MICROBIAL PATHOGENESIS
·
2024
·
IF 3.3
Zhikun Zhang,Dawei Shi,Haiwei Dou,Ruijie Wan,Qing Yuan,Peng Tu,Deli Xin
In previous study, lower levels of serum GP130 were reported in children with MPP. GP130 is an important signal transducer, the down regulation of which may influence host immune responses. In this study, we aimed to analyze the regulatory mechanism of GP130 during MP infection. Firstly, the mRNA and protein levels of GP130 both decrease and then increase with increasing multiplicity of infection (MOI: 1 to 40) of MP. The lowest levels of GP130 were detected at MOI of 5. Then, heat treated MP but not trypsin treated MP or MP extracted proteins show regulatory effect to the expression of GP130. These indicate that the down regulation of GP130 is related to protein mediate adhesion process of MP. Gene expression analysis revealed that MP affected apoptosis and the TLR4 pathway in infected cells, and the mRNA level of IL-6 was correlated with that of GP130. Further, Z-VAD-FMK (pan-caspase inhibitor) can suppress the apoptosis induced by MP infection and restore GP130 at protein level. Further studies revealed that MP infection promoted TLR4 internalization but did not activate the NF-κB pathway. The levels of surface TLR4 showed correlation with the transcription of IL-6 and GP130. TAK242 (TLR4 inhibitor) and PS341 (proteasome inhibitor) can restore the decreased transcription of GP130, both of which were able to promote NF-κB pathway activation in MP-infected cells. These suggested that the regulation of TLR4/NF-κB pathway and induced apoptosis post MP infection are involved in the down-regulation of GP130 at transcription and protein levels, respectively.
研究领域:
微生物学
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免疫学
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细胞生物学
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分子生物学
✓ 已验证
DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2020
·
IF 4.872
Ling Ou,Haixia Wang,Zhidi Wu,Panpan Wang,Li Yang,Xiaoyun Li,Kehuan Sun,Xiaofeng Zhu,Ronghua Zhang
Cadmium is an environmental metal pollutant that has been a focus of research in recent years, which is reported to cause bone disease; however, its skeletal toxicity and the mechanism involved are not yet fully known. Therefore, this study used MC3T3-E1 subclone 14 cells to determine the mechanism of cadmium toxicity on bone. Cadmium chloride (Cd) significantly reduced cell viability in a concentration-dependent manner. Exposure to Cd inhibited osteoblast-related proteins (Runx2, Col-1, STC2) and decreased alkaline phosphatase (ALP) activity. Cd caused Exportin-1 accumulation and induced DNA damage. Cd significantly down-regulated caspase 9 and induced cleaved-PARP, cleaved-caspase 3 protein level. Treatment with JNK inhibitor, SP600125, suppressed cadmium-induced elevation in the ratio of phosphorylation of JNK to JNK. Inhibition of caspase with pan-caspase inhibitor, Z-VAD-FMK, prevented MC3T3-E1 subclone 14 cells from cadmium-induced reduction of Runx2, STC2, caspase 9, and accumulation of cleaved PARP and cleaved caspase 3. Cd-induced cell survival enhanced by SP600125 but rescued by Z-VAD-FMK or KPT-335. These results suggest that cadmium cytotoxicity on bone involved exportin 1 accumulation, phosphorylation of JNK, induction of DNA damage and pro-apoptosis, which was induced by activation of caspase-dependent pathways.
研究领域:
毒理学
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细胞生物学
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环境科学
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产品关联
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2011
·
IF 2.925
Yonghua Xie,Rui Zhao,Ying Tan,Xin Zhang,Feng Liu,Yuyang Jiang,Chunyan Tan
We have developed conjugated polyelectrolyte-based fluorescence turn-on assays for caspase 3 and 8. These assays are composed of a cationic polyphenylene ethynylene polymer PPE4+ and p-nitroaniline modified caspase peptide substrate. The fluorescence of the assay is initially turned-off because of the efficient quenching of the polymer by p-nitroaniline moiety on anionic peptide substrates. A turn-on effect is observed due to the cleavage of the peptide by the enzyme and formation of the neutral p-nitroaniline unit which has no quenching on the polymer. We validated this assay design and obtained kinetic parameters of caspase 3 and caspase 8. These assays demonstrated good sensitivity as in pmol/L (0.1 units/mL) for caspase 3 and nmol/L (0.2 units/mL) for caspase 8. This method also showed high specificity by using caspase 3 assay as a model system and the results demonstrated that other proteases including caspase 8, papain, pepsin, and trypsin did not show observable fluorescence turn-on effect. The dose–response curve of a caspase inhibitor Z-VAD-FMK was evaluated by caspase 3 assay, by which the IC50 value was determined to be 0.73 μM and was in a good agreement with the literature reported value at 0.62 μM. This design could be applied into the in vitro screening of small molecular inhibitors for drug discovery.
研究领域:
生物化学
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分子生物学
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分析化学
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药物发现
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
·
2017
·
IF 2.759
Yanyan Zhu,Yameng Jiang,Lei Shi,Linying Du,Xiaodong Xu,Enxia Wang,Yong Sun,Xin Guo,Boyang Zou,Huaxin Wang,Changyuan Wang,Lidan Sun,Yuhong Zhen
7- O -Geranylquercetin (GQ) is a novel O -alkylated derivate of quercetin . In this study, we evaluated its apoptosis induction effects in human gastric cancer cell lines SGC-7901 and MGC-803 and explored the potential molecular mechanisms. The results demonstrated that GQ lowered viability of SGC-7901 and MGC-803 cells in a dose- and time-dependent manner without apparent cytotoxicity to human gastric epithelial cell line GES-1. GQ could induce apoptosis in SGC-7901 and MGC-803cells, and arrest the gastric cancer cells at G2/M phase. Mechanism study showed that GQ triggered generation of reactive oxygen species (ROS), then activated p38 and JNK signaling pathways , subsequently led to mitochondrial impairment by regulating the expression of Bcl-2, Bcl-xl and Bax, and finally promoted the release of cytochrome c and the activation of caspases to induce apoptosis. In addition, Z-VAD-FMK (caspase inhibitor) could reverse GQ-induced apoptosis. SB203580 (p38 inhibitor) and SP600125 (JNK inhibitor) could rescue GQ-induced cell death and attenuate mitochondrial signal pathway activation. Furthermore, NAC (ROS inhibitor) could rescue GQ-induced cell death, reduce ROS generation, decrease the phosphorylation of p38 and JNK, and then attenuate the activation of mitochondrial signal pathway. Taken together, GQ induces caspase-dependent apoptosis in gastric cancer cells through activating ROS-MAPK mediated mitochondrial signal pathway. This study highlights the potential use of GQ as a gastric cancer therapeutic agent.
研究领域:
肿瘤学
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药理学
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细胞生物学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
FREE RADICAL BIOLOGY AND MEDICINE
·
2025
·
IF 8.2
Liyun Zheng,Zhongwei Zhao,Li Chen,Wenjing Yang,Giorgio Ercolani,Pan Qin,Bin Lin,Mengzhu Han,Qiaoyou Weng,Yeyu Zhang,Bin Wu,Minjiang Chen,Zouying Yao,Shiji Fang,Jiansong Ji
Astragalin (ASG), a natural flavonoid glycoside, is known for its multiple pharmacological effects. In this study, we explored the antitumor effects of ASG and its underlying mechanism. Specifically, the growth inhibitory effects of ASG were assessed. Apoptosis rate, reactive oxygen species (ROS) accumulation, mitochondrial damage, and the activation of the endoplasmic reticulum stress induced by ASG were assessed. The potential target of ASG was identified and validated. The effects of ASG on immunogenic cell death (ICD) were determined. Furthermore, ASG’s growth inhibition was validated in vivo , and its potential synergistic effects with anti-PD-L1 antibody were examined. Our findings demonstrate that ASG effectively inhibits growth in liver cancer cell lines. ASG treatment induces apoptosis by promoting mitochondrial membrane potential disruption and ROS accumulation. Additionally, ASG directly bounds to quinone oxidoreductase 2 (NQO2), leading to a reduction in NQO2 protein levels and subsequent upregulation of key ER stress markers, including p-PERK, p-eIF2α, GRP78, and CHOP. Moreover, ASG induces hallmark features of ICD, including calreticulin exposure, nuclear high mobility group box 1 reduction, and adenosine triphosphate release. ASG-treated liver cancer cells effectively enhance dendritic cell maturation in a coculture system. In vivo , the tumor growth is synergistically inhibited by ASG combined with anti-PD-L1 antibody in Hepa1-6 tumor-bearing mice. This synergy is associated with increased dendritic cell maturation, enhanced CD8 + T cell infiltration, and a reduction in regulatory T cells. In conclusion, ASG can be served as a potential anticancer agent for liver cancer and enhance the antitumor efficacy of immunotherapy by activating the ROS-mediated endoplasmic reticulum stress and ICD pathways.
研究领域:
肿瘤学
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药理学
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生物化学
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免疫学
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分子生物学
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细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
International Journal of Biological Sciences
·
2025
·Vol. 21
·期 11
·4872-4894
·
IF 10
Chen Yuxing,Tao Yong,Huang Qiu,Xu Jingtao,Wang Zhenxin,Zhang Ye,Fu Guangxu,Tan Fuqiang,Feng Keyi,Ou Yunsheng
Osteosarcoma remains a challenging malignancy with poor prognosis, particularly in metastatic cases. This study investigates the therapeutic potential and molecular mechanisms of the Hinokitiol-iron complex (Fe(hino)3) against osteosarcoma. Fe(hino)3 induced dose-dependent cell death in osteosarcoma cell lines (HOS, 143b, and K7M2) through multiple pathways. At moderate doses, Fe(hino)3 triggered ferroptosis by disrupting mitochondrial function, enhancing ROS generation and lipid peroxidation, downregulating GSS and GPX4, and upregulating HO1 and Ferritin expression. At higher doses, Fe(hino)3 activated the NLRC4/Caspase-1/GSDMD pathway, leading to pyroptosis and the release of inflammatory factors. Mechanistically, Fe(hino)3 acted as a dual-mode cell death inducer through iron overload-mediated ferroptosis and NLRC4-dependent pyroptosis while modifying the immunosuppressive tumor microenvironment. In actual clinical application, Fe(hino)3 might be used as an alternative to chemotherapy or other targeted therapies for advanced osteosarcoma at a relatively low dose to improve biosafety and reduce side effects. However, when considering it in combination with immunotherapy for advanced osteosarcoma, a relatively safe high dose is more appropriate due to the pyroptosis-mediated inflammatory response but it still needs to consider the biosafety of combination therapy. These findings provide new insights into the development of Fe(hino)3 dose-dependent therapeutic strategies for advanced osteosarcoma treatment.
研究领域:
肿瘤学
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药理学
·
细胞生物学
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免疫学
·
生物化学
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分子生物学
·
癌症研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Cell Metabolism
·
2025
·
IF 30.9
Yu-Zhang Wang,Wei-Hai Chen,Zi-Yi Han,Shi-Man Zhang,Ping Ji,Cheng Zhang,Jun-Long Liang,Xian-Zheng Zhang
Bacteria-based metabolic therapy has been acknowledged as a promising strategy for tumor treatment. However, the insufficient efficiency of wild-type bacteria severely restricts their therapeutic efficacy. Here, we elaborately develop an ʟ-cyst(e)ine-addicted bacteria-nanodrug biohybrid for metabolic therapy through a dual-selection directed evolution strategy. Our evolved strain exhibits a 36-fold increase in ʟ-cystine uptake and a 23-fold improvement in total activity of cysteine desulfhydrases compared with the wild-type strain. By conjugating with DMXAA-loaded liposomes, the engineered bacteria-nanodrug biohybrid not only prevents the influx of nutrients into the tumor by blocking neovasculature but also achieves efficient and durable CySS catabolism locally. The unavailable of Cys species disrupts redox homeostasis and strikingly increases intracellular ROS level, achieving favorable therapeutic outcomes in multiple tumor models. Our study not only highlights the promise of directed evolution strategy in enhancing the stability and efficiency of bacteria-based living biocatalyst but also provides new opportunities for antitumor metabolic therapy.
研究领域:
生物医学工程
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肿瘤学
·
合成生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2025
·
IF 13.2
Shichen Zhang,Lei Guo,Yixin Tang,Yixing Wang,Heshi Liu,Chang Liu,Xiuzhang Yan,Congcong Duan,Huanyan Dai,Bing Han,Caina Xu
Conventional treatments for head and neck squamous cell carcinoma (HNSCC) cause severe side effects and functional impairment. Chemodynamic therapy (CDT), a reactive oxidative stress (ROS)-based therapy, exploits H 2 O 2 in the tumor micro-environment to produce large amounts of cytotoxic ROS to destroy cancer cells. Monotonic CDT efficacy is severely constrained by slow Fenton kinetics and insufficient intra-tumoral H 2 O 2 content. In order to overcome these barriers, a multifunctional self-reinforced nanoreactor, MAGFH, was developed for the eradication of HNSCC. This nano-system employed an Fe-based metal-organic framework, MIL-100, to deliver artesunate (ART) for the exertion of H 2 O 2 -independent CDT. A gallic acid (GA)-Fe 3+ metal-polyphenol network (MPN) coating was introduced to enhance the Fenton reaction by accelerating iron redox cycling while conferring photothermal therapy (PTT) effect. Hyaluronic acid (HA) was covered on the outermost layer to enable the tumor targeting. Following endocytosis into cancer cells, the released Fe 3+ was reduced into Fe 2+ by the consumption of glutathione (GSH), thereby catalyzing the production of hydroxyl radicals ( OH) via the Fenton reaction. The GA-Fe network functioned as an amplifier for the iron redox cycle. Concurrently, the activation of ART by Fe 2+ led to the generation of highly cytotoxic superoxide anions ( O 2 − ) and C-centered free radicals ( C). The near infrared laser (808 nm) irradiation synergistically enhanced ROS generation and GSH depletion, resulting in the high accumulation of ROS and the dysregulation of redox homeostasis, subsequently inducing cell apoptosis and ferroptosis. In addition, the introduction of the GA-Fe MPN conferred both photoacoustic imaging (PAI) and T 1 magnetic resonance imaging (MRI) capabilities, enabling the integration of therapeutics and diagnosis. Collectively, this work established a PAI/MRI-guided nanoplatform for self-amplifying CDT/PTT against HNSCC via dual induction of apoptosis-ferroptosis.
研究领域:
肿瘤学
·
纳米医学
·
生物材料
·
分子生物学
·
转化医学
✓ 已验证
产品关联
DOI
高影响因子
ACS Nano
·
2025
·
IF 16
Lei Shu,Peili Luo,Chuanyu Ren,Ziwei Lai,Xuejuan Zhang,Chuanbin Wu,Xin Pan,Zhengwei Huang
The application of ferroptosis inducer FIN56 to decrease antioxidant levels in lung adenocarcinoma (LUAD) is a promising tumor eradication technique. However, several obstacles reduce the efficacy of ferroptosis therapy including insufficient oxidative stress from monotherapy and restricted drug retention in tumor tissues. To address these challenges, we developed an inhalable hybrid liposome in which FIN56 and piperlongumine (PPL) are coloaded into silk fibroin nanoparticles to overcome the limitation of the poor therapeutic effect of single-drug ferroptosis. Subsequently, lipids containing hyaluronic acid were added to the hybrid liposome to enable it to specifically target the overexpressed CD44 receptors on the surface of LUAD cells and solve the problem of insufficient active targeting of silk fibroin nanoparticles. Compared to conventional intravenous formulations, the as-synthesized formulation FP@SLCDH increased pulmonary accumulation by 13.6-fold and lipid peroxidation products by 2.14-fold. FIN56 prompts tumor-specific ferroptosis by inhibiting glutathione peroxidase 4 (GPX4) and glutathione (GSH), whereas PPL further augments this effect by increasing intracellular reactive oxygen species levels and facilitating ferritin degradation to release Fe ions from ferritin. The role of autophagy in promoting ferroptosis and therapeutic efficacy was validated in an orthotopic LUAD tumor model. The real-time tracking of targeted retention of FP@SLCDH in LUAD cells is also possible using an aggregation-induced emission probe, which is facilitated as a “double-lock logic gate fluorescence probe”. This probe emits fluorescence signals only after entering cancer cells and arriving at the mitochondria. To summarize, our proposed hybrid liposomes represent a significantly enhanced pulmonary strategy for LUAD therapy.
研究领域:
药学
·
纳米技术
·
肿瘤学
·
生物化学
·
药物递送系统
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF COLLOID AND INTERFACE SCIENCE
·
2024
·
IF 9.4
Fang Liu,Yaru Li,Yao Li,Zheng Wang,Xin Li,Yancheng Liu,Yanjun Zhao
The clinical translation of the anticancer drug β -lapachone (LAP) has been limited by the narrow therapeutic window. Stimuli-responsive anticancer drug delivery systems have gained tremendous attention in recent years to alleviate adverse effects and enhance therapeutic efficacy. Here, we report a dual pH- and enzyme-responsive nanocarrier to address the above issue of LAP. In detail, the epigallocatechin gallate (EGCG) and ferric ions were employed to engineer nanoscale ferric ion-polyphenol complexes where LAP was physically encapsulated therein. The coordination bond between Fe 3+ and the catechol moiety of EGCG was sensitive to the low pH, enabling the triggered cargo release in the acidic endosomes/lysosomes. Afterward, the released LAP was activated by the overexpressed NAD(P)H: quinone oxidoreductase 1 (NQO1) and ferroptosis suppressor protein 1 (FSP1) in the tumor cells, followed by the generation of reactive oxygen species (ROS), and the induction of oxidative stress and apoptotic cell death. Meanwhile, EGCG could upregulate gasdermin E (GSDME), and ferric ions were involved in the Fenton reaction. Hence, EGCG and ferric ions could sensitize the toxicity of LAP through the induction of multiple cell death pathways ( e.g ., pyroptosis, ferroptosis, apoptosis, and necroptosis). The current work enlarged the LAP’s therapeutic window via controlled cargo release and vehicle sensitization.
研究领域:
药学
·
纳米技术
·
癌症治疗
·
药物递送系统
·
细胞死亡机制
✓ 已验证
产品关联
DOI
PubMed
高影响因子
FREE RADICAL BIOLOGY AND MEDICINE
·
2024
·
IF 7.1
Deshan Yao,Liuxiang Bao,Sichuan Wang,Meng Tan,Yuanyuan Xu,Tianxu Wu,Zhengang Zhang,Kaizheng Gong
Ischemia-reperfusion (I/R) injury, a multifaceted pathological process, occurs when the prolongation of reperfusion duration triggers ferroptosis-mediated myocardial damage. Isoliquiritigenin (ISL), a single flavonoid from licorice, exhibits a wide range of pharmacological impacts, but its function in ferroptosis caused by myocardial I/R injury remains unclear. This study delved into the protective effect of ISL on myocardial I/R injury-induced ferroptosis and its mechanism. Neonatal mouse cardiomyocytes (NMCM) underwent hypoxia/reoxygenation (H/R) to simulate the pathological process of myocardial I/R. ISL significantly attenuated H/R-triggered production of reactive oxygen species in NMCM, reduced the expression of malondialdehyde and the activity of lactate dehydrogenase, enhanced superoxide dismutase and catalase activity, and increased the expression of nuclear factor E2-related factor 2 (Nrf2) and its downstream heme oxygenase 1 (HO-1), thereby mitigating oxidative stress damage. CCK8 experiment revealed that the ferroptosis inhibitor Ferrostatin-1 significantly improved myocardial cell viability after 24 h of reoxygenation, and ISL treatment showed a similar effect. ISL reduced intracellular free iron accumulation, up-regulated glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11) expression, and inhibited lipid peroxidation accumulation, thereby alleviating ferroptosis. The Nrf2-specific inhibitor ML385 counteracted ISL's defensive role against H/R-triggered oxidative stress damage and ferroptosis. In vivo experiments further confirmed that by regulating the translocation of Nrf2 into the nucleus, ISL treatment increased the levels of HO-1, GPX4, and SLC7A11, inhibited the expression of ACSL4, Drp1 to exert the antioxidant role, alleviated mitochondrial damage, and ferroptosis, ultimately reducing myocardial infarction area and injury induced by I/R. ML385 nearly abolished ISL's protective impact on the I/R model by inhibiting Nrf2 function. In summary, ISL is capable of mitigating oxidative stress, mitochondrial damage, and cardiomyocyte ferroptosis caused by I/R, thereby reducing myocardial injury. A key mechanism includes triggering the Nrf2/HO-1/SLC7A11/GPX4 pathway to prevent oxidative stress damage and cardiomyocyte ferroptosis caused by I/R.
研究领域:
药理学
·
心脏病学
·
分子生物学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PEDIATRIC HEMATOLOGY AND ONCOLOGY
·
2020
·
IF 1.232
Ju Yang,Ping Liu,Dan Ma,Peng Zhao,Yan Zhang,Yinghao Lu,Yanju Li,Yi Huang,Ying Chen,Jishi Wang
Development of chemo‑resistance is ultimately responsible for treatment failure and relapse in B-cell acute lymphoblastic leukemia (B-ALL). However, the mechanism underlying glucocorticoid (GC) resistance remains unclear. This study was performed to identify GC resistance-related genes using the transcriptome chip from the GEO database, and preliminarily analyze drug resistance mechanism in B-ALL. Here, we found that ANXA5 expression was upregulated in B-ALL cells and high-level ANXA5 was associated with dexamethasone (DEX) resistance. Then, small interfering RNA (siRNA) was designed to silence ANXA5 expression in the B-ALL cell lines, and the apoptotic rate of cells treated with DEX was detected by flow cytometry. As a result, cell apoptosis was dramatically promoted in B-ALL cells following silencing of ANXA5 and DEX administration versus that in ANXA5-silenced alone or DEX-treated alone cells. It was further found that down-regulation of ANXA5 in B-ALL cells significantly increased the relative amount of cleaved Caspase 3 and Caspase 9 induced by DEX. Collectively, inhibition of ANXA5 gene expression may represent a novel method to restore the sensitivity of treatment-resistant B-ALL tumors to GC-induced cell death, which is of important clinical significance to overcome drug resistance associated with B-ALL.
研究领域:
肿瘤学
·
血液学
·
分子生物学
·
药理学
✓ 已验证
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）