ADVANCED FUNCTIONAL MATERIALS
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2023
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IF 19
Zhuo Yao,Qida Hu,Piaopiao Jin,Bowen Li,Yong Huang,Fu Zhang,Meng Wang,Junming Huang,Jing Huang,Shiyi Shao,Xinyu Zhao,Yuan Ping,Tingbo Liang
Gemcitabine (GEM), as a first-line chemotherapeutics for pancreatic ductal adenocarcinoma (PDAC) treatment, still faces several clinical challenges, restricted by instability in blood circulations, low tumor selectivity, and acquired nature characteristics of chemo-resistance. To solve these challenges, the rational design of combination therapy with GEM and other therapy modalities is imperative. Herein, a small molecular self-assembly nano-prodrug is developed, which can achieve the co-delivery of GEM, Ferrocene and nutlin-3a on the achievement of GEM-induced apoptosis with ferroptosis. In this nano-prodrug, the disulfide linkage not only acts as a GSH-responsive trigger but also plays an important role in self-assembly behavior of nanoparticle that can load nutlin-3a. Interestingly, nutlin-3a plays an important role in both ferroptosis and apoptosis, one is effectively sensitized cells to ferroptosis by inhibiting cystine uptake, and the other is promoted apoptosis by elevating p53 expression. To further enhance the drug tumor accumulation and maintain stability in systemic circulations, this nano-prodrug is then encapsulated into plectin1 receptor-targeting phospholipid micelles (DSPE-PEG-PTP), which displays high selective tumor inhibition and good biosafety on different mice models, especially in orthotopic and patient-derived xenograft (PDX) models. The findings provide new insights into the combination therapy of GEM with ferroptosis for reduced chemo-resistance on PDAC treatment.
研究领域:
肿瘤学
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药学
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纳米技术
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癌症治疗
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DOI
高影响因子
Oncology Letters
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2023
·Vol. 25
·期 6
·1-12
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IF 2.9
Boya Deng,Ailin Li,Ying Zhu,Yingying Zhou,Jing Fei,Yuan Miao
Cervical cancer (CC) is the most common human papillomavirus‑related disease. Continuous activation of the NF‑κB signaling pathway has been observed in CC. SHC binding and spindle associated 1 (SHCBP1) contributes to tumorigenesis and activation of the NF‑κB pathway in multiple cancer types, while its function in CC remains unclear. In the present study, three Gene Expression Omnibus datasets were used to identify differentially expressed genes (DEGs) in CC. Loss‑ and gain‑of‑function experiments were performed using stable SHCBP1‑silenced and SHCBP1‑overexpressing CC cells. To further explore the molecular mechanism of SHCBP1 in CC, small interfering RNA targeting eukaryotic translation initiation factor 5A (EIF5A) was transfected into stable SHCBP1‑overexpressing CC cells. The results demonstrated that SHCBP1 was an upregulated DEG in CC tissues compared with healthy control cervical tissues. Functional experiments revealed the pro‑proliferative and pro‑stemness role of SHCBP1 in CC cells (CaSki and SiHa cells), in vitro. Furthermore, the NF‑κB signaling pathway in CC cells was activated by SHCBP1. Increases in cell proliferation, stemness and activation of NF‑κB, induced by SHCBP1 overexpression in CC cells, were reversed by EIF5A knockdown. Taken together, the results indicated that SHCBP1 serves an important role in regulation of CC cell proliferation, self‑renewal and activation of NF‑κB via EIF5A. The present study demonstrated a potential molecular mechanism underlying the progression of CC.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
Journal of Materials Chemistry B
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2023
·Vol. 11
·期 19
·4211-4226
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IF 7
Zhongping Su,Haiying Xu,Ying Zhang,Huanli Zhang,Hui Zhang,Yujun Bao,Xiaodan Wu,Rui Yan,Guanghui Tan,Zhiqiang Wang,Yingxue Jin
Immune checkpoint blockade (ICB) is a kind of promising anti-tumor immunotherapy that can block the negative immune regulatory pathways using a particular antibody. Weak immunogenicity in most patients is a key obstacle to ICB therapy. Photodynamic therapy (PDT) is a non-invasive treatment that can enhance the immunogenicity of the host and realize systemic anti-tumor immunotherapy; yet tumor microenvironment hypoxia and glutathione overexpression severely restrict the PDT effect. To overcome the above issues, we design a combination therapy based on PDT and ICB. We prepared red carbon dot (RCD)-doped Cu-metal–organic framework nanoparticles (Cu-MOF@RCD) as smart nano-reactors because their tumor microenvironment and near-infrared light responsive property can decompose tumor endogenous H2O2 through Fenton-like reactions. Cu-MOF@RCD also shows clear near-infrared photothermal therapy (PTT) effect and has an ability to deplete glutathione (DG), which together enhances decomposition of cellular H2O2 and amplifies reactive oxygen species (ROS) levels in cells, thus leading to enhanced PDT and chemodynamic therapy (CDT) effect. Moreover, programmed cell death-ligand 1 antibody (anti-PD-L1) is used together to enable combination therapy, as Cu-MOF@RCD can significantly enhance host immunogenicity. In summary, the combination of Cu-MOF@RCD with anti-PD-L1 antibody exerts a synergistic PDT/PTT/CDT/DG/ICB therapy and can be used to eradicate the primary tumors and inhibit the growth of untreated distant tumors and tumor metastasis.
研究领域:
纳米技术
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癌症治疗
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免疫治疗
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光疗
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF INTERNATIONAL MEDICAL RESEARCH
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2023
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IF 1.6
Xuena Zhang,Jie Li
ObjectivesTo observe changes in actin and dendritic spines in the hippocampus after propofol anesthesia, and to evaluate the role of these changes in subsequent learning impairment in both young (3-month-old) and aged (20-month-old) male rats.MethodsThe shuttle box test was used to evaluate learning from 1, 3, 7, or 14 days after anesthesia. Both F-actin content and dendritic spines in the hippocampal CA1 region were observed using immunofluorescent staining and western blot assays.ResultsThe latency of the escape response was significantly prolonged until 7 days after anesthesia in the aged rats, and their learning curves were shifted. Dendritic spines were also decreased in the aged rats within 7 days after anesthesia, and F-actin content was significantly increased until 14 days after anesthesia.ConclusionsLearning was inhibited after propofol anesthesia, especially in aged rats. The over-polymerization of actin and subsequent reorganization of dendritic spines in the hippocampus may be responsible for this learning impairment. Our findings suggest that synaptic plasticity may be an underlying mechanism of perioperative neurocognitive disorders.
研究领域:
神经科学
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药理学
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认知科学
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产品关联
DOI
高影响因子
Nano Today
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2023
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IF 17.4
Yuehua Wang,Bingchen Zhang,Qiye Xi,Chaojie Chen,Zhenjie Wang,Fangzhou Li,Shengtao Wang,Wei Yang,Xing-Jie Liang,Zhiqiang Yu,Meng Yu
High-rate aerobic glycolysis and abnormal glutamine metabolism in tumor cells lead to their unlimited malignant proliferation and induce immune escape in the tumor microenvironment . In this study, the GLS1 inhibitor BPTES and the PDHC inhibitor CPI-613 were co-delivered by an ROS-sensitive GEM nano-prodrug (PD-G@BC), and a simultaneous inhibition of glycolysis and glutamine metabolism was achieved to deprive tumor cells of nutrient supply. In addition, this metabolism reprogramming effectively weakened the sources of glucose and glutamine in tumor cells, correspondingly thrived metabolism in antitumor immune cells , thereby increasing the intratumoral infiltration and functions of the immunogenic cells to alleviate the immunosuppressive responses. This multifunctional combination strategy will provide new insights into the design of synergistic cancer immunotherapy based on metabolic interventions.
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DOI
高影响因子
MOLECULAR BIOTECHNOLOGY
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2023
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IF 2.6
Lv Chen-Guang,Cheng Yao,Zhang Lei,Wu Guo-Gang,Liang Chun-Yan,Tao Zuo,Chen Bo
BC (breast cancer) is the leading cause of cancer death in women. Exosome component 2 (EXOSC2), an RNA exosome component, is elevated in BC tissues and may relate to BC carcinogenesis. In this work, the high EXOSC2 expression was correlated with TNM (Tumor Node Metastasis) stage. Moreover, overexpression of EXOSC2 enhanced tumorigenic capacity of BC cells via facilitating cell proliferation and cell cycle progression, increasing migration and angiogenesis, as well as exacerbating xenograft formation in vivo. Whereas, EXOSC2 knockdown showed anti-cancer effects, including inhibition of cell proliferation and angiogenesis. Mechanistically, EXOSC2 activated the wnt/β-catenin pathway, which was also abolished by EXOSC2 knockdown. In addition, there were m6A methylation modification sites in the mRNA of EXOSC2. WTAP (Wilms tumor 1-associated protein) bound to EXOSC2 mRNA and increased its m6A methylation, resulting in extending the half-life of EXOSC2 mRNA. Luciferase data also confirmed that WTAP enhanced EXOSC2 mRNA stability through binding with the 3′-UTR containing m6A sites. Furthermore, WTAP silencing exhibited cancer-inhibiting effects on cell viability, cell cycle progression and tube formation, which was effectively reversed by EXOSC2 overexpression. In conclusion, our results demonstrate that EXOSC2 promotes the malignant behaviors of BC cells via activating the wnt/β-catenin pathway. In addition, EXOSC2 mediates the function of WTAP which contributes to the m6A modification of EXOSC2. Totally, this study suggested that EXOSC2 mediated the pro-tumor role of WTAP via activating the wnt/β-catenin signal.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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癌症生物学
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产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
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2023
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IF 5
Zhaoqi Wang,Duomao Lin,Boqun Cui,Dongni Zhang,Jinjing Wu,Jun Ma
Excessive or uncontrolled mitophagy may result in a drastic shortage of healthy mitochondrial for ATP supply after reperfusion, leading to irreversible myocardial damage . Melatonin , a hormone produced by the pineal gland, has been proven to ameliorate myocardial ischemia-reperfusion (I/R) injury via regulating mitophagy. However, its underlying mechanism has not been fully elucidated. The present study focused on the role of mitophagy in the cardioprotective effects of melatonin by using the myocardial I/R rat model. The rats were pretreated with or without the apelin inhibitor ML221, the sirtuin 3 (SIRT3) inhibitor 3-TYP and then subjected to I/R injury, with melatonin administrated 10 min before reperfusion. The effects of melatonin on myocardial infarct size, biomarkers of myocardial injury, oxidative stress , and mitochondrial function were detected, and the expression of apelin, SIRT3, and mitophagy-related proteins were also measured. Excessive mitophagy was activated after I/R injury and was correlated with oxidative stress and mitochondrial dysfunction. Melatonin pretreatment ameliorated myocardial injury by decreasing oxidative stress, restoring mitochondrial function, and inhibiting excessive mitophagy. However, ML221 or 3-TYP disrupted these beneficial effects of melatonin on I/R injury. Taken together, these results suggest that melatonin pretreatment ameliorates myocardial I/R injury through regulating the apelin/SIRT3 pathway to inhibit excessive mitophagy.
研究领域:
心脏病学
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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
BIOLOGICAL TRACE ELEMENT RESEARCH
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2023
·
IF 3.9
Yan Nan,Wang Zhengdong,Li Zhou,Zheng Yang,Chang Nan,Xu Kangjie,Wang Qian,Duan Xiaoxu
This study aimed to examine the immuntoxic effects of arsenic in the nervous system. Our results showed that arsenic increased corticocerebral and hippocampal weights ( p < 0.05). Morris water maze tests revealed that arsenic significantly increased the time spent in latency to platform on the fourth day in 50 mg/L arsenic exposure and the fifth day in 25 and 50 mg/L arsenic exposure, as well as reduced the path length in target quadrant, time spent in target quadrant, and crossing times of the platform ( p < 0.05). Hematoxylin–eosin staining showed that the vacuolated degeneration and pyknosis was found in the cerebral cortex and hippocampus of arsenic-treated mice. The mRNA levels of corticocerebral and hippocampal brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) were decreased in the 50 mg/L arsenic-treated group ( p < 0.05). In addition, immunofluorescence staining showed that 25 and 50 mg/L arsenic all increased the expression of CD11b and glial fibrillary acidic protein (GFAP) in the cerebral cortex and hippocampus ( p < 0.05). Arsenic markedly raised antigen-presenting molecule MHCII and CD40 mRNA levels in the cerebral cortex and hippocampus and upregulated the cell chemokine receptor 5 (CCR5) and CCR7 mRNA levels in the cerebral cortex at the 50 mg/L arsenic group, and increased the CCR7 mRNA levels in the hippocampus at the 25 and 50 mg/L arsenic groups ( p < 0.05). Arsenic activated the nucleotide-binding domain-like receptor protein-3 (NLRP3) inflammasome, and enhanced its upstream promoter NF-κB protein level and downstream regulators IL-18 mRNA levels. Collectively, these results provide new evidences for the neuro-immune toxicity of arsenic. Graphical abstract
研究领域:
神经毒理学
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免疫毒理学
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神经科学
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产品关联
DOI
PubMed
高影响因子
International Journal of Nanomedicine
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2023
·
IF 8
Kai Yue,Chao Yang,Yu You,Xueying Wang,Xinxin Zhang
Background A good understanding of the adhesion behaviors of the nanocarriers in microvessels in chemo-hyperthermia synergistic therapy is conducive to nanocarrier design for targeted drug delivery.Methods In this study, we constructed an artificial blood vessel system using gelatins with a complete endothelial monolayer formed on the inner vessel wall. The numbers of adhered NPs under different conditions were measured, as well as the interaction forces between the arginine–glycine–aspartic acid (RGD) ligands and endothelial cells.Results The experimental results on the adhesion of ligand–coated nanoparticles (NPs) with different sizes and morphologies in the blood vessel verified that the gelatin-based artificial vessel possessed good cytocompatibility and mechanical properties, which are suitable for the investigation on NP adhesion characteristics in microvessels. When the temperature deviated from 37 °C, an increase or decrease in temperature resulted in a decrease in the number of adhered NPs, but the margination probability of NP adhesion increased at high temperatures due to the enhanced Brownian movement and flow disturbance. It is found that the effect of cooling was less than that of heating according to the observed changes in cell morphology and a decrease in cell activity under the static and perfusion culture conditions within the temperature range of 25 °C–43 °C. Furthermore, the measurement results of change in the RGD ligand-cell interaction with temperature showed good agreement with those in the number of adhered NPs.Conclusion The Findings suggest that designing ligands that can bind to the receptor and are least susceptible to temperature variation can be an effective means to enhance drug retention.
研究领域:
生物医学工程
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纳米医学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
MICROVASCULAR RESEARCH
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2023
·
IF 3.1
Yushu Liu,Dong Wang,Yimin Jin,Guifang Sun,Qi Lou,Hong Wang,Weimin Li
Atrial fibrillation (AF) is a cardiac disease characterized by disordered atrial electrical activity. Atrial inflammation and fibrosis are involved in AF progression. Costunolide (COS) is a sesquiterpene lactone containing anti-inflammatory and anti-fibrotic activities. This study aims to explore the underlying mechanisms by which COS protects against AF. Male C57BL/6 mice (8- to 10-week-old) were infused with angiotensin (Ang) II for 3 weeks. Meanwhile, different doses of COS (COS-L: 10 mg/kg, COS-H: 20 mg/kg) were administered to mice by intragastric treatment. The results showed irregular and rapid heart rates in Ang II-treated mice. Moreover, the levels of inflammatory cytokines and fibrotic factors were elevated in mice. COS triggered a reduction of Ang II-induced inflammation and fibrosis, which conferred a protective effect. Mechanistically, mitochondrial dysfunction with mitochondrial respiration inhibition and aberrant ATP levels were observed after Ang II treatment. Moreover, Ang-II-induced excessive reactive oxygen species caused oxidative stress, which was further aggravated by inhibiting Nrf2 nuclear translocation. Importantly, COS diminished these Ang-II-mediated effects in mice. In conclusion, COS attenuated inflammation and fibrosis in Ang-II-treated mice by alleviating mitochondrial dysfunction and oxidative stress. Our findings represent a potential therapeutic option for AF treatment.
研究领域:
心脏病学
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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
Human Cell
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2023
·Vol. 36
·期 3
·972-986
·
IF 4.3
Liu Naiquan,Liu Dajun,Cao Shiyu,Lei Jing
Renal fibrosis is the common final pathway in many renal diseases regardless of the underlying etiology. Adipocyte enhancer-binding protein 1 (AEBP1) was reported to play a vital role in the development of organ fibrosis, but its role in renal fibrosis has not been reported. Thus, the aim of this study was to investigate the possible function of AEBP1 in renal fibrosis and the mechanism associated with the β-catenin signaling pathway. A total of 83 genes upregulated after unilateral ureteral obstruction (UUO) were screened from two Gene Expression Omnibus (GEO) datasets and subjected to Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Among them, AEBP1 was enriched in collagen binding and the regulation of collagen fibril organization and was confirmed to be upregulated in UUO kidneys and TGF-β1-induced cells. Knockdown of AEBP1 ameliorated renal fibrosis via reducing collagen accumulation, inhibiting epithelial–mesenchymal transition and fibroblast transformation, as evidenced by decreases in the expression of collagen I and III, Col1a1, Col3a1, fibronectin, Snail, α-SMA, as well as collagen-specific staining of kidney tissues, whereas the E-cadherin was increased. Besides, AEBP1 silencing inhibited the expression of β-catenin in nucleus and β-catenin downstream proteins (Axin2, Myc, and Ccnd1). Continuously active β-catenin–S33Y further restored the inhibitory effect of AEBP1 silencing on renal fibrosis. These findings indicate that knockdown of AEBP1 could potentially slow down renal fibrosis by blocking the β-catenin signaling pathway, highlighting the potential of AEBP1 as a therapeutic target for renal fibrosis.
研究领域:
肾病学
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分子生物学
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细胞生物学
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病理生理学
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产品关联
DOI
PubMed
高影响因子
ACS Nano
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2023
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IF 17.1
Xuchun Chen,Ying Cheng,Qi Pan,Lan Wu,Xinyao Hao,Zhiye Bao,Xitan Li,Mingshi Yang,Qiuhua Luo,Heran Li
Chiral nanoparticles (NPs) with nanoscale rough surfaces have enormous application prospects in drug delivery. However, the stereoselective interactions between the chiral NPs and biosurfaces remain challenging and mysterious. Herein, we designed mesoporous silica nanocarriers (l/d/dl-TA-PEI@CMSN) exhibiting the same structural parameters (hydrophilic, electroneutral, spherical NPs, ∼120 nm) but different geometrical chirality as oral nanodrug delivery systems (Nano-DDS) for insoluble drugs nimesulide (NMS) and ibuprofen (IBU) and demonstrated their stereoselective interactions with the intestinal mucosa, that is, l-TA-PEI@CMSN as well as Nano-DDS in the l-configuration displayed apparent superior behaviors in multiple microprocesses associated with oral adsorption, including adhesion, penetration, adsorption, retention and uptake, causing by the stereomatching between the chiral mesostructures of NPs and the inherent chiral topologies of the biosurfaces. As hosting systems, l/d/dl-TA-PEI@CMSN effectively incorporated drugs in amorphous states and helped to overcome the stability, solubility and permeability bottlenecks of drugs. Subsequently, Nano-DDS in the l-configuration (including IBU/l-TA-PEI@CMSN and NMS/d-TA-PEI@CMSN owing to a chiral inversion) showed higher oral delivery efficiency of NMS and IBU evidenced by the larger relative bioavailability (1055.06% and 583.17%, respectively) and stronger anti-inflammatory and analgesic effects. In addition, l/d/dl-TA-PEI@CMSN were stable, nonirritative, biocompatible and biodegradable, benefiting for their clinical applications. These findings provided insights into the rational design of functionalized Nano-DDS and contributed to the further knowledge in the field of chiral pharmaceutical science.
研究领域:
药学
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纳米医学
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生物材料科学
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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）