Asian Journal of Pharmaceutical Sciences
·
2023
·
IF 10.2
Hongyan Zhang,Liying Chen,Yue Zhao,Ningchao Luo,Jingbin Shi,Shujun Xu,Lisha Ma,Menglin Wang,Mancang Gu,Chaofeng Mu,Yang Xiong
Cancer-associated fibroblasts (CAFs) are one of the most abundant stromal cells in the tumor microenvironment which mediate desmoplastic response and are the primary driver for an immunosuppressive microenvironment, leading to the failure of triple-negative breast cancer (TNBC) immunotherapy. Therefore, depleting CAFs may enhance the effect of immunotherapy (such as PD-L1 antibody). Relaxin (RLN) has been demonstrated to significantly improve transforming growth factor-β (TGF-β) induced CAFs activation and tumor immunosuppressive microenvironment. However, the short half-life and systemic vasodilation of RLN limit its in vivo efficacy. Here, plasmid encoding relaxin (pRLN) to locally express RLN was delivered with a new positively charged polymer named polymeric metformin (PolyMet), which could increase gene transfer efficiency significantly and have low toxicity that have been certified by our lab before. In order to improve the stability of pRLN in vivo , this complex was further formed lipid poly-γ-glutamic acid (PGA)/PolyMet-pRLN nanoparticle (LPPR). The particle size of LPPR was 205.5 ± 2.9 nm, and the zeta potential was +55.4 ± 1.6 mV. LPPR displayed excellent tumor penetrating efficacy and weaken proliferation of CAFs in 4T1 luc /CAFs tumor spheres in vitro. In vivo , it could reverse aberrantly activated CAFs by decreasing the expression of profibrogenic cytokine and remove the physical barrier to reshape the tumor stromal microenvironment, which enabled a 2.2-fold increase in cytotoxic T cell infiltration within the tumor and a decrease in immunosuppressive cells infiltration. Thus, LPPR was observed retarded tumor growth by itself in the 4T1 tumor bearing-mouse, and the reshaped immune microenvironment further led to facilitate antitumor effect when it combined with PD-L1 antibody (aPD-L1). Altogether, this study presented a novel therapeutic approach against tumor stroma using LPPR to achieve a combination regimen with immune checkpoint blockade therapy against the desmoplastic TNBC model.
研究领域:
肿瘤学
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药剂学
·
免疫学
·
分子生物学
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产品关联
DOI
PubMed
高影响因子
MOLECULAR BIOLOGY REPORTS
·
2023
·
IF 2.8
Lan Yong,Dong Min,Li Yongjun,Diao Yongpeng,Chen Zuoguan,Wu Zhiyuan
Background Endothelial cells are crucial in maintaining the homeostasis of the blood-brain barrier. Girders of actin filament (Girdin) and phosphor (p)-Girdin are essential for the engulfment of human brain microvascular endothelial cells (HBMECs) into platelets (PLTs), but the potential mechanism remains unclear and requires further study. Methods Following PLT and cytochalasin D treatment, Hoechst 33,342 detected apoptosis. The transfection efficiency of the short hairpin RNA targeting Girdin (sh-Girdin) or overexpressing Girdin (OE-Girdin) was determined using western blotting. Sh-Girdin, OE-Girdin, mutated Girdin (m-Girdin), and microfilament binding region deleted Girdin (Del-Girdin) were transfected into HBMECs under PLT conditions. Subsequently, the engulfment of HBMECs by PLTs was detected by flow cytometry and transmission electron microscopy. Girdin and phosphorylated (p)-Girdin levels were quantified by western blot. The positive expression of Girdin was measured by immunohistochemistry (IHC). The localization of PLT, Girdin, and p-Girdin and the engulfment of HBMECs in PLTs were analyzed by confocal microscopy. Result Cytochalasin D overturned the inhibitory effect of PLT on cell apoptosis. OE-Girdin enhanced the fluorescent intensity of PLT-labelling and the engulfment of HBMECs by PLTs, while sh-Girdin, m-Girdin, and Del-Girdin ran reversely. OE-Girdin elevated the Girdin and p-Girdin levels, while sh-Girdin and Del-Girdin were the opposite, but m-Girdin did not affect the p-Girdin and Girdin levels. Conclusion Girdin and p-Girdin were co-located with PLTs in HBMECs. The over-expression of Girdin was identified as being associated with the increasing engulfment of PTLs. Girdin may be an effective target to alleviate endothelial cell apoptosis.
研究领域:
细胞生物学
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分子生物学
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神经科学
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血管生物学
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产品关联
DOI
PubMed
高影响因子
Plants-Basel
·
2022
·Vol. 11
·期 20
·2797
·
IF 4.658
Mengyun Jiang,Qian Yang,He Wang,Zhi Luo,Yanjing Guo,Jiale Shi,Xiaoxiong Wang,Sheng Qiang,Reto Jörg Strasser,Shiguo Chen
Biological herbicides have received much attention due to their abundant resources, low development cost, unique targets and environmental friendliness. This study reveals some interesting effects of mycotoxin cytochalasin A (CA) on photosystem II (PSII). Our results suggested that CA causes leaf lesions onAgeratina adenophoradue to its multiple effects on PSII. At a half-inhibitory concentration of 58.5 μΜ (I50, 58.5 μΜ), the rate of O2evolution of PSII was significantly inhibited by CA. This indicates that CA possesses excellent phytotoxicity and exhibits potential herbicidal activity. Based on the increase in the J-step of the chlorophyll fluorescence rise OJIP curve and the analysis of some JIP-test parameters, similar to the classical herbicide diuron, CA interrupted PSII electron transfer beyond QAat the acceptor side, leading to damage to the PSII antenna structure and inactivation of reaction centers. Molecular docking model of CA and D1 protein ofA. adenophorafurther suggests that CA directly targets the QBsite of D1 protein. The potential hydrogen bonds are formed between CA and residues D1-His215, D1-Ala263 and D1-Ser264, respectively. The binding of CA to residue D1-Ala263 is novel. Thus, CA is a new natural PSII inhibitor. These results clarify the mode of action of CA in photosynthesis, providing valuable information and potential implications for the design of novel bioherbicides.Keywords:natural product;bioherbicide;photosynthetic inhibitor;chlorophyllafluorescence;D1 protein;molecular docking
研究领域:
植物科学
·
生物化学
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分子生物学
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环境科学
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DOI
PubMed
高影响因子
Tissue Engineering and Regenerative Medicine
·
2019
·Vol. 16
·期 6
·573-583
·
IF 2.272
Zhao Yang,Sun Qing,Wang Shurong,Huo Bo
Background: Mesenchymal stem cells (MSCs) have strong self-renewal ability and multiple differentiation potential. Some studies confirmed that spreading shape and area of single MSCs influence cell differentiation, but few studies focused on the effect of the circularity of cell shape on the osteogenic differentiation of MSCs with a confined area during osteogenic process. Methods: In the present study, MSCs were seeded on a micropatterned island with a spreading area lower than that of a freely spreading area. The patterns had circularities of 1.0 or 0.4, respectively, and areas of 314, 628, or 1256 μm 2 . After the cells were grown on a micropatterned surface for 1 or 3 days, cell apoptosis and F-actin were stained and analyzed. In addition, the expression of β-catenin and three osteogenic differentiation markers were immunofluorescently stained and analyzed, respectively. Results: Of these MSCs, the ones with star-like shapes and large areas promoted the expression of osteogenic differentiation markers and the survival of cells. The expression of F-actin and its cytosolic distribution or orientation also correlated with the spreading shape and area. When actin polymerization was inhibited by cytochalasin D, the shape-regulated differentiation and apoptosis of MSCs with the confined spreading area were abolished. Conclusion: This study demonstrated that a spreading shape of low circularity and a larger spreading area are beneficial to the survival and osteogenic differentiation of individual MSCs, which may be regulated through the cytosolic expression and distribution of F-actin.
研究领域:
干细胞生物学
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细胞工程
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组织工程
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生物医学工程
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产品关联
DOI
PubMed
高影响因子
Food Bioscience
·
2024
·
IF 4.8
Yawen Chen,Wenjing Dai,Wanli Xiong,Yi Zhou,Ziying Chen,Chengxin Ge,Yan Zhou
As a meat substitute, cell cultured meat aims to simulate the composition of real meat to provide nutrient substance. The myotube formation efficiency of myoblasts in vitro is the key for simulating the structure and composition of muscle tissue. Therefore, this study is aimed to explore the most effective groove widths for myoblasts fusion and related molecular mechanism. The results of immunofluorescence showed that the grooves with a width range of 50 μm–1000 μm were beneficial to cell arrangement compared to flat structure. At the same time, the expression of myogenin ( Myog ) and myosin heavy chain 2 ( Myh2 ) up-regulated. However, the cell fusion index of myoblasts was higher in grooves with a width of 100 μm, 200 μm and 300 μm. Furthermore, Cytochalasin D disrupted intracellular stress fibers and myotube formation. However, there were still many myotubes formed in the 200 μm groove with the addition of Cytochalasin D. The expression of fusion related genes was higher than the flat group. Moreover, incorporating groove structure into scaffolds of soybean protein isolate and pea protein isolate could enhance cell adhesion, activity and myogenic differentiation of myoblasts. This could provide ideas for scaffolds design of cultured meat products using groove structure.
研究领域:
组织工程
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细胞生物学
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生物技术
·
食品科学
✓ 已验证
DOI
高影响因子
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
·
2020
·
IF 4.105
Wendiao Zhang,Jiaxuan Gu,Yuanfang Li,Wenzhe Shan,Yingxuan Xu,Yong Chen
The movement of cell-bound membrane vesicles (CBMVs) on migrating cells is poorly understood. We hypothesized that the movement of CBMVs on migrating cells is different from that on non-migrating cells and can be interfered by external stimuli. To test it, single-vesicle tracking was performed to analyze motion type, speed, displacement, and direction of CBMVs on migrating cells treated with different reagents (Ang-1, TNF-α, LPS, VEGFα, endostatin, Cytochalasin D, and nocodazole) among which the former four promoted cell migration whereas the others inhibited cell migration. We found that cell migration changed CBMVs from non-directed to directed motion and that most CBMVs on untreated migrating cells moved along the migration axis. Interestingly, the migration-promoting reagents played positive roles in CBMV movement (improving directed motion, speed and/or maximal displacement, upregulating the amount of vesicles moving in migration direction) whereas the migration-inhibiting reagents played negative roles (impairing/abolishing directed motion, speed and/or maximal displacement, downregulating the vesicles moving forward or causing an even distribution of motion direction). The cytoskeleton (particularly microtubules) probably played vital roles in CBMV movement on migrating cells and mediated the effects of stimuli on vesicle movement. The data may provide important information for understanding the properties, behaviors, and functions of CBMVs.
研究领域:
细胞生物学
·
分子生物学
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生物物理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
·
2023
·
IF 4.4
Bing-Hui Yan,Qi-Xuan Xu,Xiao Ge,Ming-Tong Gao,Yun Li,Liang Guo,Po Hu,Yang Pan
Benign prostatic hyperplasia (BPH) is a common disease that affects the quality of life of middle-aged and older men. We investigated the therapeutical effects of Chengshi Beixie Fenqing Decoction (CBFD), a classic traditional Chinese medicine prescription, on BPH through in vivo model and network pharmacology. Bioactives in CBFD were detected through UPLC-Q-Tof-MS/MS and GC-MS, and filtered by the modified Lipinski’s rule. Target proteins associated with the filtered compounds and BPH are selected from public databases. Venn diagram identified the overlapping target proteins between the bioactives-interacted target proteins and the BPH-targeted proteins. The bioactive-protein interactive networking of BPH was analyzed through the KEGG pathway on STRING to identify potential ligand-target and visualized the rich factors on the R packet. After that, the molecular docking test (MDT) was performed between bioactives and target proteins. It showed that the mechanism of CBFD against BPH was related to 104 signaling pathways of 42 compounds. AKT1, 6-demethyl-4′-methyl-N-methylcoclaurine and relaxin signaling pathways were selected as a hub target, key bioactivitie and hub signaling pathway, respectively. In addition, three major compounds, 6-demethyl-4′-methyl-N-methylcoclaurine, isoliensinine and liensinine, had the highest affinity on MDT for the three crucial target proteins, AKT1, JUN and MAPK1. These proteins were associated with the relaxin signaling pathway, which regulated the level of nitric oxide and is implicated in both BPH development and CBFD. We concluded that the three key bioactivities found in Plumula nelumbinis of CBFD may contribute to improving BPH condition by activating the relaxin signaling pathways.Communicated by Ramaswamy H. Sarma
研究领域:
药理学
·
中医
·
泌尿科
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES
·
2018
·
IF 3.438
Wendiao Zhang,Ye Xu,Guo Chen,Kun Wang,Wenzhe Shan,Yong Chen
The composition, structure, production, motion, fate, and functions of cell-bound membrane vesicles pre-existing in the plasma membrane of cells are poorly understood. Here, single-vesicle tracking of individual cell-bound membrane vesicles in the plasma membrane of endothelial cells treated with or without various reagents was performed to investigate the motion of cell-bound membrane vesicles. The efficacy of each of these reagents was confirmed prior to single-vesicle tracking. Via single-vesicle tracking, we found that oxLDL, TNF-α, and VEGFα significantly increased the average number of cell-bound membrane vesicles per cell, implying that cell activation by oxLDL, TNF-α, and VEGFα could trigger the production of cell-bound membrane vesicles. It was also found that oxLDL, TNF-α, VEGFα, LPS, and MβCD but not LDL could significantly affect the motion speed of cell-bound membrane whereas none of them could significantly influence the displacement (moving range) of cell-bound membrane vesicles. The single-vesicle tracking further revealed that the average number of cell-bound membrane vesicles per cell and the mean speed/displacement of individual cell-bound membrane vesicles could be dramatically altered by the cytoskeleton-disrupting reagents (cytochalasin D and nocodazole). The data imply that the production and movement of cell-bound membrane vesicles are probably controlled by intracellular cytoskeletons and capable of being affected by multiple conditions e.g. cell activation, membrane fluidity alteration, and others.
研究领域:
细胞生物学
·
生物物理学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
·
2024
·
IF 12.2
Muhammad Junaid,Shulin Liu,Qiang Yue,Jun Wang
Nanoplastics (NPs) interact with cooccurring chemicals and natural organic matter (NOM) in the environment, forming complexes that can change their bioavailability and interfacial toxicity in aquatic organisms . This study aims to elucidate the single and combined impacts of 21-day chronic exposure to low levels of polystyrene NPs (size 80 nm) at 1 mg/L and 6:2 chlorinated polyfluorinated ether sulfonate (Cl-PFAES or F53B) at 200 μg/L in the presence and absence of NOM (humic acid-HA and bovine serum albumin-BSA at 10 mg/L) in adult zebrafish ( Danio rerio ). Our findings through multiple bioassays, revealed that the mixture group (M), comprising of NPs, F53B, HA, and BSA, caused a higher level of toxicity compared to the single NPs (AN), single F53B (AF), and combined NPs+F53B (ANF) groups. The mixture exposure caused the highest level of vacuolization and nuclear condensation in hepatocytes, and most of the intestinal villi were fused and highly reduced in villi length and crypt depth. Further, the T-AOC levels were significantly lower ( p < 0.05), while the MDA levels in the liver and intestine were significantly higher ( p < 0.05) in the M group with downregulation of nfkbiaa , while upregulation of prkcda , csf1ra , and il1b apoptosis genes in the liver. Pairwise comparison of gut microbiota showed significantly higher ( p < 0.05) abundances of various genera in the M group, including Gordonia , Methylobacterium , Tundrisphaera , GKS98 , Pedomicrobium , Clostridium , Candidatus and Anaerobacillus , as well as higher abundance of genera including pathogenic strains, while control group showed higher abundance of probiotic genus ZOR0006 than exposed group ( p < 0.01). The transcriptomic analysis revealed highest number of DEGs in the M group (2815), followed by the AN group (506) and ANF group (206) with the activation of relaxin signaling pathway-RSP ( slc9a1 , slc9a2 ) and AMP-activated protein kinase (AMPK) pathway ( plin1 ), and suppression of the toll-like receptor (TLR) pathway ( tlr4a , tlr2 , tlr1 ), cytokine-cytokine receptor interaction (CCRI) pathway ( tnfb , il21r1 , il21 , ifng1 ), and peroxisome proliferator-activated receptors (PPAR) pathway ( pfkfb3 ). Overall, toxicity in the M group was higher, indicating that the HA and BSA elevated the interfacial impacts of NPs and F53B in adult zebrafish after chronic environmentally relevant exposure, implying the revisitation of the critical interaction of NOM with co-occurring chemicals and associated impacts
研究领域:
环境科学
·
毒理学
·
水生生物学
·
分子生物学
·
微生物学
✓ 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）