaches to liver cancer therapy such as photothermal therapy. However, limited penetration depth of photothermal agents (PTAs) activated in the NIR-I bio-window and thermoresistance due to heat shock proteins restrict the therapeutic efficacy of PTT in HCC. Herein, we prepared a Bi@ZIF-8 (BZ) nanomaterial by a simple one-step reduction method. Then, gambogic acid, a natural inhibitor of Hsp90, was efficiently loaded onto the BZ nanomaterial via physical mixing. The characterization of the nanomaterial and release of GA due to pH change or NIR-light irradiation were separately studied. Photothermal conversion efficiency was calculated, and therapeutic studies were carried out in vitro and in vivo. This nanomaterial exhibited a significantly enhanced drug release rate when the temperature was increased under acidic conditions and had good light stability under laser irradiation and a photothermal conversion efficiency of about 24.4%. In addition, this novel nanomaterial achieved good therapeutic effects with less toxicity in vitro. The BZ nanomaterial loaded with GA caused tumor shrinkage as well as disappearance and effectively downregulated Hsp90 expression in tumors in vivo. Moreover, this novel nanomaterial exhibited good biocompatibility and potential for application in low-temperature PTT with excellent tumor destruction efficacy.
研究领域:
肿瘤学
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纳米医学
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生物材料学
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PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS
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2015
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IF 3.85
Xingwang Zhang,Tianpeng Zhang,Yanghuan Ye,Huaqing Chen,Hua Sun,Xiaotong Zhou,Zhiguo Ma,Baojian Wu
Systemic delivery of amphiphobic drugs (insoluble in both water and oil) represents a formidable challenge in drug delivery. This work aimed to engineer a functional mesoporous carbon material to efficiently load SNX-2112, an amphiphobic anticancer agent , and to evaluate its performance in tumor-targeting delivery. Hydrothermal reaction combined with high-temperature activation was used to fabricate glucose-based mesoporous carbon nanospheres (MCNs). SNX-2112-loaded MCNs stabilized by phospholipid (SN-PMCNs) were prepared by the absorption/solvent diffusion/high-pressure homogenization method. The obtained SN-PMCNs were 180 nm around in particle size, showing a high drug load (42.7%) and acceptable physical stability. SN-PMCNs demonstrated an enhanced in vitro antitumor effect and increased uptake into cancer cells in comparison with the formulation of SNX-2112 solution (SN-Sol). The in vivo antitumor effect and biodistribution in 4T1 xenograft tumor mice, a breast cancer model, were also significantly improved through SN-PMCNs. It was shown that specific clathrin-dependent and nonspecific caveolae-dependent endocytosis were involved in the cellular trafficking of SN-PMCNs. Glucose transporter-mediated transport, prolonged body residence time and improved biodistribution via EPR effect were the main mechanisms of enhanced antitumor effect. SN-PMCNs have presented excellent tumor targeting properties and should be a promising carrier to address the systemic delivery of SNX-2112.
研究领域:
药学
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肿瘤学
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材料科学
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PubMed
高影响因子
ACS Applied Nano Materials
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2023
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IF 5.9
Lingyun Ruan,Yuanyuan Cao,Caixia Ren,Huan Li,Xuesong Feng,Rongzhang Hao
As an alternative or supplement to conventional tumor treatment, photothermal therapy (PTT) is a rapid development technique for tumor elimination with the advantages of remote manipulation and minimal invasiveness. Although many different nanomaterials used in PTT have achieved excellent tumor treatment effects, poor tumor accumulation and high tumor heat resistance might lead to low PTT efficacy and frequent tumor recurrence. Herein, a kind of tumor-targeting nanoparticle (PDA-HA/STA9090 NPs) was rationally designed through conjugating hyaluronic acid (HA) on the surface of polyamine (PDA), along with loading the heat shock protein 90 (HSP90) inhibitor Ganetespib (STA9090). The PDA-HA/ST9090 NPs not only presented a high photothermal conversion efficiency (35.2%) but also enhanced the accumulation in tumoral sites for efficient downregulation of HSP90 in vitro. Accordingly, the mice treated with PDA-HA/STA9090 NPs under 808 nm laser irradiation showed the most effective tumor inhibition. Taken together, this work could not only provide a potential strategy to reduce hyperthermia side effects but also prompt the therapeutic effect of PTT with the assistance of HSP inhibition.
研究领域:
癌症研究
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纳米技术
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治疗学
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生物医学工程
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产品关联
DOI
高影响因子
PHYTOMEDICINE
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2023
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IF 7.9
Chao Meng,Lingye Zhou,Lin Huang,Qi Gu,Xinyue Du,Cheng Wang,Fanglan Liu,Chunhua Xia
Background Hypercholesterolemia is widely implicated in the etiology of coronary heart disease , stroke, and dementia. Evidence suggests that chlorogenic acid (CA) reduces the risk of cardiovascular disease. Purpose The current study aims to explore the underlying molecular mechanism of CA in lowering cholesterol based on pregnane X receptor (PXR) and sterol regulatory element-binding protein 2 (SREBP2) regulatory pathways and their interactions with heat shock protein 90 (HSP90). Methods A hypercholesterolemic mouse model, HepG2 and Caco2 cell models, metabolomics analysis, and co-immunoprecipitation (COIP) were used to study the mechanism of CA lowering cholesterol. Results Treatment of the hypercholesterolemic mice with CA for 12 weeks significantly reduced body weight, blood lipid, hepatic lipid accumulation , and increased lipid excretion. The nuclear aggregation of PXR and SREBP2 was inhibited simultaneously. In addition, the expression of downstream target genes, including Niemann-pick C1-like 1 (NPC1L1) and 3‑hydroxy-3-methylglutaryl-CoA reductase (HMGCR), was downregulated after CA administration. Furthermore, in HepG2 and Caco2 cell models, CA reduced intracellular cholesterol levels by inhibiting the nuclear translocation of PXR and SREBP2 and the expression of NPC1L1 and HMGCR. SREBP2 interacts with PXR through HSP90, and CA reduces the binding stability of SREBP2 and HSP90 and enhances the binding of PXR and HSP90, thus reducing the nuclear accumulation of SREBP2 and PXR simultaneously. Moreover, CA promoted the phosphorylation of AMP-activated protein kinase (AMPK) and its binding to SREBP2. This was not conducive to the binding of HSP90 and SREBP2 but enhanced the binding of HSP90 and PXR, thereby inhibiting the nuclear translocation of SREBP2 and PXR and reducing intracellular cholesterol levels. However, no noticeable direct binding between AMPK and PXR was observed. Conclusion CA downregulates NPC1L1 and HMGCR expression by acting on the AMPK/SREBP2 direct pathway and the AMPK/SREBP2/HSP90/PXR indirect pathway, thus retaining cholesterol homeostasis.
研究领域:
药理学
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分子生物学
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心血管疾病
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代谢组学
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PubMed
高影响因子
AQUACULTURE
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2024
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IF 3.9
Ningbo Wang,Yinan Wang,Rongrong Zhang,Aili Sun,Yin Lu,Zeming Zhang,Xizhi Shi
Triphenylphosphine oxide (TPPO) as a new organophosphorus flame retardant is extensively used in the industrial and pharmaceutical fields due to its chemical stability and abundance. In marine environments, TPPO accumulates as a result of natural ecological processes. This study aimed to evaluate the accumulation process and toxicological effects of TPPO utilizing mussels ( Mytilus coruscus ), a species traditionally employed in marine monitoring and commonly cultivated in offshore aquaculture. GC–MS/MS was employed to quantify the accumulation of TPPO in the gill, gonad, muscle, and digestive gland tissues of mussels exposed to three sublethal concentrations (20.0, 100.0, and 500.0 μg/L) over durations of 3, 7, 14, and 28 days, as well as the examining of the chemical and molecular parameters. Results showed that the accumulation of TPPO (100.0 and 500.0 μg/L) increased throughout the 28 d of exposure, and the peak accumulation of 20.0 μg/L TPPO was detected on 14 d. Short-term TPPO exposure did not cause oxidative stress in mussels. Chronic exposure for 28 days resulted in significant oxidative damage and oxidative stress in mussels, as evidenced by elevated expression and activity of SOD, increased levels of glutathione and malondialdehyde, and upregulation of HSP70 and HSP90, metallothionein, and CYP4Y1, alongside the initiation of apoptotic cell death. TPPO exposure activated natural immune genes and disrupted lipid metabolism in mussels. This study demonstrated the persistent accumulation of TPPO in mussels, highlighting its ecotoxicological hazards and underscoring the necessity to predict the risks associated with widespread environmental exposure to TPPO.
研究领域:
环境科学
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海洋生物学
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毒理学
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生态学
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DOI
高影响因子
POULTRY SCIENCE
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2021
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IF 3.352
Chen Yang,Pei Luo,Shi-jian Chen,Zhi-chao Deng,Xin-liang Fu,Dan-ning Xu,Yun-bo Tian,Yun-mao Huang,Wen-jun Liu
ABSTRACT Resveratrol, a natural antioxidant, anti-inflammatory plant extract, was found to have a protective effect in poultry subjected to heat stress. In this study, we strove to characterize resveratrol on intestinal of duck exposed to acute heat stress and investigate the underlying mechanism. A total of 120 Shan-ma ducks (60 days old) were randomly divided into 2 groups. The control group was fed a basal diet, and the resveratrol group was fed a basal diet supplemented with 400 mg/kg resveratrol. Animals in 2 groups were kept at a temperature of 24°C ± 2°C for 15 d. Then, animals of both groups were placed in an artificial climate room at 39°C. Twelve ducks of each group were sacrificed for sampling at 0, 30, and 60 min, respectively. Results indicated that resveratrol increased the ratio of villus height to crypt depth, increased the number of goblet cells, and reduced the histopathological damage of jejunum caused by acute heat stress. Furthermore, the gene expression of heat shock proteins ( HSP60, HSP70 , and HSP90 ) and tight junction proteins ( CLDN1 and OCLN ) was significantly increased in the resveratrol group compared to that in the control groups. Simultaneously, resveratrol significantly activated the SIRT1-NRF1/NRF2 signaling pathways, improved ATP level of jejunum, and increased SOD and CAT antioxidant enzymes activities. In addition, we found that the NF-κB / NLRP3 inflammasome signaling pathways were repressed under acute heat stress. Meanwhile, supplement resveratrol further inhibited the NLRP3 inflammasome pathway, decreased protein level of NLRP3 and caspase1 p20, reduced the secretion of IL-1β. Taken together, our results indicate that resveratrol against the oxidative damage and inflammation injury in duck jejunum induced by heat stress via active SIRT1 signaling pathways.
研究领域:
动物科学
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营养学
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生理学
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分子生物学
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DOI
PubMed
高影响因子
Materials Today Bio
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2025
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IF 10.2
Zhenying Diao,Youcheng Liang,Yong Liu,Dou Zhang,Long Qiu,Jianbo Sun,Qiaoyou Lu,Yanlei Liu,Daxiang Cui,Ting Yin
Blockade of heat shock protein 90 (HSP90) expression in multimodal synergistic therapy has a great prospect for cancer treatment. Nanomaterials combined with bioinformatic analysis provides accurate guidance for the design of anti-HSP90 nanomedicines. Herein, a NIR-II-responsive nanoplatform was developed under bioinformatics guided to effectly inhibit HSP90 for enhanced synergistic mild-photothermal chemotherapy without any notable tissue damage. The nanoplatforms were assembled from NIR-II-responsive gold nanobipyramids (GNBs) combined with curcumin (Cur) via hydrophobic-hydrophobic interactions and hydrogen bonds. On the basis of drug discovery and network pharmacology, we found that Cur has impressive anti-HSP90 capability and analyzed its therapeutic mechanism against NSCLC. Under the irradiation of NIR-II light, the obtained GNBs-Cur blocked the expression of HPS90 and inhibited related antiapoptotic pathways, thus enhancing the mild PTT of GNBs under 1064 nm laser irradiation. Meanwhile, Cur served as chemotherapeutic agents to induce apoptosis in tumor cells. In vivo photoacoustic imaging-guided, GNBs-Cur achieved effective tumor elimination through mild-photothermal chemotherapy without systemic toxicity. Overall, this work provides a new therapeutic modality paradigm for potential NSCLC treatment on the basis of synergistic therapies.
研究领域:
癌症治疗
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纳米技术
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药理学
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生物信息学
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医学成像
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DOI
PubMed
高影响因子
LIFE SCIENCES
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2025
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IF 5.1
Wenzhe Kong,Xudong Ding,Zhaoyu Wang,Lu Lu,Saijun Fan
As a common side effect of radiotherapy, radiation-induced intestinal injury (RIII) greatly affects the prognosis of patients and the efficacy of radiotherapy. Current therapeutic strategies for RIII are still very limited. Thus, the identification of effective radioprotective agents is of great importance. NVP-AUY922 is an HSP90 inhibitor with favorable anti-inflammatory and antioxidant activities. It has been proven to mitigate radiation-induced lung injury. However, its effects on the alleviation of RIII remain unclear. In this study, our data indicated that NVP-AUY922 remarkably increased the survival rate after radiation exposure. NVP-AUY922 treatment could enhance the viability of intestinal stem cells (ISCs) and promote the recovery of the small intestine. In addition, it also inhibited intestinal inflammation and reshaped the gut microbiota structure. We found that the radioprotective effect of NVP-AUY922 is partially dependent on EPHX1. In addition, NVP-AUY922 could attenuate dextran sulfate sodium (DSS)-induced colitis and promote intestinal barrier recovery. Thus, our results suggest that NVP-AUY922 contributes to the amelioration of intestinal injury after radiation exposure, which offers a new approach for the prevention of RIII.
研究领域:
肿瘤学
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放射生物学
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药理学
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胃肠病学
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DOI
PubMed
高影响因子
ACS Nano
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2021
·
IF 15.881
Zhongyuan Chen,Yueting Peng,Yichao Li,Xiaoxue Xie,Xiaodan Wei,Geng Yang,Hanxi Zhang,Ningxi Li,Tingting Li,Xiang Qin,Shun Li,Chunhui Wu,Fengming You,Hong Yang,Yiyao Liu
The combination of magnetic hyperthermia and chemotherapy within a nanosystem is thought to be a promising approach for cancer therapies. However, the nonspecific accumulation and fast clearance of magnetic nanoparticles in the physiological environment limited their further biomedical applications. Herein, we report a highly selective theranostic nanocomplex, ZIPP-Apt:DOX/siHSPs, built with superparamagnetic zinc-doped iron oxide nano-octahedral core, cationic PAMAM dendrimer, and functional surface modifications such as PEG, AS1411 aptamer, and fluorescent tags (FITC or Cy5.5), together with the loading of hydrophobic anticancer drug doxorubicin (DOX) and HSP70/HSP90 siRNAs. Our results demonstrate that the cellular uptake and the tumor-specific accumulation of ZIPP-Apt:DOX/siHSPs were significantly increased due to the AS1411-nucleolin affinity and further confirmed that the simultaneous depletion of HSP70 and HSP90 sensitized magnetic hyperthermia and chemotherapy-induced cell death both in vitro and in vivo. Altogether, our study provides a theranostic nanoplatform for aptamer-targeted, NIR/MR dual-modality imaging guided, and HSP70/HSP90 silencing sensitized magnetochemotherapy, which has the potential to advance versatile magnetic nanosystems toward clinical applications.
研究领域:
纳米技术
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生物医学工程
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癌症研究
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分子生物学
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药学
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医学影像
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产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）