Scientific Reports
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2025
·Vol. 15
·期 1
·44909
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IF 3.9
Xia Xiuyuan,Zhang Zhenghan,Wang Yizhen,Chen Chen,Wang Yaqi,Luo Yanting,Gao Ying,Hong Weiyong,Ren Chuanpeng
Quercetin and carnosine, natural antioxidants with anti-aging and photoprotective potential, face therapeutic limitations due to poor skin permeability. We engineered EV-QuerCar, a liposomal-based nanoparticles (LPNs) system co-encapsulating both compounds, to enhance transdermal delivery and evaluate its structural and functional efficacy. EV-QuerCar was prepared biomimetically using thermophilic bacterial lipids via ultracentrifugation, thin-film hydration, and high-pressure homogenization. Physicochemical properties, transdermal penetration, cellular uptake, and cytotoxicity were tested in vitro. Molecular docking and qPCR assessed pathway targeting. EV-QuerCar exhibited uniform size (94.70 ± 0.71 nm), high encapsulation efficiency (90.07%), sustained release, and 3.21-fold enhanced transdermal absorption compared to free compounds. Cellular uptake in fibroblasts increased time-dependently (up to 5.48-fold at 4 h). Molecular docking and qPCR confirmed interactions with NRF2 and HES1 targets, significantly upregulating their mRNA levels (2.29- and 3.35-fold, respectively) in UV-exposed human fibroblasts. EV-QuerCar improves skin permeability and antioxidant efficacy, highlighting its cosmeceutical promise.
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PubMed
高影响因子
EUROPEAN JOURNAL OF MEDICAL RESEARCH
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2024
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IF 2.8
Lu Yan,Yin-Sen Song,Jian Zhou,Lin Zhu,Tian-Wei Shi,Hui-Qian Yu,Zi-Qing Dong,Wei Wang,Ting Long,Hao-Ying Liu,Zhe-Ye Shi,Jian-Guo Li
Background Nicastrin, a subunit of the γ-secretase complex, is encoded by the NCSTN gene and regulates notch signaling, it is involved in the pathogenesis of hidradenitis suppurativa (HS), Alzheimer disease (AD), and liver cancer. However, the animal models for studying HS are relatively scarce. Methods CRISPR/Cas-mediated genetic engineering was used to generate targeted knockout offspring mice (C57BL/6J). Different doses (10 mg/kg, 20 mg/kg, and 30 mg/kg) and injection methods (subcutaneous/intraperitoneal/gavage injection) of tamoxifen were used to induce the construction of NCSTN knockout mice (mice model). The expressions of nicastrin, NICD1, hes1 in skin, brain, and liver tissue in mice model and wild-type (WT) mice were measured by qRT-PCR and IHC. Results The construction of mice model was successfully induced by tamoxifen, knockout efficiency was 93%, there was no difference in knockout efficiency among three doses, injection methods, genders ( P > 0.05). HS-like lesions appeared on the skin of NCSTN knockout mice after 1 month of treatment with tamoxifen, male mice had a higher number of skin lesions compared to female mice (male vs female = 76.5% vs 41.7%, P = 0.027). Compared with WT mice, the expressions of nicastrin (skin P = 0.0009, brain P = 0.0194, liver P = 0.0066), NICD1 (skin P = 0.0115, brain P = 0.0307, liver P = 0.008), hes1 (skin P = 0.0476, brain P = 0.0143, liver P = 0.0003) in mice model all decreased. Conclusions The NCSTN knockout mouse might be employed as HS animal model; Reducing nicastrin may affect the expression of notch1–hes1 pathway molecules in skin, brain, and liver tissues; low dose (10 mg/kg/d) tamoxifen could be used to induce the deletion of the target gene in mice.
研究领域:
分子生物学
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遗传学
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病理学
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肿瘤学
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DOI
PubMed
高影响因子
CELLULAR SIGNALLING
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2023
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IF 4.8
Yingying Chen,Zhong He,Bo Zhao,Rui Zheng
Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease and a severe form of pulmonary fibrosis. Epithelial-mesenchymal transition (EMT) of alveolar epithelial cells is induced in response to epithelial injury, which leads to the accumulation of extracellular matrix in the lung parenchyma and contributes to pulmonary fibrosis. NPAS2 (neuronal PAS domain protein 2) is significantly increased in the lung tissues of IPF patients according to microarray dataset GSE10667 and NPAS2 is downregulated in differentiated human pulmonary type 2 epithelial cells in vitro based on microarray dataset GSE3306 from Gene Expression Omnibus (GEO). In this study, we demonstrated that NPAS2 was increased in bleomycin (BLM)- induced fibrotic lungs in mice. Knockdown of NPAS2 inhibited EMT in primary mouse lung alveolar type 2 epithelial (pmATII) cells and human lung alveolar type 2 epithelial cell line A549 cells under BLM challenge in vitro. Moreover, the silence of NPAS2 alleviated the BLM-induced pulmonary fibrosis in a murine model. Mechanistically, NPAS2 promotes EMT through positively regulating hairy and enhancer of split 1 (HES1) expression. In this study, we present novel findings that have not been previously reported, emphasizing that p53 transcriptionally activates NPAS2 in ATII cells and overexpression of NPAS2 weakens the effects of TP53 knockdown on EMT of pmATII and A549 cells. Our results suggest NPAS2 is a novel target gene of p53 in regulating BLM-mediated EMT in ATII cells and pulmonary fibrosis.
研究领域:
呼吸病学
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分子生物学
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细胞生物学
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基因组学
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PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
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2022
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IF 5.195
Ningbo Cai,Bingtian Xu,Xing Li,Yunyun Qin,Mengfan Li,Kechun Chen,Jiangping Xu,Haitao Wang
The loss of tight junction (TJ) and adherens junction (AJ) proteins leads to the damage of the blood-brain barrier (BBB) during cerebral ischemia . Inhibition of cyclic nucleotide phosphodiesterase 4 (PDE4) by roflumilast (Roflu) protects against ischemic stroke-induced neuronal damage. However, the effects of Roflu on vascular endothelial injury and BBB integrity remain unknown. Here, we investigated whether and how Roflu protects against cerebrovascular endothelial injury caused by cerebral ischemia/reperfusion. We demonstrated that PDE4B knocking-down increased the expression of TJ and AJ proteins in human brain microvascular endothelial cells (HBMECs) subjected to oxygen-glucose deprivation reperfusion (OGD/R). Inhibition of PDE4 by Roflu (1.0 μM) showed similar effects as PDE4B knocking-down. We then found that Roflu activated Notch1/Hairy and enhancer of split 1 (Hes1) signaling. Consistently, the effects of Roflu on TJ and AJ proteins were reversed by the γ-secretase inhibitor DAPT or Hes1 knocking-down. Furthermore, Roflu (1.0 mg/kg) improved neurobehavioral outcomes and ameliorated BBB disruption in rats following ischemic stroke. Roflu also increased the levels of TJ proteins and AJ proteins in vivo . Collectively, these data suggest that Roflu is a promising compound for the prevention of BBB damage. The protective effects of Roflu are mediated through activation of the Notch1/Hes1 pathway.
研究领域:
神经科学
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药理学
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脑血管疾病
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PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2024
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IF 7.7
Zheng Wang,Mingyu Zhao,Yue Su,Qiangsen Zhao,Zhenhua Ma,Qiaoxian Yue,Zhiwei Zhu,Lihuan Zhang,Zhuocheng Hou,Huifeng Li
Excessive abdominal fat deposition negatively impacts poultry meat production and carcass yield. Identification of novel adipogenesis regulators may help improve production performance declines caused by excessive fat deposition. NUMB Endocytic Adaptor Protein ( NUMB ) typically functions as a cell fate determinant and plays a significant role in cell development and various diseases. Here, we found that NUMB is abundantly expressed in chicken abdominal fat depots and is induced in cultured adipocytes following adipogenic treatment. The gain- and loss-of-function experiments demonstrated that NUMB promotes the proliferation and G1/S transition of chicken adipocytes, enhances adipocyte differentiation, and increases the expression of PPARγ1 transcript. Through mRNA-seq analysis and molecular experiments, we further confirmed that NUMB inhibits the transcriptional activation of the NOTCH1 pathway and the expression of the downstream transcription factor HES1 by inducing NOTCH1 degradation. Nevertheless, the inhibition of the NOTCH1 / HES1 axis alone cannot fully explain NUMB 's role in adipogenesis, as NUMB also regulates the expression of multiple adipogenic transcription factors such as E2F1 , EGR2 , and NR4A3 . Our data suggest that NUMB is a potent activator of adipogenesis and enhances our understanding of its regulatory mechanisms in chicken abdominal fat deposition.
研究领域:
动物科学
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分子生物学
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细胞生物学
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PubMed
高影响因子
Regenerative Biomaterials
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2025
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IF 8.1
Xia Hangbin,Yang Chen,Li Huili,Huang Lingwei,Zeng Zhen,Chi Runrun,Yang Ziwei,Wang Yuzen,Chang Jiang,Jiao Yiren,Li Wenzhong
Muscle satellite cells (MuSCs) play a vital role in skeletal muscle regeneration. However, in intractable muscle diseases such as volumetric muscle loss (VML), the quantity and function of MuSCs are significantly reduced, severely limiting the body's inherent muscle regeneration capability. In this study, we propose a novel strategy to modulate the fate of MuSCs using a combination of bioactive magnesium (Mg) and silicon (Si) ions, sustainably delivered through magnesium silicate (MgSiO3, MS) bioceramic-based scaffolds. In vitro, Mg and Si ions synergistically promote the proliferation and differentiation of MuSCs. Similarly, Mg and Si ions derived from MS/poly (L-lactic acid) (MS/PLLA) composite scaffold also increases the proliferation and differentiation ability of MuSCs. Furthermore, MS/PLLA composite scaffolds facilitate the activation of MuSCs, regeneration of muscle fiber, and neovascularization, while inhibiting fibrosis, thereby effectively restoring muscle function and promoting tibialis anterior muscle functional regeneration in a VML mouse model. Mechanistically, the combination of Mg and Si ions promotes the activation and proliferation of MuSCs by activating the Notch1-Hes1 pathway. Besides, the combination of Mg and Si ions also improves the differentiation of MuSCs by up-regulating Myod and Myog, and enhances fusion by up-regulating Mymk and Mymx expression. The outcomes of our research introduce a promising approach to the treatment of skeletal muscle injuries and related diseases.
研究领域:
再生医学
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生物材料学
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分子生物学
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PubMed
高影响因子
Oxidative Medicine and Cellular Longevity
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2018
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IF 4.936
Liming Yu,Zhi Li,Xue Dong,Xiaodong Xue,Yu Liu,Shu Xu,Jian Zhang,Jinsong Han,Yang Yang,Huishan Wang
Diabetes exacerbates oxidative/nitrative stress during myocardial ischemia-reperfusion (MI/R) injury. Recent studies highlighted the cardioprotective actions of polydatin. However, its effect on diabetic MI/R injury and the underlying mechanisms remain unknown. This work was undertaken to evaluate the effect of polydatin on diabetic MI/R injury with a focus on Notch1/Hes1 signaling and myocardial oxidative/nitrative stress. Streptozotocin- (STZ-) induced diabetic rats were administered with polydatin (20 mg/kg/d) in the absence or presence of DAPT (a γ-secretase inhibitor) or LY294002 (a PI3K/Akt inhibitor) and then subjected to MI/R injury. Polydatin administration preserved cardiac function and reduced myocardial infarct size. Moreover, polydatin ameliorated myocardial oxidative/nitrative stress damage as evidenced by decreased myocardial superoxide generation, malondialdehyde, gp91phox expression, iNOS expression, NO metabolite level, and nitrotyrosine content and increased eNOS phosphorylation. However, these effects were blocked by DAPT administration. DAPT also inhibited the stimulatory effect of polydatin on the Notch1/Hes1-Pten/Akt signaling pathway in a diabetic myocardium. Additionally, LY294002 not only abolished polydatin’s antiapoptotic effect but also reversed its inhibitory effect on myocardial oxidative/nitrative stress. Polydatin effectively reduced MI/R injury and improved left ventricular functional recovery under diabetic condition by ameliorating oxidative/nitrative stress damage. Importantly, Notch1/Hes1-mediated activation of Pten/Akt signaling played a crucial role in this process.
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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糖尿病研究
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PubMed
高影响因子
Nature Chemical Biology
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2024
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IF 12.9
Gan Lu,Jiang Qiwei,Huang Dong,Wu Xueji,Zhu Xinying,Wang Lei,Xie Wei,Huang Jialuo,Fan Runzhu,Jing Yihang,Tang Guihua,Li Xiang David,Guo Jianping,Yin Sheng
Liver fibrosis is an urgent clinical problem without effective therapies. Here we conducted a high-content screening on a natural Euphorbiaceae diterpenoid library to identify a potent anti-liver fibrosis lead, 12-deoxyphorbol 13-palmitate (DP). Leveraging a photo-affinity labeling approach, apolipoprotein L2 (APOL2), an endoplasmic reticulum (ER)-rich protein, was identified as the direct target of DP. Mechanistically, APOL2 is induced in activated hepatic stellate cells upon transforming growth factor-β1 (TGF-β1) stimulation, which then binds to sarcoplasmic/ER calcium ATPase 2 (SERCA2) to trigger ER stress and elevate its downstream protein kinase R-like ER kinase (PERK)–hairy and enhancer of split 1 (HES1) axis, ultimately promoting liver fibrosis. As a result, targeting APOL2 by DP or ablation of APOL2 significantly impairs APOL2–SERCA2–PERK–HES1 signaling and mitigates fibrosis progression. Our findings not only define APOL2 as a novel therapeutic target for liver fibrosis but also highlight DP as a promising lead for treatment of this symptom.
研究领域:
药理学
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分子生物学
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肝病学
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PubMed
高影响因子
Frontiers in Aging Neuroscience
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2022
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IF 5.702
Yang Xiao-bo,Zu Heng-bing,Zhao Yong-fei,Yao Kai
Agomelatine, an agonist of melatonergic MT1 and MT2 receptors and a selective 5-hydroxytryptamine 2C receptor antagonist, is widely applied in treating depression and insomnia symptoms in several neurogenerative diseases. However, the neuroprotective effect of agomelatine in Alzheimer’s disease (AD) is less known. In this study, a total of 30 mice were randomly divided into three groups, namely, wild type (WT), APP/PS1, and agomelatine (50 mg/kg). After 30 days, the Morris water maze was performed to test the cognitive ability of mice. Then, all mice were sacrificed, and the hippocampus tissues were collected for ELISA, Western blot, and immunofluorescence analysis. In this study, we found that agomelatine attenuated spatial memory deficit, amyloid-β (Aβ) deposition, tau phosphorylation, and neuroinflammation in the hippocampus of APP/PS1 mice. Further study demonstrated that agomelatine treatment upregulated the protein expression of DHCR24 and downregulated P-Akt, P-mTOR, p-p70s6k, Hes1, and Notch1 expression. In summary, our results identified that agomelatine could improve cognitive impairment and ameliorate AD-like pathology in APP/PS1 mice via activating DHCR24 signaling and inhibiting Akt/mTOR and Hes1/Notch1 signaling pathway. Agomelatine may become a promising drug candidate in the therapy of AD.
研究领域:
神经科学
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药理学
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神经退行性疾病
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PubMed
高影响因子
Frontiers in Immunology
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2023
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IF 7.3
Tingyan Liu,Caiyan Zhang,Jiayun Ying,Yaodong Wang,Gangfeng Yan,Yufeng Zhou,Guoping Lu
Background Notch signaling is critical for regulating the function of vascular endothelial cells (ECs). However, the effect of the intracellular domain of Notch1 (NICD) on EC injury in sepsis remains unclear. Methods We established a cell model of vascular endothelial dysfunction and induced sepsis in a mouse model via lipopolysaccharide (LPS) injection and cecal ligation and puncture (CLP). Endothelial barrier function and expression of endothelial-related proteins were determined using CCK-8, permeability, flow cytometry, immunoblot, and immunoprecipitation assays. The effect of NICD inhibition or activation on endothelial barrier function was evaluated in vitro . Melatonin was used for NICD activation in sepsis mice. The survival rate, Evans blue dye of organs, vessel relaxation assay, immunohistochemistry, ELISA, immunoblot were used to explore the specific role of melatonin for sepsis induced vascular dysfunction in vivo . Results We found that LPS, interleukin 6, and serum collected from septic children could inhibit the expression of NICD and its downstream regulator Hes1, which impaired endothelial barrier function and led to EC apoptosis through the AKT pathway. Mechanistically, LPS decreased the stability of NICD by inhibiting the expression of a deubiquitylating enzyme, ubiquitin-specific proteases 8 (USP8). Melatonin, however, upregulated USP8 expression, thus maintaining the stability of NICD and Notch signaling, which ultimately reduced EC injury in our sepsis model and elevated the survival rate of septic mice. Conclusions We found a previously uncharacterized role of Notch1 in mediating vascular permeability during sepsis, and we showed that inhibition of NICD resulted in vascular EC dysfunction in sepsis, which was reversed by melatonin. Thus, the Notch1 signaling pathway is a potential target for the treatment of sepsis.
研究领域:
免疫学
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细胞生物学
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分子生物学
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药理学
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PubMed
高影响因子
TOXICOLOGY AND APPLIED PHARMACOLOGY
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2020
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IF 3.347
Xiaolei Wang,Kaiyan Lou,Xiaodong Song,Huijuan Ma,Xinyi Zhou,Huan Xu,Wei Wang
Mebendazole (MBZ) is a tubulin-suppressive antihelmintic agent with low toxicity, which has been repurposed to treat different types of tumors. Chemoresistance is quite common in refractory or relapsed T cell acute lymphoblastic leukemia (T-ALL), which leads to dismal chances of recovery. In this study, MBZ was found to suppress the proliferation and reduce the viability of T-ALL cell line, CCRF-CEM, and its chemoresistant derivative, CEM/C1, at nanomolar concentrations. The inhibitive effects were found to be dose-dependent and not to be affected by the chemoresistance of CEM/C1 cells. Cell cycle arrest, caspase 3/7 activation and tubulin disruption were found in the MBZ-treated T-ALL cells. Notch1 signaling, which is often aberrantly activated in T-ALL cells, was showed to be suppressed by MBZ treatments. MBZ administration in murine T-ALL models also suppressed the growth of CEM/C1 cells, indicating that MBZ may be developed as a therapeutic agent for chemoresistant T-ALLs. The mRNA levels of the Notch1 and Hes1 were also confirmed to be suppressed by MBZ in vivo, which was consistent with the in vitro observations. This study demonstrated, for the first time, that MBZ could inhibit chemoresistant T-ALL cells both in vitro and in vivo , and the Notch1 signaling pathway was suppressed by MBZ treatment.
研究领域:
肿瘤学
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药理学
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细胞生物学
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DOI
PubMed
高影响因子
ACS Nano
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2023
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IF 17.1
Xu Zhang,Zhang Yuan,Jianshuang Wu,Ye He,Guifang Lu,Dan Zhang,Yan Zhao,Rongqian Wu,Yi Lv,Kaiyong Cai,Shuixiang He
Traditional drug-based treatments for inflammatory bowel disease (IBD) have significant limitations due to their potential off-target systemic side-effects. Currently, there is a lack of understanding on how to effectively address excessive oxidative stress, dysregulated immune homeostasis, and microbiota dysbiosis within the IBD microenvironment. Herein, we introduce a nanotherapeutic approach, named LBL-CO@MPDA, for IBD treatment. LBL-CO@MPDA is an orally administered formulation that supplies carbon monoxide (CO) for therapeutic purposes. To create the LBL-CO@MPDA nanocomposite, we developed a layer by layer (LBL) self-assembly strategy where we coated chitosan/alginate polyelectrolytes onto the surface of CO prodrug-loaded mesoporous polydopamine nanoparticles (CO@MPDA). Benefiting from the negatively charged surface of the LBL coating, it allows for targeted accumulation of LBL-CO@MPDA specifically onto the positively charged inflamed colon lesions through electrostatic interactions. Furthermore, in the oxidative microenvironment of the inflamed colon, the nanotherapeutic system releases CO in a responsive manner. Interestingly, CO@MPDA ameliorates inflammatory conditions by MPDA-mediated ROS-scavenging and CO-mediated immunomodulation. CO-supplying activates heme oxygenase-1, leading to macrophage M2 polarization via the Notch/Hes1/Stat3 signaling pathway, while suppressing the inflammatory response by down-regulating the p38 MAPK and NF-κB (p50/p65) signaling pathways. In the mice model of dextran sulfate sodium (DSS)-induced IBD, LBL-CO@MPDA effectively reverses the pro-inflammatory microenvironment and restores gut barrier functions through multiple mechanisms, including scavenging oxidative stress, restoring immune homeostasis, and modulating the gut microbiota. Collectively, our findings highlight the promising potential of this innovative nanotherapeutic strategy for the targeted treatment of IBD.
研究领域:
药学
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纳米技术
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免疫学
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胃肠病学
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生物医学工程
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PubMed
高影响因子
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