ADVANCED FUNCTIONAL MATERIALS
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2019
·Vol. 29
·期 12
·1806916
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IF 15.621
Xiaowei Liu,Yanlin Feng,Guangchao Xu,Yang Chen,Ya Luo,Jinen Song,Yu Bao,Jiqiao Yang,Chune Yu,Yanna Li,Haoyu Ye,Bowen Ke,Bo Chen,Jianping Hu,Jie Xu,Huan Meng,Haiyuan Zhang,Hubing Shi
The combination of BRAF/MEK-targeted therapy with immune checkpoint blockade is regarded as a promising regimen for patients with metastatic melanoma due to their complementary advantages. However, MEK-inhibitor-induced T-cell toxicity impedes effective cooperation. In this experiment, a pH-responsive on-demand controlled release mesoporous silica nanoparticles (MSNPs) system is designed. Fluorescein-isothiocyanate-loaded MSNP can be specifically delivered into tumor cells rather than T-cells. MEK-inhibitor-loaded MSNP avoids proliferative and functional inhibitions of T-cells, while preserving growth suppression of tumor cells in vitro. In an in vivo model, MSNP encapsulation reverses the MEK-inhibitor-induced suppression of activated CD8 + T-cells, and enhances the secretion of INF-γ and IL-2. The combination of BRAF inhibitor plus MSNP-loaded MEK inhibitor and anti-PD-1 antibody synergistically inhibits tumor growth via promoting robust immune-related antitumor response. This work provides a novel and generalized framework for combining T-cell-impaired targeted therapy and immune checkpoint blockade by using a nanoparticle-based delivery system.
研究领域:
肿瘤学
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药理学
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纳米技术
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免疫疗法
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PHYTOTHERAPY RESEARCH
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2026
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IF 8.1
Lijing Du,Shikai Yan,Xiaopeng Ren,Syed Shams ul Hassan,Yuanfang Sun,Yu Gan,Xue Xiao,Shasha Li,Huizi Jin
Alzheimer's disease (AD) is a progressive neurodegenerative disorder associated with cognitive decline and neuroinflammation. Xanthoceras sorbifolia Bunge oil (XSBO), a woody plant oil rich in bioactive fatty acids, has shown potential health benefits. This study aimed to investigate the neuroprotective effects and underlying mechanisms of XSBO in AD. A scopolamine-induced AD rat model was established to evaluate the effects of XSBO on cognitive function, pathological changes, and neuroinflammation. Gut microbiota alterations were analyzed by 16S rDNA sequencing. Fecal microbiota transplantation (FMT) and short-chain fatty acid (SCFA) supplementation experiments were performed to explore the role of gut microbiota-derived metabolites. The TLR4/MyD88/MAPK signaling pathway was further examined. XSBO treatment improved cognitive deficits, reduced neuronal damage and neuroinflammation, and enhanced intestinal barrier integrity in AD rats. XSBO restored gut microbiota dysbiosis and increased SCFA-producing bacteria. FMT and SCFA supplementation confirmed that microbiota-derived metabolites contributed to XSBO-mediated cognitive improvement and neuroprotection. Mechanistically, XSBO inhibited lipopolysaccharide-induced neuroinflammation by suppressing TLR4/MyD88/MAPK signaling activation. XSBO alleviates AD-related cognitive impairment and neuroinflammation by modulating the gut microbiota–SCFA axis and inhibiting TLR4/MyD88/MAPK-mediated inflammatory responses. These findings suggest that XSBO may serve as a promising dietary intervention for neurodegenerative disease management.
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Drug Design Development and Therapy
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2022
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IF 4.319
Debao Li,Yuling Jia,Yiwen Hou,Dingshi Chen,Chiyang Zheng,Lifen Chen,Li Zhou,Zuyue Sun
Background The Qilin pill (QLP) is a traditional Chinese compound prescription comprising 15 herbs that has demonstrated significant therapeutic effects on premature ovarian insufficiency (POI) in recent years. However, a pharmacological evaluation of QLP on ovarian function remains to be conducted, and the key mechanism of QLP treatment on POI is unclear.Methods Premature ovarian insufficiency rats were established by bilateral partial ovariectomy. The model rats were administrated with low (QLP-L), medium (QLP-M) and high (QLP-H) doses of QLP for 4 weeks to evaluate the ovarian function in terms of estrous cycle, hormone level, and follicle count. The mechanism of QLP in the treatment of POI was systematically explored by network pharmacology, and expression levels of the MAPK and PI3K-AKT signaling pathways were verified by Western blotting and molecular docking.Results The rat model of resection-induced POI was successfully established, and QLP could significantly recover the estrous cycle, decrease serum FSH levels, and decelerate follicle depletion after 4 weeks of administration. The optimal dose of QLP in the experiment was preliminarily determined to be 0.9 g/kg. Based on the network pharmacology methods, we constructed the compound-target network and protein protein interaction (PPI) network of QLP for the treatment of POI. The experimental verification of the enrichment analysis showed that QLP inhibited the MAPK and PI3K-AKT signaling pathways, and the key compounds and key targets involved were verified by molecular docking.Conclusion QLP exerted significant therapeutic effects on resection-induced POI rats, and this was achieved by the inhibition of the MAPK and PI3K-AKT signaling pathways. This study is the first to systematically investigate the effects and mechanism of QLP on POI rats, which will provide valuable guidance in clinic.
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Nutrients
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2022
·Vol. 14
·期 13
·2765
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IF 6.706
Xuejiao Zhang,Bowei Zhang,Bo Peng,Jin Wang,Yaozhong Hu,Ruican Wang,Shuo Wang
Sugar reduction and sugar control are advocated and gaining popularity around the world. Sucrose, as the widely consumed ingredient in our daily diet, has been reported a relation to gastrointestinal diseases. However, the role of sucrose in inflammatory bowel disease remains controversial. Hence, our study aimed to elucidate the potential role of three doses of sucrose on DSS-induced colitis in C57BL/6 mice and the underlying mechanisms. The results showed that low-dose sucrose intervention alleviated colitis in mice, reducing the expression of inflammatory cytokines and repairing mucosal damages. In contrast, high-dose sucrose intervention exacerbated colitis. Furthermore, three doses of sucrose administration markedly altered gut microbiota composition. Notably, the low-dose sucrose restored microbial dysfunction and enhanced the production of short chain fatty acids (SCFAs). Specifically, the abundance of SCFAs-producing bacteriaFaecalibaculum,Bacteroides,andRomboutsiawere increased significantly in the LOW group. Consistently, PPAR-γ, activated by SCFAs, was elevated in the LOW group, thereby inhibiting the MAPK/NF-κB pathway. Together, our study demonstrates the differential effects of sucrose on colitis at different doses, providing a scientific basis for measuring and modifying the safe intake level of sugar and providing favorable evidence for implementing sugar reduction policies.Keywords:sucrose;gut microbiota;SCFAs;PPAR-γ;MAPK/NF-κB
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INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
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2022
·Vol. 23
·期 14
·7666
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IF 6.208
Ping Li,Yiting Yang,Zijin Lin,Shijin Hong,Ling Jiang,Han Zhou,Lu Yang,Liang Zhu,Xiaodong Liu,Li Liu
Liver injury is often associated with hepatic retinopathy, resulting from accumulation of retinal toxins due to blood–retinal barrier (BRB) dysfunction. Retinal pigment epithelium highly expresses MRP1/Mrp1. We aimed to investigate whether liver injury affects the function and expression of retinal Mrp1 using bile duct ligation (BDL) rats. Retinal distributions of fluorescein and 2,4-dinitrophenyl-S-glutathione were used for assessing Mrp1 function. BDL significantly increased distributions of the two substrates and bilirubin, downregulated Mrp1 protein, and upregulated phosphorylation of p38 and MK2 in the retina. BDL neither affected the retinal distribution of FITC-dextran nor expressions of ZO-1 and claudin-5, demonstrating intact BRB integrity. In ARPE-19 cells, BDL rat serum or bilirubin decreased MRP1 expression and enhanced p38 and MK2 phosphorylation. Both inhibiting and silencing p38 significantly reversed the bilirubin- and anisomycin-induced decreases in MRP1 protein. Apparent permeability coefficients of fluorescein in the A-to-B direction (Papp, A-to-B) across the ARPE-19 monolayer were greater than Papp, B-to-A. MK571 or bilirubin significantly decreased Papp, A-to-Bof fluorescein. Bilirubin treatment significantly downregulated Mrp1 function and expression without affecting integrity of BRB and increased bilirubin levels and phosphorylation of p38 and MK2 in rat retina. In conclusion, BDL downregulates the expression and function of retina Mrp1 by activating the p38 MAPK pathway due to increased bilirubin levels.Keywords:bile duct ligation;blood–retinal barrier;multidrug resistance-associated protein 1;liver injury;p38 MAPK;bilirubin
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Antioxidants
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2021
·Vol. 10
·期 12
·2019
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IF 6.313
Zebin Huang,Lingna Xie,Yongyu Xu,Kai Zhao,Xuetong Li,Jiaben Zhong,Yujing Lu,Xuetao Xu,Susan Goodin,Kun Zhang,Lanyue Zhang,Chunlian Li,Xi Zheng
Zingiber striolatumDiels (Z. striolatum), a widely popular vegetable in China, is famous for its medicinal and nutritional values. However, the anti-inflammatory effects of essential oil fromZ. striolatum(EOZS) remain unclear. In this study, EOZS from seven regions in China were extracted and analyzed by GC–MS. LPS-induced RAW264.7 cells and 12-O-Tetradecanoylphorbol 13-acetate (TPA)-stimulated mice were used to evaluate the anti-inflammatory effects of EOZS. Results show that 116 compounds were identified in EOZS from seven locations. Samples 2, 4 and 5 showed the best capability on DPPH radical scavenging and NO inhibition. They also significantly reduced the production of ROS, pro-inflammatory cytokines, macrophage morphological changes, migration and phagocytic capability. Transcriptomics revealed MAPK and NF-κB signaling pathways may be involved in the anti-inflammatory mechanism, and the predictions were proven by Western blotting. In TPA-induced mice, EOZS reduced the degree of ear swelling and local immune cell infiltration by blocking the activation of MAPK and NF-κB signaling pathways, which was consistent with the in vitro experimental results. Our research unveils the antioxidant capability and potential molecular mechanism of EOZS in regulating inflammatory response, and suggests the application of EOZS as a natural antioxidant and anti-inflammatory agent in the pharmaceutical and functional food industries.Keywords:Zingiber striolatumDiels;essential oil;oxidant stress;anti-inflammatory activity;MAPK;NF-κB
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Advanced Science
·
2021
·Vol. 9
·期 3
·2102460
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IF 16.806
Rui Zheng,Mulong Du,Man Tian,Zhaozhong Zhu,Chengcheng Wei,Haiyan Chu,Cong Gan,Jiayuan Liang,Renjie Xue,Fang Gao,Zhenguang Mao,Meilin Wang,Zhengdong Zhang
Fine particulate matter less than 2.5 µm in diameter (PM 2.5 ) is a major risk factor for acute asthma attacks in children. However, the biological mechanism underlying this association remains unclear. In the present study, PM 2.5 -treated HBE cells-secreted extracellular vesicles (PM 2.5 -EVs) caused cytotoxicity in “horizontal” HBE cells and increased the contractility of “longitudinal” sensitive human bronchial smooth muscle cells (HBSMCs). RNA sequencing showed that let-7i-5p is significantly overexpressed in PM 2.5 -EVs and asthmatic plasma; additionally, its level is correlated with PM 2.5 exposure in children with asthma. The combination of EV-packaged let-7i-5p and the traditional clinical biomarker IgE exhibits the best diagnostic performance (area under the curve [AUC] = 0.855, 95% CI = 0.786–0.923). Mechanistically, let-7i-5p is packaged into PM 2.5 -EVs by interacting with ELAVL1 and internalized by both “horizontal” recipient HBE cells and “longitudinal” recipient-sensitive HBSMCs, with subsequent activation of the MAPK signaling pathway via suppression of its target DUSP1 . Furthermore, an injection of EV-packaged let-7i-5p into PM 2.5 -treated juvenile mice aggravated asthma symptoms. This comprehensive study deciphered the remodeling of the extracellular environment mediated by the secretion of let-7i-5p-enriched EVs during PM 2.5 -induced asthma attacks and identified plasma EV-packaged let-7i-5p as a novel predictor of childhood asthma.
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Food & Function
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2021
·Vol. 12
·期 16
·7198-7213
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IF 5.396
Xinyao Liu,Fei Zheng,Sheng Li,Zhitong Wang,Xinyuan Wang,Liankui Wen,Yang He
Malvidin (MV) and its derivatives, such as malvidin-3-O-guaiacol (Mv3C) and malvidin-3-O-6-(acrylic acid-(2-hydroxy,4-carboxy-cyclohexanol)ester)-guaiacol (Mv3ACEC), are natural compounds with antioxidant properties. However, the basic mechanisms underlying their functional activities are unclear. In this study, we show that MV, Mv3C, and Mv3ACEC inhibit reactive oxygen species production and malondialdehyde content, promote glutathione peroxidase activity, and increase superoxide dismutase levels in ARPE-19 cells treated with H2O2. Western blotting and immunofluorescence analysis revealed that MV, Mv3C, and Mv3ACEC regulate mitogen-activated protein kinase signal transduction pathways related to endoplasmic reticulum stress. Interestingly, Mv3C and Mv3ACEC showed greater beneficial properties than MV. Our results show that MV and its derivatives have potential as therapeutic compounds for ocular diseases associated with oxidative stress, such as age-related macular degeneration.
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Chinese Journal of Natural Medicines
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2018
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IF 1.991
Yan-Zi LI,Zhi-Na MA,Yin-Shi SUN,Shen REN,Shuang JIANG,Wei-Zhe ZHANG,Zi WANG,Wei LI
The present study was designed to evaluate protective activity of an ethanol extract of the stems of Schisandra chinensis (SCE) and explore its possible molecular mechanisms on acetaminophen (APAP) induced hepatotoxicity in a mouse model. The results of HPLC analysis showed that the main components of SCE included schisandrol A, schisandrol B, deoxyschisandrin, schisandrin B, and schisandrin C and their contents were 5.83, 7.11, 2.13, 4.86, 0.42 mg·g −1 , respectively. SCE extract was given for 7 consecutive days before a single hepatotoxic dose of APAP (250 mg·kg −1 ) was injected to mice. Our results showed that SCE pretreatment ameliorated liver dysfunction and oxidative stress, which was evidenced by significant decreases in aspartate transaminase (AST), alanine aminotransferase (ALT), malondialdehyde (MDA) contents and elevations in reduced glutathione (GSH) and superoxide dismutase (SOD) levels. These findings were associated with the result that the SCE pretreatment significantly decreased expression levels of 4-hydroxynonenal (4-HNE) and 3-nitrotyrosine (3-NT). SCE also significantly decreased the expression levels of Bax, mitogen- activated protein kinase (MAPK), and cleaved caspase-3 by APAP exposure. Furthermore, supplementation with SCE suppressed the expression levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), suggesting alleviation of inflammatory response. In summary, these findings from the present study clearly demonstrated that SCE exerted significant alleviation in APAP-induced oxidative stress, inflammation and apoptosis mainly via regulating MAPK and caspase-3 signaling pathways.
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Advanced Healthcare Materials
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2024
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IF 10
Zongpu Han,Yixiong Lin,Xinyu Guo,Jieyun Xu,Xiaomeng Gao,Ruihan Yang,Yuan Zhao,Mixiao Gui,Linjun Zhang,Yuanlong Guo,Zetao Chen
The strategy of re-organogenesis provides an optimal framework for restoring complex organ structures and functions in adult damage. While the focus has often been on restoring organogenesis stem cells, there is limited investigations of reverting the environmental niche to support this approach. The guiding principle of “Nature selects the fittest to survive” drives the intricate dynamic changes in cellular events within the niche environment, especially through immune surveillance. The extracellular matrix (ECM) serves as the “self-associated molecular patterns” of the niche, containing extensive data on cell-niche reaction data and acting as the active tuner of immune surveillance. In this study, hyaluronic acid (HA) is identified as a unique component of the ECM in cranial osteo-organogenesis. Mechanistically, HA activates the Cluster of Differentiation 44 (CD44)-Mitogen-Activated Protein Kinase (MAPK)/Extracellular Signal-Regulated Kinase (ERK)-Ets Variant 1/5 (ETV1/5)- Mannose Receptor C-Type 1 (MRC1) axis in macrophages, establishing a distinct immune surveillance during osteo-organogenesis. Furthermore, HA is utilized as a novel engineered material for an “Osteo-organogenesis niche”, restoring immune surveillance and synergistically regulating stem cells to achieve re-osteo-organogenesis in cranial defects of rats. Taken together, the study unveils a previously unknown strategy for leveraging re-organogenesis by utilizing “organogenesis niche” ECM engineered materials to manipulate immune surveillance, thereby comprehensively regulating stem cells and other tissue cells effectively for re-organogenesis.
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JOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE
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2024
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IF 3.3
Jun-qi Zhan,Jun-xin Wu,Jing-jing Fu,Gao-shang Li,Fang Wu,Yue-wen Chen
BACKGROUND Giant salamander protein peptide is a peptide with rich functional properties. Giant salamander protein peptide KGEYNK (KK-6) is a peptide with both antioxidant and anti-inflammatory properties. The antioxidant and anti-inflammatory mechanisms of KK-6 are still unclear. When we studied the functional mechanism of KK-6, we found that the antioxidant property of KK-6 has a synergistic and promoting effect on anti-inflammatory properties. RESULTS KK-6 enhances cellular resistance to LPS via the MAPK/NF-κB signaling pathway, leading to increased levels of inflammatory factors: interleukin-1β (764.81 ng mL −1 ), interleukin-6 (1.06 ng mL −1 ) and tumor necrosis factor-α (4440.45 ng mL −1 ). KK-6 demonstrates potent antioxidant properties by activating the Nrf2 signaling pathway, resulting in elevated levels of antioxidant enzymes (glutathione peroxidase: 0.03 μg mL −1 ; superoxide dismutase: 0.589 μg mL −1 ) and a reduction in the concentration of the oxidative product malondialdehyde (967.05 μg mL −1 ). CONCLUSION Our findings highlight the great potential of KK-6, a peptide extracted from giant salamander protein, as a remedy for intestinal inflammation. Through its dual role as an antioxidant and anti-inflammatory agent, KK-6 offers a promising avenue for alleviating inflammation-related damage and oxidative stress. This study lays the foundation for further exploration of giant salamander products and highlights their importance in health and novel food development. © 2024 Society of Chemical Industry.
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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2024
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IF 7.7
Yadan Zhang,Xiaoyu Zhang,Tianhan Kai,Lin Zhang,Anping Li
Plant-derived exosome-like nanovesicles (ELNs) are nano-sized vesicles extracted from edible plants. Lycium ruthenicum Murray (LRM) has been gaining increasing attention due to its nutritional and medicinal value, but the ELNs in LRM has not been reported. In this study, LRM-ELNs were obtained, and the proteins, lipids, microRNAs (miRNAs) and active components in LRM tissues and LRM-ELNs was analyzed by LC-MS/MS, LC-MS, high-throughput sequencing techniques, and physical and chemical analysis. LRM-ELNs can be uptaken by PC12 cells through macropinocytosis and caveolin-mediated endocytosis primarily. Transcriptomic and western blot experiments indicate that LRM-ELNs can inhibit Aβ-induced apoptosis in PC12 cells through the MAPK and PI3K/AKT signaling pathways, with miRNAs playing a crucial role. These results indicate that LRM-ELNs have the protection effect on PC12 cells and can be considered as dietary supplements for alleviating neurodegenerative diseases.
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