CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY
·
2026
·Vol. 53
·期 9
·e70153
·
IF 2.5
Renchuang Cao,Qingying Meng,Gengyuan Li,Shumei Yuan,Chunmei Li,Xin Zhao,Dongmei Zhang
Heat shock factor 2 (HSF2) and hypoxia‐inducible factor 1α are activated by angiotensin II (ANGII) in cardiomyocytes. The endoplasmic reticulum (ER) stress plays a critical role in cardiac hypertrophy. Moreover, HIF‐1α is known to be regulated by HSF2 in tumour cells. In this study, we hypothesised and clarified whether HSF2 trans‐activated HIF‐1α through initiation of ER stress in hypertrophic cardiomyocytes. Myocardial hypertrophy was induced by the treatment of ANGII. Expression of the gene or protein was assessed by applying RT‐PCR, WB, ICC and IHC. Luciferase and CHIP were applied to detect the transcription of HIF‐1α by HSF2. Both in vitro and in vivo, the expression of HIF‐1α, ER stress markers and HSF2 was increased in ANGII‐treated hypertrophic cardiomyocytes. Blocking ER stress suppressed the expression of HSF2 and HIF‐1α in ANGII‐treated cardiomyocytes. Silencing HSF2 inhibited HIF‐1α, thereby reducing hypertrophy but had no effect on ER stress. Similarly, silencing HIF‐1α reduced hypertrophy without affecting ER stress or HSF2 expression. HSF2 transcriptionally activated HIF‐1α. We concluded that ER stress induced by ANGII activates HSF2, which then trans‐activates HIF‐1α, promoting cardiac hypertrophy.
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FASEB JOURNAL
·
2025
·Vol. 39
·期 22
·e71250
·
IF 4.2
Jian Zhao,Yili Chen,Di Lu,Yuanyuan Zeng,Jianjun Li,Jianjie Zhu,Zhe Lei,Jian-an Huang,Zeyi Liu
Copper ionophores such as elesclomol (ES) have been identified as effective agents capable of inducing cuproptosis, a recently characterized form of regulated cell death driven by copper overload. However, the interplay among copper toxicity, endoplasmic reticulum stress, and metabolic rewiring in lung adenocarcinoma (LUAD) remains poorly understood. Here, we demonstrate that ES selectively transports extracellular copper into human LUAD cells, inducing ER stress and upregulating PCK2, a gluconeogenic enzyme with context-dependent roles in cancer. RNA sequencing and functional assays revealed that PCK2 elevation under copper overload affects glucose metabolism and lipid metabolism to suppress malignant phenotypes. Clinically, high PCK2 expression is correlated with favorable prognosis in LUAD patients, as evidenced by analyses of public datasets. Knocking down PCK2 paradoxically increased proliferation and cell motility, suggesting that PCK2 plays a tumor-suppressive role under copper stress. KRAS G12D transgenic mice-derived lung cancer organoids were used to validate the in vitro therapeutic effects of ES + Cu by regulating PCK2 expression. In vivo experiments revealed that ES inhibited tumor growth and upregulated PCK2. Taking together, our findings reveal that the ES-ER stress-PCK2 axis is a critical mediator of copper-induced metabolic disruption, providing a rationale for targeting cuproptosis pathways in LUAD therapy. Graphical Schematic diagram of copper-induced cell death in LUAD. Elesclomol, as a copper ionophore, promotes copper influx into LUAD cells. This copper influx leads to cellular copper overload. Copper overload induces ER stress in LUAD cells. ER stress upregulates PCK2, which in turn inhibits the tricarboxylic acid (TCA) cycle. Collectively, these pathways orchestrate the cellular responses to excessive copper levels in LUAD cells, highlighting the complex interplay between copper homeostasis, metabolic reprogramming, and cell death mechanisms.
研究领域:
肿瘤学
·
分子生物学
·
癌症代谢
·
细胞死亡机制
·
药理学
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iScience
·
2025
·
IF 4.1
Weiyu Wu,Ren Zhang,Geer Chen,Ziyu Chen,Zicong Lin,Yin Chen,Jiaqi Li,Weilin Liao,Junyi Wang,Xiaoxuan Wang,Junhao Huang,Lijuan Ma,Haijie Yu
Natural compounds are valuable templates for anticancer drug development. Through high-throughput screening of 1,880 natural compounds and structure-activity analysis, we identified sappanchalcone (SC) as a potent agent that induces intracellular calcium elevation and causes G2/M phase arrest in H1975, H1299, and A549 cells. Transcriptomic and protein-protein interaction network analyses revealed multi-target effects of SC, involving oxidative stress, cell cycle dysregulation, and ion homeostasis perturbation. Mechanistically, SC induced ROS accumulation, upregulated the DNA damage, and enhanced the expression of p21 and GADD45α, thereby suppressing the CDK1/Cyclin B1 complex. SC also activated ER stress pathways by phosphorylating IRE1α and PERK. Notably, SC downregulated the mechanosensitive ion channel PIEZO1, and its inhibitor ruthenium red (RR) significantly reversed SC-induced proliferation inhibition and G2/M arrest. This study delineates an antitumor mechanism of SC mediated via a calcium–ER stress–cell cycle axis with translational potential for NSCLC therapy.
研究领域:
肿瘤学
·
药理学
·
分子生物学
·
天然产物化学
·
细胞信号传导
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CURRENT MEDICINAL CHEMISTRY
·
2024
·
IF 3.5
Gan Xin,Xie Jingwen,Dong Zhaojun,Wu Yuna,Zeng Xiaoqing,Yang Zhenzhen,Liu Bo,Zhu Min,Wang Bozhen,Li Wulan,Wang Ledan,Zhang Huajie,Wu Jianzhang,Hu Yue
Background: Pyroptosis, a cell death process triggered by chemotherapy drugs, has
emerged as a highly promising mechanism for combating tumors in recent years. As the lead of
new drugs, natural products play an important role in the discovery of anticancer drugs. Compared
to other natural products, the medicine food homologous natural products (MFHNP) exhibit a superior
safety profile. Among a series of MFHNP molecular skeletons, this study found that only
benzylideneacetophenone (1) could induce cancer cell pyroptosis. However, the anti-cancer activity
of 1 remains to be improved.
Aims: This study aimed to find a pyroptosis inducer with highly effective antitumor activity by
modifying the chalcone structure.
Methods: To examine the effect of the Michael receptor in compound 1 on the induction of pyroptosis,
several analogs were synthesized by modifying the Michael acceptor. Subsequently, the anticancer
activity was tested by MTT assay, and morphological indications of pyroptosis were observed
in human lung carcinoma NCI-H460 and human ovarian cancer CP-70 cell lines. Furthermore,
to improve the activity of the chalcone skeleton, the anticancer group 3,4,5-
trimethoxyphenyl was incorporated into the phenyl ring. Subsequently, compounds 2-22 were designed,
synthesized, and screened in human lung cancer cells (NCI-H460, H1975, and A549). Additionally,
a quantitative structure-activity relationship (QSAR) model was established using the
eXtreme Gradient Boosting (XGBoost) machine learning library to identify the pharmacophore.
Furthermore, both in vitro and in vivo experiments were conducted to investigate the molecular
mechanisms of pyroptosis induced by the active compound.
Results: α, β-unsaturated ketone was the functional group of the chalcone skeleton and played a
pivotal role in inducing cancer cell pyroptosis. QSAR models showed that the regression coefficients
(R2) were 0.992 (A549 cells), 0.990 (NCI-H460 cells), and 0.998 (H1975 cells). Among these
compounds, compound 7 was selected to be the active compound. Moreover, compound 7 was
found to induce pyroptosis in lung cancer cells by upregulating the expression of CHOP by increasing
the ROS level. Furthermore, it effectively suppressed the growth of lung cancer xenograft
tumors.
Conclusion: Compound 7 exhibits antineoplastic activity by regulating the ROS/ER stress/pyroptosis
axis and is a kind of promising pyroptosis inducer.
研究领域:
肿瘤学
·
药理学
·
药物化学
·
分子生物学
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Frontiers in Chemistry
·
2023
·
IF 5.5
Huang Hanchang,Zhong Yanyi,Li Mingchen,Cui Wenda,Yu Tongcheng,Zhao Guomin,Xing Zhongyang,Guo Chuan,Han Kai
In Yb-Er co-doped upconversion (UC) nanomaterials, upconversion luminescence (UCL) can be modulated to generate multiband UCL emissions by changing the concentration of activator Er3+. Nonetheless, the effect of the Er3+ concentrations on the kinetics of these emissions is still unknown. We here study the single β-NaYF4:Yb3+/Er3+ microcrystal (MC) doped with different Er3+ concentrations by nanosecond time-resolved spectroscopy. Interestingly, different Er3+ doping concentrations exhibit different UCL emission bands and UCL response rates. At low Er3+ doping concentrations (1 mol%), multiband emission in β-NaYF4:Yb3+/Er3+ (20/1 mol%) MCs could not be observed and the response rate of UCL was slow (5–10 μs) in β-NaYF4:Yb3+/Er3+. Increasing the Er3+ doping concentration to 10 mol% can shorten the distance between Yb3+ ions and Er3+ ions, which promotes the energy transfer between them. β-NaYF4:Yb3+/Er3+ (20/10 mol%) can achieve obvious multiband UCL and a quick response rate (0.3 µs). However, a further increase in the Er doping concentration (80 mol%) makes MCs limited by the CR process and cannot achieve the four-photon UC process (4F5/2 → 2K13/2 and 2H9/2 → 2D5/2). Therefore, the result shows that changing the Er3+ doping concentration could control the energy flow between the different energy levels in Er3+, which could affect the response time and UCL emission of the Yb/Er doped rare earth materials. Our work can facilitate the development of fast-response optoelectronics, optical-sensing, and display industries.
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OPTICAL MATERIALS
·
2023
·
IF 3.9
Meiting Li,Bo Chen,Chi Zhang,Xuejiao Wang,Fufa Wu,Rongda Zhao
Tartrate (Tar 2− ) was originally employed as a chelating/structure-directing agent for hydrothermal synthesis of CdWO 4 :Yb 3+ ,RE 3+ (RE = Ho and Er) micro/nanocrystallites, followed by calcination at 700 °C for 2 h. It was clearly demonstrated that Tar 2− restricted the exposed ab planes and 3D self-assembly of microplates, resulting in ∼50 nm sized nanoparticles . Up-/down-conversion (UC/DC) photoluminescence were revealed to be strongly size dependent. Under 978 nm pump laser excitation, flower-like assembly was found to exhibit the stronger UC emissions of Ho 3+ and Er 3+ , among which two CdWO 4 :Yb 3+ ,Ho 3+ phosphors generated orange-yellow fluorescence via three-photon processes, while CdWO 4 :Yb 3+ ,Er 3+ microflowers and nanoparticles showed yellowish-green and pale green colors, respectively. Moreover, nanoparticles intensified the dominant green DC emissions of Ho 3+ and Er 3+ by ∼3 and 2 times, implying the pivotal roles of morphology engineering in tunable photoluminescence . This research may provide insights into crystallite/architecture engineering and luminescence optimization for near-infrared response solar cells and solid-state lighting.
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Nanomaterials
·
2023
·Vol. 13
·期 15
·2153
·
IF 5.3
Hao Cui,Daguang Li,Yu Yang,Yuewu Fu,Yanhui Dong,Jing Yin,Weiping Qin,Zhixu Jia,Dan Zhao
Polymer-based waveguide amplifiers are essential components in integrated optical systems, as their gain bandwidths directly determine the operating wavelength of optical circuits. However, development of the wideband gain media has been challenging, making it difficult to fabricate devices with broadband amplification capability. Rare earth ion-doped nanoparticles (NPs) are a key component in the gain media, and their full width at half maximum (FWHM) of the emission peak decides the final gain bandwidth of the gain media. Here, KMnF3: Yb, Er, Ce@KMnF3: Yb NPs with the broad full width at half maximum (FWHM) of the emission peak covering the S+C band was prepared. The NPs were synthesized using a hydrothermal method, and the FWHM of the emission peak of NPs reached 76 nm under the excitation of a 980 nm laser. The introduction of Ce3+ions and a core-shell structure coating greatly enhanced the emission intensity of NPs at C band. Since KMnF3: Yb, Er, Ce@KMnF3: Yb NPs have exceptional broadband luminescence properties at C band, KMnF3: Yb, Er, Ce@KMnF3: Yb NPs can be the potential gain medium in the future polymer-based waveguide amplifiers.Keywords:KMnF3;nanoparticles;active-shell;core-shell;1.5 μm
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JOURNAL OF THE AMERICAN CERAMIC SOCIETY
·
2022
·Vol. 105
·期 12
·7548-7557
·
IF 4.186
Sara Adeeba Ismail,Donglin Han
La 2 Ce 2 O 7 is a fluorite-type oxide, showing almost pure oxide ion conduction in dry oxygen atmosphere. Under wet oxygen atmosphere, protons are introduced into La 2 Ce 2 O 7 through hydration reaction, making the material proton-conducting. However, compared with the oxide ion conductivity, the proton conductivity is negligibly small in La 2 Ce 2 O 7 . Here we report the effect of doping trivalent rare earth cations R 3+ ( R = Y, Ho, Er, Yb, or Tm) and elevating partial pressure of water vapor on the proton concentration and conductivity of La 2 Ce 2 O 7 . The samples show single fluorite phases with the doping level up to 0.2, and the solubilities of these dopants were within 0.2–0.3 in La 2 Ce 2 O 7 . The proton concentration increased by doping, due to higher amount of hydratable oxygen vacancies, and statistical coordination of oxide ions surrounded by R 3+ in addition to La 3+ . The sample with the Y content ( x ) of 0.05 showed the highest conductivity at 600°C among La 2 (Ce 1− x Y x ) 2 O 7− δ ( x = 0–0.3) samples, possibly due to the balance between the improved hydration ability and decreased mobility of protons with the increasing Y doping level. Then, the dopant content was fixed to 0.05, and La 2 (Ce 0.95 R 0.05 ) 2 O 7− δ ( R = Y, Ho, Er, Tm, or Yb) was prepared. It was found that as the water vapor partial pressure increased, the proton concentration and conductivity increased regardless of the dopants. Y-doped La 2 Ce 2 O 7− δ ha the highest proton concentration and conductivity.
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BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
·
2022
·
IF 5.011
Xijie Yu,Xiaoxiao Xu,Wei Dong,Chang Yang,Yao Luo,Ying He,Chenxi Jiang,Yanru Wu,Jiawei Wang
Endoplasmic reticulum (ER) stress is an evolutionarily conserved cellular stress response related to multiple diseases, including temporomandibular joint (TMJ) cartilage-related diseases. Recent studies have indicated that DDIT3/CHOP (a downstream transcription factor of ER stress) is an important effector in mediating ER stress to inhibit chondrogenesis . However, the underlying mechanism by which DDIT3 regulates chondrogenesis remains unclear. In this study, tunicamycin (an ER stress agonist)-induced ER stress inhibited chondrocyte differentiation and matrix synthesis in vitro and led to an osteoarthritis-like phenotype in mouse TMJ cartilage. Meanwhile, DDIT3 expression in chondrocytes was robustly upregulated. Loss-of-function experiments validated the inhibiting effect of DDIT3 on chondrocyte differentiation and matrix synthesis. Mechanistically, the inhibiting effect was attributed to the direct and indirect regulatory effect of DDIT3 on SIRT1 (sirtuin1, silent mating type information regulation protein type 1, a member of NAD+ dependent class III histone deacetylases). On one hand, DDIT3 directly promoted the transcription of SIRT1. On the other hand, DDIT3 indirectly increased the expression of SIRT1 by promoting AMPKα phosphorylation and activation. Furthermore, activation of AMPKα or SIRT1 with the corresponding agonist AICAR or resveratrol in the DDIT3-knockdown cells partially restored the inhibiting effect of DDIT3 on chondrocyte differentiation and matrix synthesis. Collectively, these novel findings indicate that DDIT3 regulates the inhibitory effect of ER stress on chondrocyte differentiation and matrix synthesis partially via the AMPKα-SIRT1 pathway. A thorough understanding of ER stress in regulating chondrocyte homeostasis and its role in the onset of osteoarthritis may be promising to develop therapeutic targets and prevent condyle cartilage destruction.
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Nanoscale Research Letters
·
2022
·Vol. 17
·期 1
·1-8
·
IF 5.418
Yuan Maohui,Yang Zining,Yang Xu,Wang Linxuan,Wang Rui,Lan Sheng,Han Kai,Wang Hongyan,Xu Xiaojun
Controlling the upconversion luminescence (UCL) intensity ratio, especially pumped at 808 nm, is of fundamental importance in biological applications due to the water molecules exhibiting low absorption at this excitation wavelength. In this work, a series of β-NaYbF 4 :Er microrods were synthesized by a simple one-pot hydrothermal method and their intense green (545 nm) and red (650 nm) UCL were experimentally investigated based on the single-particle level under the excitation of 808 nm continuous-wave (CW) laser. Interestingly, the competition between the green and red UCL can be observed in highly Yb 3+ -doped microcrystals as the excitation intensity gradually increases, which leads to the UCL color changing from green to orange. However, the microcrystals doped with low Yb 3+ concentration keep green color which is independent of the excitation power. Further investigations demonstrate that the cross-relaxation (CR) processes between Yb 3+ and Er 3+ ions result in the UCL competition. Graphical Abstract
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CATALYSIS TODAY
·
2022
·
IF 6.562
Yunfei Ma,Wenhui Yue,Zehong Xu,Ziwei Ye,Jinlong Zhang
Composite nanoparticles consisting upconversion nanoparticles (β-NaYF 4 :Yb/Er) and nitrogen doped TiO 2 nanoparticles were constructed via a chemical assembly method. Efficient energy transfer was enabled since the upconverted energy matched up with the band gap of N-TiO 2 . This enables the resulting composite nanoparticles to possess excellent Rhodamine B (RhB) degradation activity under near infrared (NIR) light irradiation.
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ACS Applied Materials & Interfaces
·
2020
·
IF 8.758
Haoran Ning,Lihong Jing,Yi Hou,Sergii Kalytchuk,Yingying Li,Xiaodan Huang,Mingyuan Gao
Epitaxially growing a semiconductor shell on the surface of upconversion nanocrystals to form a core/shell structure is believed to be a promising strategy to improve the luminescent efficiency of lanthanide ions doped in particle cores and, meanwhile, enriches the optical properties of the resulting nanocrystals. However, liquid-phase synthesis of such core/shell-structured nanocrystals comprised of a lanthanide ion-doped core and semiconductor shell remains challenging because of the chemical incompatibilities between lanthanides and the most intermediate gap semiconductors. In this context, the successful growth of ZnS shell on a KMnF3 core codoped with Yb3+/Er3+ ions is reported to enhance the upconversion luminescence of Er3+ ions. The underlying core/shell formation mechanism is elucidated in detail combining the hard–soft acid–base theory with structural analysis of the resulting nanocrystals. Quite unexpectedly, Mn2+ diffusion across the core/shell interface occurs during ZnS shell growth, giving rise to Mn2+ emission from the ZnS shell. Thus, the resulting core/shell particles exhibited unique up/downconversion luminescence from doped lanthanide metal ions and transition-metal ions, respectively. By manipulating the ion diffusion and shell growth kinetics, the upconversion and downconversion luminescent performance of KMnF3:Yb,Er@ZnS nanocrystals are further optimized and the related mechanisms are discussed. Further, temperature-dependent upconversion and downconversion photoluminescence properties of KMnF3:Yb,Er@ZnS nanocrystals show potential for ratiometric luminescence temperature sensing.
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