Small
·
2025
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IF 12.1
Qi Han,Jiaqi Li,Hao Deng,Sirong Shi,Mi Zhou,Xiaoxiao Cai,Yu Chen,Yunfeng Lin
Diabetic periodontitis presents a unique therapeutic challenge, primarily due to its chronic inflammatory profile and the associated bone loss driven by immune dysregulation. Metformin (Met) is recognized for its potent anti-inflammatory properties, yet its limited cellular uptake has hindered its clinical effectiveness in diabetic periodontitis. A tetrahedral framework nucleic acid (tFNA)-based delivery system is developed to enhance Met cellular uptake and investigate its effects on diabetic periodontitis in this study. The tFNA-loaded Met complex (TMC) demonstrates efficient Met loading efficiency and rapid cellular internalization. These results show that in vitro, TMC significantly inhibited pro-inflammatory cytokines and matrix metalloproteinaseat both mRNA and protein levels under high glucose conditions. Mechanistically, TMC suppresses NLRP3-mediated pyroptosis by downregulating NLRP3, Caspase-1, Caspase-11, and GSDMD, ultimately reducing Mature-IL-1β and Mature-IL-18 production. Furthermore, TMC activates AMPK while inhibiting NF-κB signaling, thus mitigating the inflammatory response in diabetic periodontitis. In vivo, intraperitoneal administration of TMC in a diabetic periodontitis mouse model significantly reduces inflammatory cell infiltration, collagen degradation, and osteoclast formation, thus alleviating alveolar bone loss. These findings highlight the therapeutic potential of tFNA as an efficient Met delivery vehicle to tackle diabetic periodontitis-associated inflammation and bone resorption, providing a promising strategy for managing diabetic complications.
研究领域:
口腔医学
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分子生物学
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药剂学
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DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
·
2025
·
IF 4.7
Fengjie Zhang,Shiyu Hu,Yuyuan Ying,Meiru Zhou,Xunuo Wen,Qingru Sun,Zhaohuan Lou,Jianli Gao
Thymus is the core organ that reflects the degree of aging, and the anti-aging effect of rapamycin(RAPA) has been confirmed by multiple studies, but the dynamic changes of the thymus after the administration of RAPA have been lacking systematic research. Here, we observed the involution of thymus induced by RAPA (1 mg/kg/day, i.p. for 3 days) and its regeneration kinetics after withdrawal of RAPA, to explore the possible mechanism of RAPA’s anti-aging effects based on changes in thymus function. The results show that the thymus weight decreased by 46.15% post-RAPA, then regenerated from 20.45 mg to 57.97 mg, reaching 1.3-fold baseline levels in age-matched controls. RAPA can cause acute involution in thymic structure and function, such as loss of medullary thymic epithelial cells (mTECs) and subcapsular thymic epithelial cells (sTECs), abnormal differentiation of thymocytes, reduction of peripheral T cell proportion, and up-regulation of Foxn1 and Klf6 mRNA levels. Regeneration featured expanded double positive (DP) T cells, CD3 + TCRβ + T cells, CD8 single-positive (SP) T cells, medullary dilatation, and thymocyte telomere elongation. IL-7 and MET have pro-regeneration effects, but neither of them could accelerate RAPA-mediated thymic regeneration. IL-7 can prolong telomere length of thymocytes and restore peripheral T cell homeostasis, while MET can promote T cell positive selection and increase Sirt3 and Gimap4 mRNA levels. These results demonstrate that RAPA triggers transient thymic suppression followed by thymus volume and functional recovery. It seems that RAPA-mediated immune reconstitution may be an important reason for the potential anti-aging effect of RAPA.
研究领域:
免疫学
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衰老研究
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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
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DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2025
·
IF 13.2
Tinglong Chen,Xueliang Zhang,Shengzhe Zhou,Dong Fang,Dinghao Luo,Zhaoyang Ran,Yingchun Liu,Cheng Xu,Jinhao Cao,Xiaodong Li,Yongqiaong Hao,Xiaoqing Wang,Liang Deng
Persistent infections, oxidative stress, and vascular damage in diabetic wounds require multifunctional dressings tailored to complex wound healing process. Herein, a coordination nanocomplexes of Zn@Met were synthesized by chelating Zn 2+ with metformin (Met). These coordination nanocomplexes were subsequently integrated into an injectable self-healing hydrogel comprising methacrylic anhydride-modified gelatin (GelMA) and oxidized konjac glucomannan (OKGM). Through free-radical polymerization as well as hydrogen and schiff base bonds formation, we fabricated an pH-responsive composite hydrogel, named GO@ZM, which exhibited remarkable antibacterial efficacy, antioxidant capabilities, and potent modulation of inflammatory responses. In the final stages of wound healing, the composite hydrogel significantly enhanced macrophage polarization, angiogenesis, and collagen deposition, expediting the wound site’s re-epithelialization process. Collectively, this study introduces a pioneering hydrogel for the treatment of infected diabetic wounds and holds the potential to spark fresh perspectives on the development of high-performance hydrogels for diverse biomedical applications.
研究领域:
生物材料学
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药剂学
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组织工程学
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DOI
高影响因子
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
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2012
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IF 3.346
Lianbao Ye,Yuanxin Tian,Zhonghuang Li,Hong Jin,Zhengguang Zhu,Shanhe Wan,Junyan Zhang,Pengjiu Yu,Jiajie Zhang,Shuguang Wu
Deregulation of receptor tyrosine kinase c-Met has been reported in human cancers and is considered as an attractive target for small molecule drug discovery . In this study, a series of spiro[indoline-3, 4′-piperidine]-2-ones were designed, synthesized and evaluated as novel c-Met inhibitors. The results showed that the majority of the compounds exhibited significant inhibitory effect on c-Met with IC 50 values of 0.0147–17 μM in TR-FRET-based assay and IC 50 values of 1.56–1400 μM in cell-based assay. Furthermore, our docking experiments verified the results and explained the molecular mechanism of eminent activities to c-Met.
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DOI
PubMed
高影响因子
Oncology Letters
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2017
·Vol. 14
·期 2
·2254-2260
·
IF 1.39
Ying Liang,Jiao Liu,Ting Liu,Xingsheng Yang
Radiotherapy is preferred to chemotherapy as an adjuvant therapy for postoperative cervical cancer owing to its convenience and minimal effects on various non-targeted systems. The present study sought to investigate whether the utilization of anti-MET proto-oncogene, receptor tyrosine kinase (c-Met) antibodies conjugated to hollow gold nanospheres (anti-c-Met/HGNs) may enhance the efficiency of radiation therapy for cervical cancer. Anti-c‑Met/HGNs were synthesized and confirmed to target c‑Met, which was overexpressed on the cell membrane of multiple malignancies. The successful synthesis of HGNs was observed using transmission electron microscopy (TEM). Overrepresentation of c‑Met in the human cervical cancer cell line CaSki was verified by immunofluorescence. The cellular uptake of HGNs was assessed using inductively coupled plasma atomic emission spectroscopy (ICP‑AES). To assess the toxicity of functionalized gold nanospheres, a cell proliferation and toxicity assay was used and flow cytometry, with staining by propidium iodide (PI), was performed to study the cell cycle changes. Each experiment was conducted on three groups: Control, HGNs alone and anti-c‑Met/HGNs, with each group also assessed with or without X‑rays. The variation of apoptotic rate was observed by flow cytometry using a dual‑staining Annexin V-fluorescein isothiocyanate/PI kit. Expression of apoptosis‑associated proteins was examined by western blot analysis. TEM revealed a number of hollow spheres with cells with an average diameter of 56.25 nm and a mean wall thickness of 6.56 nm. CaSki cells were detected by inverted fluorescence microscopy via a layer of fluorescent green marker, and ICP‑AES confirmed the distinct uptake of anti‑c‑Met/HGNs by each CaSki cell. Anti‑c‑Met/HGNs induced 38.7% of cells to stay in the G2/M phase, whereas the equivalent proportion in the control group was 19.8%. Compared with other groups, CaSki cells treated with anti‑c‑Met/HGNs and 5 Gy X‑ray radiation exhibited a higher apoptosis rate (16.92%) and a higher early apoptotic rate (12.30%) compared with cells under other conditions (control+0 Gy: 3.16 and 1.69%; HGN+0 Gy: 3.98 and 1.94%; anti‑c‑Met/HGN+0 Gy: 3,47 and 1.85%; control+5 Gy: 5.35 and 3.66%; HGN+5 Gy: 7.91 and 4.06%). The anti‑c‑Met/HGN X‑ray‑treated group also evidently overexpressed caspase‑3 and BCL2 associated X, apoptosis regulator. Anti‑c‑Met/HGN may, therefore, aid the sensitivity of radiation therapy in cervical cancer.
研究领域:
肿瘤学
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纳米技术
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放射生物学
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分子生物学
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DOI
PubMed
高影响因子
Nature Chemical Biology
·
2024
·
IF 12.9
Yang Sihui,Wang Miao,Tian Dawei,Zhang Xiaoyu,Cui Kaiqing,Lü Shouqin,Wang Hong-hui,Long Mian,Nie Zhou
Synthetic signaling receptors enable programmable cellular responses coupling with customized inputs. However, engineering a designer force-sensing receptor to rewire mechanotransduction remains largely unexplored. Herein, we introduce nongenetically engineered artificial mechanoreceptors (AMRs) capable of reprogramming non-mechanoresponsive receptor tyrosine kinases (RTKs) to sense user-defined force cues, enabling de novo-designed mechanotransduction. AMR is a modular DNA–protein chimera comprising a mechanosensing-and-transmitting DNA nanodevice grafted on natural RTKs via aptameric anchors. AMR senses intercellular tensile force via an allosteric DNA mechano-switch with tunable piconewton-sensitive force tolerance, actuating a force-triggered dynamic DNA assembly to manipulate RTK dimerization and activate intracellular signaling. By swapping the force-reception ligands, we demonstrate the AMR-mediated activation of c-Met, a representative RTK, in response to the cellular tensile forces mediated by cell-adhesion proteins (integrin, E-cadherin) or membrane protein endocytosis (CI-M6PR). Moreover, AMR also allows the reprogramming of FGFR1, another RTK, to customize mechanobiological function, for example, adhesion-mediated neural stem cell maintenance.
研究领域:
生物技术
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细胞生物学
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分子生物学
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纳米技术
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产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
·
2024
·
IF 12.8
Pingting Ye,Chunhui Wang,Yixuan Wen,Kang Fang,Qi Li,Xin Zhang,Jingxian Yang,Ruihao Li,Mengyao Chen,Xiaohan Tong,Shuo Shi,Chunyan Dong
Triple-negative breast cancer (TNBC) is a particularly aggressive subtype of breast cancer due to poor immunogenicity and limited immune cell infiltration, efficient therapeutics are still deficiency. Ferroptosis, a reactive oxygen species (ROS)-reliant cell death, can enhance cellular immunogenicity and then active immune system. To sustain a long-term “hot” tumour immune microenvironment (TIME), an immune-modulator is indispensable. Metformin (MET), a commonly used oral drug for type 2 diabetes, has played a vital role in fostering an immunostimulatory environment. Herein, we confirm the TIME can be remodeled by MET and further promotes ferroptosis via upregulating cellular concentration of l -Glutamine. In light of this, we have design a self-assembled MET-loaded Fe 3+ -doped polydopamine nanoparticle (Fe-PDA-MET NP) that can disorder the cellular redox homeostasis and induce robust ferroptosis under 808 nm irradiation, resulting in a strong immune response. Based on the function of MET, there is a marked increase in the infiltration of activated CD8 + T cells and NK cells, which subsequently augments ferroptosis to a greater extent. Taken together, Fe-PDA-MET NPs activate a ferroptotic positive-feedback loop for effectively control TNBC progression, which offers a promising therapeutic modality to enhance the immunogenicity and reshape the TIME.
研究领域:
肿瘤学
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免疫疗法
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纳米技术
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癌症生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF INTERNATIONAL MEDICAL RESEARCH
·
2022
·
IF 1.573
Wen Zhao,Ye Xu,Qingkui Guo,Wenliang Qian,Chen Zhu,Min Zheng
ObjectiveTo synthesize a novel chalcone-1,3,4-thiadiazole hybrid and investigate its anticancer effects against NCI-H460 cells.Methods(E)-3-(4-bromophenyl)-1-(4-hydroxyphenyl)prop-2-en-1-one, 1,3-dibromopropane and 1,3,4-thiadiazole-2-thiol were used as chemical materials to synthesize compound ZW97. The NCI-H460 lung cancer cell line was selected to explore the antitumor effects of compound ZW97 in vitro and in vivo.ResultsCompound ZW97 selectively inhibited cell proliferation against lung cancer cell lines NCI-H460, HCC-44 and NCI-H3122 with IC50 values of 0.15 μM, 2.06 μM and 1.17 μM, respectively. ZW97 suppressed migration and the epithelial–mesenchymal transition process in NCI-H460 cells in a concentration-dependent manner. Based on the kinase activity results and docking analysis, compound ZW97 is a novel tyrosine-protein kinase Met (c-Met kinase) inhibitor. It also inhibited NCI-H460 cell growth in xenograft models without obvious toxicity to normal tissues.ConclusionsCompound ZW97 is a potential c-Met inhibitor that might be a promising agent to treat lung cancer by inhibiting the epithelial–mesenchymal transition process.
研究领域:
肿瘤学
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药理学
·
细胞生物学
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产品关联
DOI
PubMed
高影响因子
ACS Sustainable Chemistry & Engineering
·
2023
·
IF 8.4
Xuejian Liu,Yan Li,Guang-Jin Chen,Dao-Yi Chen,Bo Sun,Zhenyuan Yin
CO2 capture and sequestration are broadly recognized as the most effective technology for reducing CO2 emissions and mitigating global climate change. In this regard, hydrate-based CO2 sequestration (HBCS) has been proposed as an effective method for long-term safe and stable CO2 sequestration. It is a promising technology for reducing the concentration of CO2 in the atmosphere and achieving carbon neutrality. However, one major challenge related to HBCS technology is the lack of understanding of how to improve the formation kinetics of CO2 hydrate effectively. Herein, in this study, we identified the synergistic promotion effect on CO2 hydrate formation when a low-dose thermodynamic promoter (tetrahydrofuran, THF) is coupled with an environment-friendly kinetic promoter (l-methionine, l-Met). Based on the kinetic experiments and the morphological observation, 0.6 mol % THF coupled with 0.1 wt %l-Met yields the optimal CO2 gas uptake. In situ Raman spectra reveal the mechanism of the observed two-step growth behavior at the molecular level, where low-dose THF promotes the initial CO2-THF sII hydrate nucleation and growth in the solution and l-Met promotes the subsequent CO2 sI hydrate growth along the surface of the reactor. Our study unveils the underlying synergistic mechanism when thermodynamic and kinetic promoters are coupled for CO2 hydrate formation. The results provide guidance for the identification and use of novel bio-friendly thermodynamic and kinetic promoters and are beneficial to a series of sustainable hydrate-based technologies when fast CO2 formation is required.
研究领域:
化学工程
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环境科学
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材料科学
·
可持续能源
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产品关联
DOI
高影响因子
CHEMICAL RESEARCH IN TOXICOLOGY
·
2026
·
IF 4.1
Zihan Li,Boxuan Xie,Xilei Liu,Zihan He,Zhongwei Zhang,Jianming Zhou,Tong Zhou,Huai Wang
As the most frequently occurring cancer worldwide, lung cancer is notoriously diagnosed at advanced stages, resulting in high mortality rates. The primary factor underlying this persistent global health burden remains tobacco consumption. Nicotine, a key component of cigarette smoke, is one of the major contributing factors to the development of lung cancer, but the molecular mechanisms remain incompletely elucidated. α7-nAChR, β2-AR, and HGF/c-Met are known to contribute to lung cancer development, respectively. However, the specific signaling cascade through which they interact in nicotine-induced malignancy is unclear. In this study, using CCK-8 assays across a range of concentrations (0–5 μM), we determined that 1 μM nicotine treatment for 48 h optimally enhances A549 cell proliferation, establishing this condition for subsequent experiments. This study uncovers nicotine’s role in driving malignant behaviors including proliferation, migration, and invasion in nonsmall cell lung cancer A549 cells. Notably, nicotine potently stimulated migration and invasion, accompanied by upregulation of Cyclin D1 and MMP-2, and downregulation of BAX, BAD, and Caspase-3. Mechanistically, nicotine induced synergistic engagement of α7-nAChR and β2-AR, leading to activation of the HGF/c-Met/PI3K/AKT axis and enhancing the secretion of both HGF and MMP-2. Importantly, we reveal a previously unrecognized bidirectional regulatory loop between α7-nAChR and β2-AR that functionally converges on the HGF/c-Met axis, which acts as a critical signaling hub to drive the downstream PI3K/AKT pathway and facilitate tumor progression. Our findings provide the first evidence of a coordinated α7-nAChR/β2-AR interface regulating HGF/c-Met signaling that orchestrates both intracellular signaling and extracellular secretory programs in nicotine-promoted lung cancer progression. This offers innovative insights for identifying potential antitumor therapeutic targets and presents novel perspectives for the prevention and clinical management of lung cancer, particularly in smokers with nonsmall cell lung cancer.
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DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2023
·
IF 6.1
Junjie Lin,Chun Cui,Yunzi Feng
Kokumi is a beneficial feeling for the evaluation of food quality, and thus, preparing and understanding the taste properties of kokumi compounds are important for the flavor of food. N-acetyl-Val/Leu/Ile/Met/Phe/Trp/Tyr is a type of kokumi compound found in food and usually prepared by chemical reagents. In this study, we first prepared these six kokumi compounds using transglutaminase and protease A2SD in aqueous solution by using amino acids and acetic acid as substrates and evaluated their kokumi characteristics. HPLC and LC–MS were used to identify quantitative N-acetyl amino acids. Using Phe and acetic acid as substrates, transglutaminase and protease A2SD showed the highest yields for N-acetyl-Phe of 22.75 and 42.21%, respectively, under the optimal conditions. For N-acetyl-Val/Leu/Ile/Met/Trp/Tyr, these two enzymes showed the synthesis yield in the ranges of 2.22–20.12 and 0.75–12.91%, respectively. Six N-acetyl-amino acids were succesully enriched by ethyl acetate with a recovery over 50% and purity over 95%. Sensory evaluation found that N-acetyl-Val/Leu/Ile/Met/Phe are kokumi compounds that enhance sweet, umami, and salt tastes in 5% sucrose, 0.3% NaCl, and 0.5% sodium glutamate, especially N-acetyl-Val, with the salt- and umami-enhancing threshold values of 0.63 and 1.25 g/L, respectively. Therefore, transglutaminase and protease A2SD for the synthesis of partial N-acetyl amino acid might have the potential to be applied in food as a kokumi compound.
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PubMed
高影响因子
CELL
·
2025
·
IF 42.5
Zhao Yang,Yu-Qi Ping,Ming-Wei Wang,Chao Zhang,Shu-Hua Zhou,Yue-Tong Xi,Kong-Kai Zhu,Wei Ding,Qi-Yue Zhang,Zhi-Chen Song,Ru-Jia Zhao,Zi-Lu He,Meng-Xin Wang,Lei Qi,Christian Ullmann,Albert Ricken,Torsten Schöneberg,Zhen-Ji Gan,Xiao Yu,Peng Xiao,Fan Yi,Ines Liebscher,Jin-Peng Sun
Androgens, such as 5α-dihydrotestosterone (5α-DHT), regulate numerous functions by binding to nuclear androgen receptors (ARs) and potential unknown membrane receptors. Here, we report that the androgen 5α-DHT activates membrane receptor GPR133 in muscle cells, thereby increasing intracellular cyclic AMP (cAMP) levels and enhancing muscle strength. Further cryoelectron microscopy (cryo-EM) structural analysis of GPR133-Gs in complex with 5α-DHT or its derivative methenolone (MET) reveals the structural basis for androgen recognition. Notably, the presence of the “Φ(F/L) 2.64 -F 3.40 -W 6.53 ” and the “F 7.42 ××N/D 7.46 ” motifs, which recognize the hydrophobic steroid core and polar groups, respectively, are common in adhesion GPCRs (aGPCRs), suggesting that many aGPCRs may recognize different steroid hormones. Finally, we exploited in silico screening methods to identify a small molecule, AP503, which activates GPR133 and separates the beneficial muscle-strengthening effects from side effects mediated by AR. Thus, GPR133 represents an androgen membrane receptor that contributes to normal androgen physiology and has important therapeutic potentials.
研究领域:
药理学
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分子生物学
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结构生物学
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细胞生物学
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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）