ACS Nano
·
2024
·
IF 15.8
Zhenhu Guo,Xiaohan Gao,Jingsong Lu,Ying Li,Zeping Jin,Abdul Fahad,Neema Ufurahi Pambe,Hirotaka Ejima,Xiaodan Sun,Xiumei Wang,Wensheng Xie,Guifeng Zhang,Lingyun Zhao
Regarded as one of the hallmarks of tumorigenesis and tumor progression, the evasion of apoptotic cell death would also account for treatment resistance or failure during cancer therapy. In this study, a Ca2+/Cu2+ dual-ion “nano trap” to effectively avoid cell apoptosis evasion by synchronously inducing paraptosis together with apoptosis was successfully designed and fabricated for breast cancer treatment. In brief, disulfiram (DSF)-loaded amorphous calcium carbonate nanoparticles (NPs) were fabricated via a gas diffusion method. Further on, the Cu2+-tannic acid metal phenolic network was embedded onto the NPs surface by self-assembling, followed by mDSPE-PEG/lipid capping to form the DSF-loaded Ca2+/Cu2+ dual-ions “nano trap”. The as-prepared nanotrap would undergo acid-triggered biodegradation upon being endocytosed by tumor cells within the lysosome for Ca2+, Cu2+, and DSF releasing simultaneously. The released Ca2+ could cause mitochondrial calcium overload and lead to hydrogen peroxide (H2O2) overexpression. Meanwhile, Ca2+/reactive oxygen species-associated mitochondrial dysfunction would lead to paraptosis cell death. Most importantly, cell paraptosis could be further induced and strengthened by the toxic dithiocarbamate (DTC)–copper complexes formed by the Cu2+ combined with the DTC, the metabolic products of DSF. Additionally, the released Cu2+ will be reduced by intracellular glutathione to generate Cu+, which can catalyze the H2O2 to produce a toxic hydroxyl radical by a Cu+-mediated Fenton-like reaction for inducing cell apoptosis. Both in vitro cellular assays and in vivo antitumor evaluations confirmed the cancer therapeutic efficiency by the dual ion nano trap. This study can broaden the cognition scope of dual-ion-mediated paraptosis together with apoptosis via a multifunctional nanoplatform.
研究领域:
癌症生物学
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纳米技术
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药学
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细胞生物学
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治疗学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Pharmaceutical Analysis
·
2024
·
IF 6.1
Huanhuan Xue,Peijie Li,Jing Guo,Tinggui Chen,Shifei Li,Liwei Zhang
Ulcerative colitis (UC) is an idiopathic, relapsing, and etiologically complicated chronic inflammatory bowel disease. Despite substantial progress in the management of UC, the outcomes of mucosal barrier repair are unsatisfactory. In this study, phillygenin (PHI) treatment alleviated the symptoms of chronic colitis in mice, including body weight loss, severe disease activity index scores, colon shortening, splenomegaly, oxidative stress, and inflammatory response. In particular, PHI treatment ameliorated the tight junction proteins (TJs) reduction, fibrosis, apoptosis, and intestinal stem cell activity, indicating that PHI exerted beneficial effects on the intestinal mucosal barrier in mice with chronic colitis. In the NCM460 cells damage model, dextran sulfate sodium triggered the sequential induction of TJs reduction, fibrosis, and apoptosis. Takeda G protein-coupled receptor-5 (TGR5) dysfunction mediated NCM460 cell injury. Moreover, PHI treatment enhanced TJs and suppressed fibrosis and apoptosis to maintain NCM460 cell function, depending on TGR5 activation. PHI promoted TGR5 activation and elevated intracellular cyclic adenosine monophosphate levels in HEK 293T cells transfected with TGR5 expression plasmids. Cellular thermal shift assay and molecular docking studies confirmed that PHI directly binds to TGR5, indicating that PHI is an agonist of TGR5. The process of PERK-eIF2α pathway-mediated endoplasmic reticulum Ca 2+ release was involved in NCM460 cell injury as well, which was associated with TGR5 dysfunction. When NCM460 cells were pretreated with PHI, the PERK-eIF2α pathway and elevated Ca 2+ levels were blocked. In conclusion, our study demonstrated a novel mechanism that PHI inhibited the PERK-eIF2α-Ca 2+ pathway through TGR5 activation to against DSS-induced TJs reduction, fibrosis, and apoptosis.
研究领域:
胃肠病学
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药理学
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细胞生物学
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炎症性肠病
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE
·
2017
·Vol. 41
·期 2
·1138-1146
·
IF 2.341
Xiu‑Yin Shen,Tao Luo,Sheng Li,Ou‑Yang Ting,Feng He,Jie Xu,Hua‑Qiao Wang
Alzheimer's disease (AD) is a common neurodegenerative disorder characterized by aberrant tau protein hyperphosphorylation, which eventually leads to the formation of neurofibrillary tangles. Hyperphosphorylated tau protein is considered as a vital factor in the development of AD and is highly associated with cognitive impairment. Therefore, it is recognized to be a potential therapeutic target. Quercetin (QUE) is a naturally occurring flavonoid compound. In the present study, the inhibitory effect of QUE on okadaic acid (OA)-induced tau protein hyperphosphorylation in HT22 cells was explored. Western blotting results indicated that QUE significantly attenuated OA‑induced tau protein hyperphosphorylation at the Ser396, Ser199, Thr231 and Thr205 sites. Further experiments demonstrated that QUE inhibited the activity of cyclin‑dependent kinase 5 (CDK5), a key enzyme in the regulation of tau protein, and blocked the Ca2+‑calpain‑p25‑CDK5 signaling pathway. These observations indicate the ability of QUE to decrease tau protein hyperphosphorylation and thereby attenuate the associated neuropathology. In conclusion, these results support the potential of QUE as a therapeutic agent for AD and other neurodegenerative tauopathies.
研究领域:
神经科学
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药理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
POLYMER
·
2022
·
IF 4.432
Yifan Guo,Lianwei Li,Jinxian Yang
In this work, by combing static light scattering (SLS), dynamic light scattering (DLS) and atomic force microscopy (AFM), we have explored how the topological effect influences the intrachain and interchain complexation of polyelectrolytes and divalent ions. First, by a combination of atom transfer radical polymerization (ATRP) and click reaction, two polyacrylic acid (PAA) bottlebrush samples, i.e. PPA 1210 - g -PAA 20 and PPA 2570 - g -PAA 20 , with nearly identical graft density and PAA sidechain length but different backbone lengths, have been prepared. Second, for comparison, a linear sample l -PAA 7710 , with a similar chain size compared to PPA 1210 - g -PAA 20 , has been also prepared. Third, we have systematically investigated the intrachain and interchain complexation between NaPAA topological chains and divalent calcium ions . It is revealed that the intrachain interaction for linear l -PPA 7710 is much stronger than that for bottlebrush samples due to the flexibility feature, while the interchain interaction displays the opposite trend. It is also found that the addition of Ca 2+ results in the change of conformation from loose random coils to dense sphere for l -PAA 7710 , while the overall conformations of PPA 1210 - g -PAA 20 and PPA 2570 - g -PAA 20 almost remain unchange, which can be ascribed to the unique branched structure and enhanced structural rigidity .
研究领域:
高分子化学
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胶体科学
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材料科学
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DOI
高影响因子
ACTA PHARMACOLOGICA SINICA
·
2021
·Vol. 42
·期 11
·1860-1874
·
IF 6.15
Liu Zhen-zhen,Liu Xiao-ning,Fan Rui-cheng,Jia Yu-ping,Zhang Qing-ke,Gao Xin-qing,Wang Yu-qing,Yang Meng-qing,Ji Li-zhen,Zhou Yong-qing,Li Hong-li,Li Ping,Tang Bo
Glioblastoma multiforme (GBM) is the most common and malignant type of primary brain tumor, and 95% of patients die within 2 years after diagnosis. In this study, aiming to overcome chemoresistance to the first-line drug temozolomide (TMZ), we carried out research to discover a novel alternative drug targeting the oncogenic NFAT signaling pathway for GBM therapy. To accelerate the drug’s clinical application, we took advantage of a drug repurposing strategy to identify novel NFAT signaling pathway inhibitors. After screening a set of 93 FDA-approved drugs with simple structures, we identified pimavanserin tartrate (PIM), an effective 5-HT 2A receptor inverse agonist used for the treatment of Parkinson’s disease-associated psychiatric symptoms, as having the most potent inhibitory activity against the NFAT signaling pathway. Further study revealed that PIM suppressed STIM1 puncta formation to inhibit store-operated calcium entry (SOCE) and subsequent NFAT activity. In cellula, PIM significantly suppressed the proliferation, migration, division, and motility of U87 glioblastoma cells, induced G1/S phase arrest and promoted apoptosis. In vivo, the growth of subcutaneous and orthotopic glioblastoma xenografts was markedly suppressed by PIM. Unbiased omics studies revealed the novel molecular mechanism of PIM’s antitumor activity, which included suppression of the ATR/CDK2/E2F axis, MYC, and AuroraA/B signaling. Interestingly, the genes upregulated by PIM were largely associated with cholesterol homeostasis, which may contribute to PIM’s side effects and should be given more attention. Our study identified store-operated calcium channels as novel targets of PIM and was the first to systematically highlight the therapeutic potential of pimavanserin tartrate for glioblastoma.
研究领域:
肿瘤学
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药理学
·
细胞生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY
·
2017
·
IF 3.505
Jun Tian,Zhaoqun Lu,Yanzhen Wang,Man Zhang,Xueyan Wang,Xudong Tang,Xue Peng,Hong Zeng
The antifungal activity of Nerol (NEL) against Candida albicans , a pathogenic fungus, has a minimum inhibitory concentration (MIC) of 4.4 mM that causes noteworthy candidacidal activity through an apoptosis-like mechanism. Calcium (Ca 2+ ) levels and reactive oxygen species (ROS) production, which are the major causes of apoptosis, were determined in C. albicans cells treated with NEL and were found to increase, which related to mitochondrial dysfunction and disruption. A series of characteristic changes of apoptosis caused by NEL, including mitochondrial membrane depolarization, cytochrome c (cyt c) release, and metacaspase activation were examined using a flow cytometer and Western blot . The results showed that an increase in intracellular Ca 2+ and ROS led to dramatically decreased mitochondrial membrane potential (MMP); cyt c was also released from the mitochondria to the cytosol. Other early apoptotic features were also observed with the metacaspase activation. Finally, the morphological changes of the cells were observed, including phosphatidylserine (PS) externalization, nuclear condensation, and DNA fragmentation through Annexin V-FITC and PI double staining, TUNEL assay , and DAPI staining. The results supported the hypothesis that NEL was involved in the apoptosis of C. albicans cells not only at the early stages, but also at the late stages. In summary, NEL can trigger mitochondrial dysfunction and disruption via elevation of Ca 2+ and ROS leading to apoptosis in C. albicans . This research on the mechanism of cell death triggered by NEL against C. albicans has important significance for providing a novel treatment of C. albicans infections.
研究领域:
微生物学
·
药理学
·
细胞生物学
✓ 已验证
DOI
PubMed
高影响因子
WATER RESEARCH
·
2021
·
IF 11.236
Qianyuan Yang,Longqian Xu,Qunbiao He,Deli Wu
Electrochemical precipitation is a promising technique for hardness abatement without the addition of external ions. However, the scale layer on cathode deteriorated the removal efficiency and limited the practical application. Herein, a fenced cathode structure was designed to prevent cathodic precipitation. The cathode was fenced by a crystallization-inducing material for separating the OH − production and crystallization processes. Precipitation on the cathode was confirmed to shift to the crystallization-inducing material, and the clean fenced cathode provided efficient long-term OH − production. At a current density of 40 A/m 2 , the Ca 2+ or Mg 2+ removal efficiency increased by 12.8% or 46.1%, respectively, compared to those of a traditional cathode. Thermodynamic equilibrium in synthetic water and mine water, mass transfer and the location of precipitation were analyzed to elucidate the electrochemical precipitation process. The enhanced mechanism was ascribed to the crystallization-inducing material, which remarkably promoted the crystallization process, and hindered OH − migration, thereby increased the pH of alkaline microenvironment. Notably, a recovery design was proposed to recover pure calcite and brucite from alkalinity-free wastewater. The design reveals a promising strategy for enhancing the crystallization process and reducing cathodic scale, also initiating a new research direction toward hardness removal.
研究领域:
环境工程
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水处理
·
电化学
·
材料科学
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产品关联
DOI
PubMed
高影响因子
CHEMISTRY-A EUROPEAN JOURNAL
·
2018
·Vol. 24
·期 24
·6458-6463
·
IF 5.16
Xinyue Song,Zihong Yue,Jiayu Zhang,Yanxialei Jiang,Zonghua Wang,Shusheng Zhang
Graphical By taking advantage of a lack of spectral overlapping and single NIR excitation wavelengths, sandwich-structured multicolor upconversion nanoparticles (SWUCNPs) were used to establish a dual luminescence resonance energy transfer (LRET) nanoprobe with special recognition ligands. The quenched fluorescence would be recovered after the detachment and/or absorbance change of the attached ligands (see scheme) to investigate the interplaying roles of [Ca 2+ ] i and pH i . Intracellular [Ca 2+ ] i and pH i have a close relationship, and their abnormal levels can result in cell dysfunction and accompanying diseases. Thus, simultaneous determination of [Ca 2+ ] i and pH i can more accurately investigate complex biological processes in an integrated platform. Herein, multicolor upconversion nanoparticles (UCNPs) were prepared with the advantages of no spectral overlapping, single NIR excitation wavelengths, and greater tissue penetration depth. The upconversion nanoprobes were easily prepared by the attachment of two fluorescent dyes, Fluo-4 and SNARF-4F. Based on the dual luminescence resonance energy transfer (LRET) process, the blue and green fluorescence of the UCNPs were specially quenched and selectively recovered after the detachment and/or absorbance change of the attached fluorescent dyes, enabling dual detection. Importantly, the developed nanoprobe could successfully be applied for the detection of [Ca 2+ ] i and pH i change in adenosine triphosphate (ATP) and ethylene glycol tetraacetic acid (EGTA) stimulation in living cells.
研究领域:
生物化学
·
分子生物学
·
纳米技术
·
细胞生物学
·
分析化学
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产品关联
DOI
PubMed
高影响因子
SEPARATION AND PURIFICATION TECHNOLOGY
·
2021
·
IF 7.312
Haoyu Yue,Zhijie Shang,Pan Xu,Dongyue Feng,Xinxue Li
A novel EDTA functionalized chitooligosaccharide/sodium alginate/Ca 2+ physical double network hydrogel (ECSDNH) was prepared by using of high-salinity oilfield produced water. The formation and structure of ECSDNH were characterized by FT-IR and SEM. Various factors, including EDTA functionalized chitooligosaccharide content, pH of solution, initial concentration of heavy metal ions, temperature and contact time, were thoroughly investigated to explore their effect on adsorption capacity of ECSDNH. The obtained results showed that ECSDNH had higher adsorption capacity for Zn 2+ , Ni 2+ and Mn 2+ . The maximum adsorption capacities of Zn 2+ , Ni 2+ and Mn 2+ were 160.19 mg/g, 72.67 mg/g and 52.43 mg/g at 298 K, respectively. The pseudo-second-order kinetic model and Langmuir isotherm model fit the experimental data fairly well. The thermodynamic parameters of the adsorption, Δ H ° , Δ S ° , and Δ G ° , were also calculated. In addition, the ECSDNH still had higher removal efficiency for three metal ions after three adsorption-regeneration cycles, indicating its potential application for removing heavy metal ions from wastewater.
研究领域:
环境科学
·
材料科学
·
化学工程
✓ 已验证
产品关联
DOI
高影响因子
Frontiers in Physiology
·
2020
·
IF 3.367
Wang Zhe,Zhang Jie,Ma Xiu-Feng,Chang Hui,Peng Xin,Xu Shen-Hui,Wang Hui-Ping,Gao Yun-Fang
To explore the possible mechanism of the sarcoplasmic reticulum (SR) in the maintenance of cytoplasmic calcium (Ca2+) homeostasis, we studied changes in cytoplasmic Ca2+, SR Ca2+, and Ca2+-handling proteins of slow-twitch muscle (soleus, SOL), fast-twitch muscle (extensor digitorum longus, EDL), and mixed muscle (gastrocnemius, GAS) in different stages in hibernating Daurian ground squirrels (Spermophilus dauricus). Results showed that the level of cytoplasmic Ca2+ increased and SR Ca2+ decreased in skeletal muscle fiber during late torpor (LT) and inter-bout arousal (IBA), but both returned to summer active levels when the animals aroused from and re-entered into torpor (early torpor, ET), suggesting that intracellular Ca2+ is dynamic during hibernation. The protein expression of ryanodine receptor1 (RyR1) increased in the LT, IBA, and ET groups, whereas the co-localization of calsequestrin1 (CSQ1) and RyR1 in GAS muscle decreased in the LT and ET groups, which may increase the possibility of RyR1 channel-mediated Ca2+ release. Furthermore, calcium pump (SR Ca2+-ATPase 1, SERCA1) protein expression increased in the LT, IBA, and ET groups, and the signaling pathway-related factors of SERCA activity [i.e., β-adrenergic receptor2 protein expression (in GAS), phosphorylation levels of phospholamban (in GAS), and calmodulin kinase2 (in SOL)] all increased, suggesting that these factors may be involved in the up-regulation of SERCA1 activity in different groups. The increased protein expression of Ca2+-binding proteins CSQ1 and calmodulin (CaM) indicated that intracellular free Ca2+-binding ability also increased in the LT, IBA, ET, and POST groups. In brief, changes in cytoplasmic and SR Ca2+ concentrations, SR RyR1 and SERCA1 protein expression levels, and major RyR1 and SERCA1 signaling pathway-related factors were unexpectedly active in the torpor stage when metabolic functions were highly inhibited.
研究领域:
生理学
·
分子生物学
·
细胞生物学
·
动物学
✓ 已验证
DOI
PubMed
高影响因子
FISH & SHELLFISH IMMUNOLOGY
·
2018
·
IF 3.185
Wei Shi,Xiaofan Guan,Yu Han,Cheng Guo,Jiahuan Rong,Wenhao Su,Shanjie Zha,Yichen Wang,Guangxu Liu
Exposure to heavy metals such as Cadmium (Cd) may exert detrimental impacts on the immune responses of marine bivalve species. However, the immunotoxicity of Cd on blood clams remains unknown to date. Furthermore, though Cd 2+ is known to compete with calcium (Ca 2+ ) ions for their binding sites in cells and inhibit Ca 2+ influx, whether Cd 2+ weakens the immune responses of marine bivalves through inducing intracellular Ca 2+ disorders still remains unclear. Therefore, the immunotoxicity of Cd 2+ at different waterborne Ca 2+ concentrations on blood clam, Tegillarca granosa , were investigated in the present study. Results obtained demonstrated that the total number, phagocytic activity , and red granulocytes ratio of the haemocytes were all significantly reduced after 10 days exposure of individuals to 25 μg/L Cd 2+ . However, when the waterborne Ca 2+ concentrations were elevated by 10% and 20% (approximately 370 and 410 mg/L, respectively), mitigation effects on the immune responses of individuals were detected. In addition, though the expressions of genes from the Ca 2+ signaling and Ca 2+ -related apoptosis pathways were significantly altered by Cd 2+ exposure, the expression patterns of these genes were similar to that of the control when the waterborne Ca 2+ concentrations were elevated, suggesting a relieving effect of waterborne Ca 2+ on Cd 2+ induced toxicity to haemocytes. The results obtained in the present study revealed that waterborne Cd 2+ may hamper the immune responses of T. granosa through influencing Ca 2+ signaling and Ca 2+ -related apoptosis pathways, which can be partially mitigated by elevating the waterborne Ca 2+ concentrations.
研究领域:
海洋生物学
·
毒理学
·
免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
·
2024
·
IF 12.8
Meiqi Chang,Lu Zhang,Tingting Zhang,Yanqiu Duan,Wei Feng,Shaoling Yang,Yu Chen,Zeyu Wang
The excessive intracellular Ca 2+ can induce oxidative stress, mitochondrial damage and cell apoptosis, which has been extensively explored for tumor therapy. However, the low Ca 2+ accumulation originated from Ca 2+ -based nanosystems substantially weakens the therapeutic effect. Herein, a functional plant polyphenol-appended enzyodynamic nanozyme system CaFe 2 O 4 @BSA-curcumin (abbreviation as CFO-CUR) has been rationally designed and engineered to achieve magnified Ca 2+ accumulation process, deleterious reactive oxygen species (ROS) production, as well as mitochondrial dysfunction through enzyodynamic-Ca 2+ overload synergistic effect. The exogenous Ca 2+ released by CaFe 2 O 4 nanozymes under the weakly acidic tumor microenvironment and Ca 2+ efflux inhibition by curcumin boost mitochondria-dominant antineoplastic efficiency. The presence of Fe components with multivalent characteristic depletes endogenous glutathione and outputs the incremental ROS due to the oxidase-, peroxidase-, glutathione peroxidase-mimicking activities. The ROS burst-triggered regulation of Ca 2+ channels and pumps strengthens the intracellular Ca 2+ accumulation. Especially, the exogenous ultrasound stimulation further amplifies mitochondrial damage. Both in vitro and in vivo experimental results affirm the ultrasound-augmented enzyodynamic-Ca 2+ overload synergetic tumor inhibition outcomes. This study highlights the role of ultrasound coupled with functional nanozyme in the homeostasis imbalance and function disorder of mitochondria for highly efficient tumor treatment.
研究领域:
生物医学工程
·
肿瘤学
✓ 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）