Cellular & Molecular Immunology
·
2022
·Vol. 19
·期 5
·602-618
·
IF 22.096
Ma Xiaojian,Tan Xi,Yu Bingbing,Sun Wanwei,Wang Heping,Hu Huijun,Du Yanyun,He Ruirui,Gao Ru,Peng Qianwen,Cui Zhihui,Pan Ting,Feng Xiong,Wang Junhan,Xu Chengqi,Zhu Bin,Liu Wei,Wang Chenhui
Fungal infections cause ~1.5 million deaths each year worldwide, and the mortality rate of disseminated candidiasis currently exceeds that of breast cancer and malaria. The major reasons for the high mortality of candidiasis are the limited number of antifungal drugs and the emergence of drug-resistant species. Therefore, a better understanding of antifungal host defense mechanisms is crucial for the development of effective preventive and therapeutic strategies. Here, we report that DOCK2 (dedicator of cytokinesis 2) promotes indispensable antifungal innate immune signaling and proinflammatory gene expression in macrophages. DOCK2-deficient macrophages exhibit decreased RAC GTPase (Rac family small GTPase) activation and ROS (reactive oxygen species) production, which in turn attenuates the killing of intracellular fungi and the activation of downstream signaling pathways. Mechanistically, after fungal stimulation, activated SYK (spleen-associated tyrosine kinase) phosphorylates DOCK2 at tyrosine 985 and 1405, which promotes the recruitment and activation of RAC GTPases and then increases ROS production and downstream signaling activation. Importantly, nanoparticle-mediated delivery of in vitro transcribed (IVT) Rac1 mRNA promotes the activity of Rac1 and helps to eliminate fungal infection in vivo. Taken together, this study not only identifies a critical role of DOCK2 in antifungal immunity via regulation of RAC GTPase activity but also provides proof of concept for the treatment of invasive fungal infections by using IVT mRNA.
研究领域:
免疫学
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微生物学
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分子生物学
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药理学
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DOI
PubMed
高影响因子
EBioMedicine
·
2024
·
IF 9.7
Harry Cheuk-Hay Lau,Xiang Zhang,Fenfen Ji,Yufeng Lin,Wei Liang,Qing Li,Danyu Chen,Winnie Fong,Xing Kang,Weixin Liu,Eagle Siu-Hong Chu,Queena Wing-Yin Ng,Jun Yu
Abstract
Background: Gut probiotic depletion is associated with non-alcoholic fatty liver disease-associated hepatocellular carcinoma (NAFLD-HCC). Here, we investigated the prophylactic potential of Lactobacillus acidophilus against NAFLD-HCC.
Methods: NAFLD-HCC conventional and germ-free mice were established by diethylnitrosamine (DEN) injection with feeding of high-fat high-cholesterol (HFHC) or choline-deficient high-fat (CDHF) diet. Orthotopic NAFLD-HCC allografts were established by intrahepatic injection of murine HCC cells with HFHC feeding. Metabolomic profiling was performed using liquid chromatography-mass spectrometry. Biological functions of L. acidophilus conditional medium (L.a CM) and metabolites were determined in NAFLD-HCC human cells and mouse organoids.
Findings: L. acidophilus supplementation suppressed NAFLD-HCC formation in HFHC-fed DEN-treated mice. This was confirmed in orthotopic allografts and germ-free tumourigenesis mice. L.a CM inhibited the growth of NAFLD-HCC human cells and mouse organoids. The protective function of L. acidophilus was attributed to its non-protein small molecules. By metabolomic profiling, valeric acid was the top enriched metabolite in L.a CM and its upregulation was verified in liver and portal vein of L. acidophilus-treated mice. The protective function of valeric acid was demonstrated in NAFLD-HCC human cells and mouse organoids. Valeric acid significantly suppressed NAFLD-HCC formation in HFHC-fed DEN-treated mice, accompanied by improved intestinal barrier integrity. This was confirmed in another NAFLD-HCC mouse model induced by CDHF diet and DEN. Mechanistically, valeric acid bound to hepatocytic surface receptor GPR41/43 to inhibit Rho-GTPase pathway, thereby ablating NAFLD-HCC.
Interpretation: L. acidophilus exhibits anti-tumourigenic effect in mice by secreting valeric acid. Probiotic supplementation is a potential prophylactic of NAFLD-HCC.
研究领域:
微生物学
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肝病学
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癌症生物学
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代谢组学
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DOI
PubMed
高影响因子
Frontiers in Plant Science
·
2023
·
IF 5.6
Haihong Chen,Yiyi Hu,Guanpin Yang,Pingping Li,Jingru Yin,Xiaoqing Feng,Qiong Wu,Jingyu Zhang,Baoheng Xiao,Zhenghong Sui
Macropinocytosis is an endocytic process that plays an important role in animal development and disease occurrence but until now has been rarely reported in organisms with cell walls. We investigated the properties of endocytosis in a red alga, Gracilariopsis lemaneiformis . The cells non-selectively internalized extracellular fluid into large-scale endocytic vesicles (1.94 ± 0.51 μm), and this process could be inhibited by 5-(N-ethyl-N-isopropyl) amiloride, an macropinocytosis inhibitor. Moreover, endocytosis was driven by F-actin, which promotes formation of ruffles and cups from the cell surface and facilitates formation of endocytotic vesicles. After vesicle formation, endocytic vesicles could be acidified and acquire digestive function. These results indicated macropinocytosis in G. lemaneiformis . Abundant phosphatidylinositol kinase and small GTPase encoding genes were found in the genome of this alga, while PI3K, Ras, and Rab5, the important participators of traditional macropinocytosis, seem to be lacked. Such findings provide a new insight into endocytosis in organisms with cell walls and facilitate further research into the core regulatory mechanisms and evolution of macropinocytosis.
研究领域:
植物学
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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
INDUSTRIAL CROPS AND PRODUCTS
·
2022
·
IF 6.449
Meiling Sun,Zhenghui Luo,Qi Yang,Chunxu Huang,Yu Kuang,Mei Kang,Jie Liu
Methicillin-resistant Staphylococcus aureus (MRSA) has evolved to tolerate almost all known β-lactam antibiotics, and been exhibiting resistance to vancomycin . Developing new drugs against the MRSA infection are urgently needed. Natural resource is enriched with antimicrobial molecules. Here, we report an extract from leaves of Cyclocarya paliurus (ECPL), a species of tree native to China and being traditionally cultivated as medicinal plant , which shows a broad spectrum of bacteriostatic and bactericidal effects at MIC 50 15.99 ± 0.55 μg/ml against methicillin-susceptible and -resistant S. aureus . The ECPL suppresses bacterial expression of FtsZ at both transcriptional and protein levels, inhibits its GTPase activity, blocks the assembly dynamics of FtsZ, and disrupts the formation of Z-ring. The bacteria cells fail to divide, enlarge initially, and lyse eventually. In mouse model, the ECPL facilitates skin wound healing with MRSA infection as effective as vancomycin. Our study unveils the potential of identifying novel molecule in ECPL for development of new class of antibiotic against both methicillin-susceptible and -resistant S. aureus , and support domestication of the C. paliurus growing from wild to cultivated, and further scale up the cultivation into industrialized farm for sustainable harvest for pharmaceutic interest.
研究领域:
微生物学
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药理学
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植物科学
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传染病学
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产品关联
DOI
高影响因子
MOLECULAR CELL
·
2023
·
IF 16
Chenchen Xu,Xiaoqing Pan,Dong Wang,Yuanyuan Guan,Wenyu Yang,Xing Chen,Ying Liu
The mechanistic target of rapamycin complex 1 (mTORC1) regulates metabolism and cell growth in response to nutrient levels. Dysregulation of mTORC1 results in a broad spectrum of diseases. Glucose is the primary energy supply of cells, and therefore, glucose levels must be accurately conveyed to mTORC1 through highly responsive signaling mechanisms to control mTORC1 activity. Here, we report that glucose-induced mTORC1 activation is regulated by O-GlcNAcylation of Raptor, a core component of mTORC1, in HEK293T cells. Mechanistically, O-GlcNAcylation of Raptor at threonine 700 facilitates the interactions between Raptor and Rag GTPases and promotes the translocation of mTOR to the lysosomal surface, consequently activating mTORC1. In addition, we show that AMPK-mediated phosphorylation of Raptor suppresses Raptor O-GlcNAcylation and inhibits Raptor-Rags interactions. Our findings reveal an exquisitely controlled mechanism, which suggests how glucose coordinately regulates cellular anabolism and catabolism.
研究领域:
细胞生物学
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分子生物学
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代谢
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信号通路
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DOI
PubMed
高影响因子
JOURNAL OF VIROLOGY
·
2024
·
IF 4
Qiankai Shi,Ran Zhao,Linna Chen,Tianyi Liu,Tao Di,Chunwei Zhang,Zhiying Zhang,Fangfang Wang,Zongxi Han,Junfeng Sun,Shengwang Liu
As an intrinsic cellular mechanism responsible for the internalization of extracellular ligands and membrane components, caveolae-mediated endocytosis (CavME) is also exploited by certain pathogens for endocytic entry [e.g., Newcastle disease virus (NDV) of paramyxovirus]. However, the molecular mechanisms of NDV-induced CavME remain poorly understood. Herein, we demonstrate that sialic acid-containing gangliosides, rather than glycoproteins, were utilized by NDV as receptors to initiate the endocytic entry of NDV into HD11 cells. The binding of NDV to gangliosides induced the activation of a non-receptor tyrosine kinase, Src, leading to the phosphorylation of caveolin-1 (Cav1) and dynamin-2 (Dyn2), which contributed to the endocytic entry of NDV. Moreover, an inoculation of cells with NDV-induced actin cytoskeletal rearrangement through Src to facilitate NDV entry via endocytosis and direct fusion with the plasma membrane. Subsequently, unique members of the Rho GTPases family, RhoA and Cdc42, were activated by NDV in a Src-dependent manner. Further analyses revealed that RhoA and Cdc42 regulated the activities of specific effectors, cofilin and myosin regulatory light chain 2, responsible for actin cytoskeleton rearrangement, through diverse intracellular signaling cascades. Taken together, our results suggest that an inoculation of NDV-induced Src-mediated cellular activation by binding to ganglioside receptors. This process orchestrated NDV endocytic entry by modulating the activities of caveolae-associated Cav1 and Dyn2, as well as specific Rho GTPases and downstream effectors.
研究领域:
病毒学
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细胞生物学
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分子生物学
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免疫学
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产品关联
DOI
PubMed
高影响因子
SPECTROCHIMICA ACTA PART A-MOLECULAR AND BIOMOLECULAR SPECTROSCOPY
·
2024
·
IF 4.3
Xinru Wu,Chen Ruan,Siqi Zhou,Lina Zou,Rong Wang,Gaiping Li
Tandem enzyme can catalyze some cascade reactions with high efficiency, and some few tandem enzyme-like mimics have been discovered recently. Further improving the catalytic efficiency of tandem nanoenzymes with facile method may undoubtedly promote and broaden their applications in various fields. In this work, cupric oxide nanoparticles (CuO NPs) with dual-functional enzyme mimics were synthesized using the rapid deposition method in advance, which simultaneously combined with lanthanide infinite coordination polymers (Ln ICPs) during the self-assemble of Tb 3+ , guanine-5′-triphosphate (GTP) and auxiliary ligand terephthalic acid (TA). Excitingly, the obtained Tb-GTP/TA@CuO ICPs, not only displayed obviously enhanced tandem catalytic activity compared with pure CuO NPs, but also provided a versatile ratiometric platform for ultrahigh selective and sensitive detection of glutathione (GSH) under single-wavelength excitation. A good linear relationship between the ratio signal and the GSH concentration was spanning from 0.001 to 20 μM with an impressive detection limit of 0.50 nM. This study opens a new and universal avenue for preparing integrated multifunctional probes by coupling of nanoenzyme catalytic activity with superior luminescent Ln ICPs through facile method.
研究领域:
材料科学
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纳米技术
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分析化学
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生物化学
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产品关联
DOI
PubMed
高影响因子
CANCER GENE THERAPY
·
2022
·Vol. 29
·期 12
·1939-1950
·
IF 5.854
Yang Fan,Li Lin,Mu Zhenzhen,Liu Pengyue,Wang Ying,Zhang Yue,Han Xiuping
The nuclear import receptor karyopherin β1 (KPNB1), a member of the Karyopherin protein family, is reported to be overexpressed in various cancers and promote carcinogenesis. By analyzing the correlation between the expression of KPNB1 and the overall survival rate of melanoma patients, we found that melanoma patients with higher expression of KPNB1 had worse survival. Furthermore, the database analyzed that the KPNB1 mRNA level was higher in melanoma samples than that in skin nevus tissues. We thus proposed that KPNB1 played a role in promoting melanoma development, and conducted gain-of- and loss-of-function experiments to test our hypothesis. We found that KPNB1 knockdown significantly retarded the growth and metastasis of melanoma cells in vitro and in vivo, and increased their sensitivity towards the anti-tumor drug cisplatin. KPNB1 overexpression had opposite effects. Notably, in melanoma cells, KPNB1 overexpression significantly decreased Ras-GTPase-activating protein SH3 domain-binding protein 1 (G3BP1) protein level, which was also overexpressed in melanoma samples and enhanced malignant behaviors of melanoma cells. We further demonstrated that KPNB1 overexpression induced deubiquitination of G3BP1, and prevented its degradation. However, KPNB1 overexpression hardly affected the nuclear translocation of G3BP1. Additionally, alterations induced by KPNB1 overexpression were partly reversed by G3BP1 inhibition. Therefore, the results suggest that KPNB1 may promote melanoma progression by stabilizing the G3BP1 protein. KPNB1-G3BP1 axis represents a potential therapeutic targetable node for melanoma.
研究领域:
癌症生物学
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分子生物学
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细胞生物学
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肿瘤学
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产品关联
DOI
PubMed
高影响因子
RESPIRATORY RESEARCH
·
2023
·Vol. 24
·期 1
·1-14
·
IF 5.8
Liu Jin,Chen Yuqian,Chen Huan,Wang Yan,Li Danyang,Zhang Qianqian,Chai Limin,Qiu Yuanjie,Zhang Jia,Shen Nirui,Wang Qingting,Wang Jian,Li Manxiang
Background Macrophage migration inhibitory factor (MIF) and GTPase dynamin-related protein 1 (Drp1)-dependent aberrant mitochondrial fission are closely linked to the pathogenesis of asthma. However, it is unclear whether Drp1-mediated mitochondrial fission and its downstream targets mediate MIF-induced proliferation of airway smooth muscle cells (ASMCs) in vitro and airway remodeling in chronic asthma models. The present study aims to clarify these issues. Methods In this study, primary cultured ASMCs and ovalbumin (OVA)-induced asthmatic rats were applied. Cell proliferation was detected by CCK-8 and EdU assays. Western blotting was used to detect extracellular signal-regulated kinase (ERK) 1/2, Drp1, autophagy-related markers and E-cadherin protein phosphorylation and expression. Inflammatory cytokines production, airway reactivity test, histological staining and immunohistochemical staining were conducted to evaluate the development of asthma. Transmission electron microscopy was used to observe the mitochondrial ultrastructure. Results In primary cultured ASMCs, MIF increased the phosphorylation level of Drp1 at the Ser616 site through activation of the ERK1/2 signaling pathway, which further activated autophagy and reduced E-cadherin expression, ultimately leading to ASMCs proliferation. In OVA-induced asthmatic rats, MIF inhibitor 4-iodo-6-phenylpyrimidine (4-IPP) treatment, suppression of mitochondrial fission by Mdivi-1 or inhibiting autophagy with chloroquine phosphate (CQ) all attenuated the development of airway remodeling. Conclusions The present study provides novel insights that MIF promotes airway remodeling in asthma by activating autophagy and degradation of E-cadherin via ERK/Drp1 signaling pathway, suggesting that targeting MIF/ERK/Drp1 might have potential therapeutic value for the prevention and treatment of asthma.
研究领域:
免疫学
·
肺科学
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细胞生物学
·
药理学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2020
·
IF 4.192
Xiang Zhou,Yu-Mei Feng,Pu-Ying Qi,Wu-Bin Shao,Zhi-Bing Wu,Li-Wei Liu,Yi Wang,Hao-Dong Ma,Pei-Yi Wang,Zhong Li,Song Yang
Xanthomonas oryzae pv. oryzae (Xoo) is an offensive phytopathogen that can invade a wide range of plant hosts to develop bacterial diseases, including the well-known rice bacterial leaf blight. However, few agrochemicals have been identified to effectively prevent and eliminate Xoo-induced diseases. Thus, designing novel antibacterial compounds on the basis of the potential targets from Xoo may lead to the discovery of highly efficient and innovative anti-Xoo agents. Filamentous temperature-sensitive protein Z (FtsZ), an important functional protein in the progression of cell division, has been widely reported and exploited as a target for creating antibacterial drugs in the field of medicine. Therefore, the fabrication of innovative frameworks targeting XooFtsZ may be an effective method for managing bacterial leaf blight diseases via blocking the binary division and reproduction of Xoo. As such, a series of novel N-(cinnamoyl)-N′-(substituted)acryloyl hydrazide derivatives containing pyridinium moieties were designed, and the anti-Xoo activity was determined. The bioassay results showed that compound A7 had excellent anti-Xoo activity (EC50 = 0.99 mg L–1) in vitro and distinct curative activity (63.2% at 200 mg L–1) in vivo. Further studies revealed that these designed compounds were XooFtsZ inhibitors, validating by the reduced GTPase activity of recombinant XooFtsZ, the nonfilamentous XooFtsZ assembly observed in the TEM images, and the prolonged Xoo cells from the fluorescence patterns. Computational docking studies showed that compound A7 had strong interactions with ASN34, GLN193, and GLN197 residues located in the α helix regions of XooFtsZ. The present study demonstrates the developed FtsZ inhibitors can serve as agents to control Xoo-induced infections.
研究领域:
植物病理学
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分子生物学
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药物化学
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产品关联
DOI
PubMed
高影响因子
Biomaterials Advances
·
2023
·
IF 0
Bowen Zhang,Junqing Leng,Zhicong Ouyang,Zijian Yang,Qing Zhang,Qingchu Li,Dichen Li,Huiyu Zhao
Polyetheretherketone (PEEK) has been widely used in the preparation of orthopedic implants due to its biological inertness and similar mechanical modulus to natural bone. However, the affinity between biological tissue (bone and soft tissue) and PEEK surface is weak, leading to low osseointegration and an increased risk of inflammation. The situation could be improved by modifying PEEK surface. Surfaces with good hydrophilicity and proper microtopography would promote cellular adhesion and proliferation. This work presented a two-step surface modification method to achieve the effect. Polyacrylic acid (PAA) chains were grafted on PEEK surface by UV irradiation. Then, ethylenediamine (EDA) was added to introduce amino groups and promote the cross-linking of PAA chains. Furthermore, a mathematical model was built to describe and regulate the surface topography growth process semi-quantitatively. The model fits experimental data quite well (adjusted R 2 = 0.779). Results showed that the modified PEEK surface obtained superhydrophilicity. It significantly improved the adhesion and proliferation of BMSCs and MFBs by activating the FAK pathway and Rho family GTPase. The cellular affinity performed better when the surface topography was in network structure with holes in about 25 μm depth and 20–50 μm diameter. Good hydrophilicity seems necessary for the FAK pathway activation, but simply improving surface hydrophilicity might not be enough for cellular affinity improvement. Surface topography at micron scale should be a more important cue. This simple surface modification method could be contributed to further study of cell-microtopography interaction and have potential applications in clinical PEEK orthopedic implants.
研究领域:
生物材料
·
组织工程
·
骨科
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
JOURNAL OF COLLOID AND INTERFACE SCIENCE
·
2023
·
IF 9.9
Zengyi Liu,Ruixin Kang,Ning Yang,Xiuhua Pan,Jie Yang,Hongjie Yu,Wanli Deng,Zengguang Jia,Jun Zhang,Qi Shen
The induction of immunogenic ferroptosis in cancer cell is limited by the complex and delicate antioxidant system in the organism. Synergistic induction of oxidative damage and inhibition of the defensive redox system in tumor cells is critical to promote lethal accumulation of lipid peroxides and activate immunogenic death (ICD). To address this challenge, we present a multifunctional and dual-responsive layered double hydroxide (LDH) nanosheet to enhance immunogenic ferroptosis. The MTX-LDH@MnO 2 nanoplatform is constructed by intercalating methotrexate (MTX) into LDH interlayers and electrostatically absorbing biomineralized ovalbumin (OVA)-MnO 2 onto the LDH surface. Specifically, the released Mn 2+ from the incorporated MnO 2 triggers a Fenton-like reaction, leading to reactive oxygen species (ROS) accumulation, while the depletion of reduced glutathione (GSH) further intensifies oxidative stress , resulting in the induction of ferroptosis. MTX is released in response to the acidic environment of tumor cells and inhibits the regeneration of tetrahydrobiopterin (BH4), modulating the GTP cyclic hydrolase 1 (GCH1)/BH4 axis. MTX disrupts the antioxidant metabolic activity regulated by GCH1/BH4 axis and inhibits ROS consumption, further boosting the ferroptosis effect, which promoted the release of damage-associated molecular patterns (DAMPs) and triggered ICD in the tumor. This activation subsequently leads to significant antitumor immune reactions, including DCs maturation, infiltration of CD4 + /CD8 + T cells and cytokines release. The redox-controllable nanoplatform demonstrates promising anticancer efficacy in a mouse breast model providing a novel strategy for cancer immunotherapy.
研究领域:
癌症生物学
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纳米技术
·
免疫疗法
·
药理学
·
生物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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