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学者姓名：李金宇
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Abstract ：
The angiopoietin (Ang)-Tie axis, critical for endothelial cell function and vascular development, is a promising therapeutic target for treating vascular disorders and inflammatory conditions like sepsis. This study aimed to enhance the binding affinity of recombinant Ang1 variants to the Tie2 and explore their therapeutic potential. Structural insights from the Ang1-Tie2 complex enabled the identification of key residues within the Ang1 receptor binding domain (RBD) critical for Tie2 interaction. Molecular dynamics simulations revealed that Met436Arg (M436R) and Ala451Asp (A451D) could improve Ang1's Tie2 binding affinity. One variant, Ang1-RBDA451D, demonstrated a 100-fold increase compared to the wild type. Cellular assays revealed that Ang1A451D enhanced Tie2 phosphorylation, promoting endothelial cell migration and tube formation. In vivo, this variant effectively reduced inflammatory cytokines and attenuated organ damage in septic mice. These findings highlight Ang1A451D as a promising therapeutic candidate for vascular diseases, offering notable clinical potential for mitigating sepsis-related vascular dysfunction.
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| GB/T 7714 | Wang, Rui , Li, Hao , Xie, Zhinuo et al. Development of a recombinant Ang1 variant with enhanced Tie2 binding and its application to attenuate sepsis in mice [J]. | SCIENCE ADVANCES , 2025 , 11 (3) . |
| MLA | Wang, Rui et al. "Development of a recombinant Ang1 variant with enhanced Tie2 binding and its application to attenuate sepsis in mice" . | SCIENCE ADVANCES 11 . 3 (2025) . |
| APA | Wang, Rui , Li, Hao , Xie, Zhinuo , Huang, Meijuan , Xu, Peng , Yuan, Cai et al. Development of a recombinant Ang1 variant with enhanced Tie2 binding and its application to attenuate sepsis in mice . | SCIENCE ADVANCES , 2025 , 11 (3) . |
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The development of RNA interference (RNAi) therapy offers a potential solution for Alzheimer's disease (AD). However, the brain-blood barrier (BBB) with its selective permeability and pharmacokinetic-related challenges poses restrictions on the delivery of small interfering RNA (siRNA) to the central nervous system (CNS). In this study, we demonstrate that the incorporation of 2 '-fluoro (2 '-F) substitutions and L-carnitine modification facilitates the self-assembly of siRNA through triple interaction, leading to the formation of nanorings, called LCSF-NR. Based on the enhanced cellular uptake and lysosomal escape by 2 '-F substitution and the transport across the BBB promoted by L-carnitine, the nanorings realized the improved brain-targeted delivery of siRNA, both in zebrafish and mice models. Moreover, our findings highlight the therapeutic potential of LCSF-NR formulation in an AD zebrafish model through a synergistic effect of downregulating the beta-site APP cleavage enzyme 1 (BACE1) gene and L-carnitine-mediated neuroprotection, effectively inhibiting pathological processes. Overall, these results suggest that the chemical modification-based siRNA self-assembly strategy enables trans-BBB delivery and presents a concise approach for synergistic therapy of AD.
Keyword ：
Alzheimer's disease Alzheimer's disease blood-brain barrier blood-brain barrier chemical modification chemical modification self-assembly self-assembly siRNA siRNA
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| GB/T 7714 | Jiang, Yifan , Li, Lisha , Fang, Xiao et al. Self-assembling chemically modified siRNA nanorings for RNAi therapy and neuroprotection in Alzheimer's disease [J]. | SCIENCE CHINA-CHEMISTRY , 2025 , 68 (6) : 2552-2564 . |
| MLA | Jiang, Yifan et al. "Self-assembling chemically modified siRNA nanorings for RNAi therapy and neuroprotection in Alzheimer's disease" . | SCIENCE CHINA-CHEMISTRY 68 . 6 (2025) : 2552-2564 . |
| APA | Jiang, Yifan , Li, Lisha , Fang, Xiao , Zeng, Tao , Su, Lichao , Liu, Yichang et al. Self-assembling chemically modified siRNA nanorings for RNAi therapy and neuroprotection in Alzheimer's disease . | SCIENCE CHINA-CHEMISTRY , 2025 , 68 (6) , 2552-2564 . |
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The heterogeneity of hepatocellular carcinoma (HCC) and the complexity of the tumor microenvironment (TME) pose challenges to efficient drug delivery and the antitumor efficacy of combined or synergistic therapies. Herein, a metal-coordinated carrier-free nanodrug (named as USFe3+ LA NPs) was developed for ferroptosis-mediated multimodal synergistic anti-HCC. Natural product ursolic acid (UA) was incorporated to enhance the sensitivity of tumor cells to sorafenib (SRF). Surface decoration of cell penetration peptide and epithelial cell adhesion molecule aptamer facilitated the uptake of USFe3+ LA NPs by HepG2 cells. Meanwhile, Fe3+ ions could react with intracellular hydrogen peroxide, generating toxic hydroxyl radical (& sdot;OH) for chemodynamical therapy (CDT) and amplified ferroptosis by cystine/glutamate antiporter system (System Xc ), which promoted the consumption of glutathione (GSH) and inhibited the expression of glutathione peroxidase 4 (GPX4). Notably, these all-in-one nanodrugs could inhibit tumor metastasis and induced immunogenic cell death (ICD). Last but not least, the nanodrugs demonstrated favorable biocompatibility, augmenting the immune response against the programmed death-ligand 1 (PD-L1) by increasing cytotoxic T cell infiltration. In vivo studies revealed significant suppression of tumor growth and distant metastasis. Overall, our work introduced a novel strategy for applications of metalcoordinated co-assembled carrier-free nano-delivery system in HCC combination therapy, especially in the realms of cancer metastasis prevention and immunotherapy.
Keyword ：
Chemodynamical therapy Chemodynamical therapy Ferroptosis Ferroptosis Immunotherapy Immunotherapy Metal -coordinated nanoplatform Metal -coordinated nanoplatform Synergistic chemotherapy Synergistic chemotherapy
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| GB/T 7714 | Zhao, Rui-Rui , Wu, Ju-Hong , Li, Jin -Yu et al. Multifunctional metal-coordinated Co-assembled carrier-free nanoplatform based on dual-drugs for ferroptosis-mediated cocktail therapy of hepatocellular carcinoma growth and metastasis [J]. | JOURNAL OF COLLOID AND INTERFACE SCIENCE , 2024 , 660 : 257-276 . |
| MLA | Zhao, Rui-Rui et al. "Multifunctional metal-coordinated Co-assembled carrier-free nanoplatform based on dual-drugs for ferroptosis-mediated cocktail therapy of hepatocellular carcinoma growth and metastasis" . | JOURNAL OF COLLOID AND INTERFACE SCIENCE 660 (2024) : 257-276 . |
| APA | Zhao, Rui-Rui , Wu, Ju-Hong , Li, Jin -Yu , Lu, Yu-sheng , Shao, Jing -Wei . Multifunctional metal-coordinated Co-assembled carrier-free nanoplatform based on dual-drugs for ferroptosis-mediated cocktail therapy of hepatocellular carcinoma growth and metastasis . | JOURNAL OF COLLOID AND INTERFACE SCIENCE , 2024 , 660 , 257-276 . |
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Sialylation, a critical post-translational modification, regulates glycoprotein structure and function by tuning their molecular heterogeneity. However, characterizing its subtle and dynamic conformational effects at the intact glycoprotein level remains challenging. We introduce a glycoform-resolved unfolding approach based on a high-throughput ion mobility-mass spectrometry (IM-MS) platform. This method integrates high-throughput unfolding with parallel fragmentation, enabling simultaneous analysis of sialylation patterns, stoichiometries, and their impact on conformational stability. Applying this approach to fetuin, we identified distinct sialylation patterns and their differential influence on protein conformation, namely sialylation-induced stabilization during early unfolding and increased flexibility in later unfolding stages. IM-MS-guided molecular dynamics simulations revealed that increased sialylation enhances the initial conformational stability, likely through enhanced electrostatic interactions and hydrogen bonding. These findings highlight the complex interplay between sialylation and protein dynamics and establish glycoform-resolved unfolding IM-MS as a powerful tool for characterizing glycoprotein conformational landscapes. A glycoform-resolved unfolding ion mobility-mass spectrometry approach reveals how sialylation patterns modulate glycoprotein conformational stability and dynamics, providing insights into the relationship between sialylation and protein structure.
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| GB/T 7714 | Jia, Yifei , Liu, Yichang , Wang, Yamei et al. Sialylation-induced stabilization of dynamic glycoprotein conformations unveiled by time-aligned parallel unfolding and glycan release mass spectrometry [J]. | CHEMICAL SCIENCE , 2024 , 15 (35) : 14431-14439 . |
| MLA | Jia, Yifei et al. "Sialylation-induced stabilization of dynamic glycoprotein conformations unveiled by time-aligned parallel unfolding and glycan release mass spectrometry" . | CHEMICAL SCIENCE 15 . 35 (2024) : 14431-14439 . |
| APA | Jia, Yifei , Liu, Yichang , Wang, Yamei , Li, Jinyu , Li, Gongyu . Sialylation-induced stabilization of dynamic glycoprotein conformations unveiled by time-aligned parallel unfolding and glycan release mass spectrometry . | CHEMICAL SCIENCE , 2024 , 15 (35) , 14431-14439 . |
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Because of the high similarity in structure and sequence, it is challenging to distinguish the S1 pocket among serine proteases, primarily due to the only variability at residue 190 (A190 and S190). Peptide or protein-based inhibitors typically target the negatively charged S1 pocket using lysine or arginine as the P1 residue, yet neither discriminates between the two S1 pocket variants. This study introduces two arginine analogues, L-4-guanidinophenylalanine (12) and L-3-(N-amidino-4-piperidyl)alanine (16), as novel P1 residues in peptide inhibitors. 16 notably enhances affinities across all tested proteases, whereas 12 specifically improved affinities towards proteases possessing S190 in the S1 pocket. By crystallography and molecular dynamics simulations, we discovered a novel mechanism involving a water exchange channel at the bottom of the S1 pocket, modulated by the variation of residue 190. Additionally, the specificity of 12 towards the S190-presenting S1 pocket is dependent on this water channel. This study not only introduces novel P1 residues to engineer inhibitory potency and specificity of peptide inhibitors targeting serine proteases, but also unveils a water-mediated molecular mechanism of targeting serine proteases.
Keyword ：
P1 residue P1 residue Peptide inhibitors Peptide inhibitors S1 pocket S1 pocket Serine protease Serine protease Specificity Specificity
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| GB/T 7714 | Lin, Haili , Xu, Mingming , Jiang, Longguang et al. Water-medicated specifically targeting the S1 pockets among serine proteases using an arginine analogue [J]. | BIOORGANIC CHEMISTRY , 2024 , 152 . |
| MLA | Lin, Haili et al. "Water-medicated specifically targeting the S1 pockets among serine proteases using an arginine analogue" . | BIOORGANIC CHEMISTRY 152 (2024) . |
| APA | Lin, Haili , Xu, Mingming , Jiang, Longguang , Yuan, Cai , Jiang, Chuan , Huang, Mingdong et al. Water-medicated specifically targeting the S1 pockets among serine proteases using an arginine analogue . | BIOORGANIC CHEMISTRY , 2024 , 152 . |
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l-Tryptophan decarboxylase (TDC) and l-3,4-dihydroxyphenylalanine decarboxylase (DDC) catalyze the decarboxylation of l-tryptophan, 5-hydroxytryptophan, and l-3,4-dihydroxyphenylalanine. In this study, we analyzed the amino acid compositions of the substrate-binding pockets of TDC from Catharanthus roseus (CrTDC) and DDC from Sus scrofa (SsDDC), explored the specificity of key amino acids within these pockets, and elucidated mechanisms influencing substrate selectivity and catalytic activity in both enzymes, using whole-cell catalysis to screen mutants and determine enzymatic kinetic parameters. The results demonstrated that residues Ala-103 and Val-122 in CrTDC, along with their corresponding sites Thr-82 and Ile-101 in SsDDC, significantly influence substrate selectivity and catalytic efficiency. Molecular dynamics simulations revealed that substrate selectivity and catalytic efficiency depends on the nucleophilic attack distance between the substrate's amino group and the C4 ' of pyridoxal 5 '-phosphate. This study elucidates the catalytic mechanisms and structural bases of TDC and DDC, guiding enhancements in the related aromatic monoamine biosynthesis.
Keyword ：
catalytic efficiency catalytic efficiency CrTDC CrTDC moleculardynamics moleculardynamics SsDDC SsDDC substrate selectivity substrate selectivity
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| GB/T 7714 | Liu, Qinghao , Wu, Juhong , Chen, Maosen et al. Unraveling the Molecular Determinants of Catalytic Efficiency and Substrate Specificity in l-Amino Acid Decarboxylases [J]. | JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY , 2024 , 72 (48) : 26996-27006 . |
| MLA | Liu, Qinghao et al. "Unraveling the Molecular Determinants of Catalytic Efficiency and Substrate Specificity in l-Amino Acid Decarboxylases" . | JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 72 . 48 (2024) : 26996-27006 . |
| APA | Liu, Qinghao , Wu, Juhong , Chen, Maosen , Zhong, Jie , Huang, Jianzhong , Wang, Bingmei et al. Unraveling the Molecular Determinants of Catalytic Efficiency and Substrate Specificity in l-Amino Acid Decarboxylases . | JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY , 2024 , 72 (48) , 26996-27006 . |
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The transport behaviors of aqueous solution in two-dimensional (2D) nanomaterial-based separation membranes are correlated with the structure of the nanoconfined geometry. However, little is known about the impact of asymmetric structures on the transport behavior of aqueous solutions in membranes. In this work, we use molecular dynamics (MD) simulations to investigate the transport behaviors of aqueous solution in non-parallel stacked graphitic carbon nitride (g-C3N4) nanochannels. Interestingly, the non-parallel stacking of g-C3N4 could lead to the local aggregation of water, resulting in an inhomogeneous density distribution within the nanochannel. The high-density region in g-C3N4 nanochannel significantly disrupted the continuum fluid of water. Moreover, the inhomogeneous density distribution of water could impede ion transport in the non-parallel g-C3N4 nanochannel. It was found that ions cannot maintain compact hydration structures in the high-density region. This work reveals the unique properties of slightly tilted membrane structures, providing novel perspective for the design of next-generation nanofluidic devices.
Keyword ：
Desalination Desalination Graphitic carbon nitride Graphitic carbon nitride Inhomogeneous confined structure Inhomogeneous confined structure Molecular dynamics Molecular dynamics Two-dimensional nanochannel Two-dimensional nanochannel
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| GB/T 7714 | Liu, Yichang , Zou, Yujin , Zhu, Hao et al. Effect of inhomogeneous structure on the water desalination performance of graphitic carbon nitride nanochannels: A molecular dynamics study [J]. | JOURNAL OF MOLECULAR LIQUIDS , 2024 , 396 . |
| MLA | Liu, Yichang et al. "Effect of inhomogeneous structure on the water desalination performance of graphitic carbon nitride nanochannels: A molecular dynamics study" . | JOURNAL OF MOLECULAR LIQUIDS 396 (2024) . |
| APA | Liu, Yichang , Zou, Yujin , Zhu, Hao , Xie, Song , Wu, Juhong , Li, Jinlong et al. Effect of inhomogeneous structure on the water desalination performance of graphitic carbon nitride nanochannels: A molecular dynamics study . | JOURNAL OF MOLECULAR LIQUIDS , 2024 , 396 . |
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Proper chromosome segregation during cell division relies on the timely dissolution of chromosome cohesion. Separase (EC 3.4.22.49), a cysteine protease, plays a critical role in mitosis by cleaving the kleisin subunit of cohesin, thereby presenting a promising target for cancer therapy. However, challenges in isolating active human separase suitable for high-throughput screening have limited the identification of effective inhibitors. Here, we conducted a high-throughput screening of small-molecule inhibitors using the protease domain of Chaetomium thermophilum separase (ctSPD), which not only shares significant sequence similarity with human separase but is also readily available. After conducting a primary screening of a library containing 9,172 compounds and subsequent validation using human separase, we identified walrycin B and its analogs, toxoflavin, 3-methyltoxoflavin, and 3-phenyltoxoflavin, as potent inhibitors of human separase. Subsequent microscale thermophoresis assays and molecular dynamics simulations revealed that walrycin B binds to the active site of separase and competes with substrates for binding. Additionally, cell-based studies showed that walrycin B and its analogs effectively induce cell cycle arrest at the M phase, activate apoptosis, and ultimately lead to cell death in mitosis. Finally, in a mouse xenograft model, walrycin B exhibited significant antitumor efficacy with minimal side effects. Together, these findings highlight the therapeutic potential of walrycin B for cancer treatment and its utility as a chemical tool in future studies involving separase.
Keyword ：
Anticancer Anticancer Inhibitor Inhibitor Separase Separase Toxoflavin Toxoflavin Walrycin B Walrycin B
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| GB/T 7714 | Zhu, Qinwei , Du, Liyang , Wu, Juhong et al. Walrycin B, as a novel separase inhibitor, exerts potent anticancer efficacy in a mouse xenograft model [J]. | BIOCHEMICAL PHARMACOLOGY , 2024 , 229 . |
| MLA | Zhu, Qinwei et al. "Walrycin B, as a novel separase inhibitor, exerts potent anticancer efficacy in a mouse xenograft model" . | BIOCHEMICAL PHARMACOLOGY 229 (2024) . |
| APA | Zhu, Qinwei , Du, Liyang , Wu, Juhong , Li, Jinyu , Lin, Zhonghui . Walrycin B, as a novel separase inhibitor, exerts potent anticancer efficacy in a mouse xenograft model . | BIOCHEMICAL PHARMACOLOGY , 2024 , 229 . |
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The combination of infrared spectroscopy (IR) and ion mobility mass spectrometry (IM-MS) has revealed that protein secondary structures are retained upon transformation from aqueous solution to the gas phase under gentle conditions. Yet the details about where and how these structural elements are embedded in the gas phase remain elusive. In this study, we employ long time scale molecular dynamics (MD) simulations to examine the extent to which proteins retain their solution structures and the impact of protonation state on the stability of secondary structures in the gas phase. Our investigation focuses on two well-studied proteins, myoglobin and beta-lactoglobulin, representing typical helical and beta-sheet proteins, respectively. Our simulations accurately reproduce the experimental collision cross section (CCS) data measured by IM-MS. Based on accurately reproducing previous experimental collision cross section data and dominant secondary structural species obtained from IM-MS and IR, we confirm that both proteins largely retain their native secondary structural components upon passing from aqueous solution to the gas phase. However, we observe significant reductions in secondary structure contents (19.2 +/- 1.2% for myoglobin and 7.3 +/- 0.6% for beta-lactoglobulin) in specific regions predominantly composed of ionizable residues. Further mechanistic analysis suggests that alterations in protonation states of these residues after phase transition induce changes in their local interaction networks and backbone dihedral angles, which potentially promote the unfolding of secondary structures in the gas phase. We anticipate that similar protonation state induced unfolding may be observed in other proteins possessing distinct secondary structures. Further studies on a broader array of proteins will be essential to refine our understanding of protein structural behavior during the transition to the gas phase.
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| GB/T 7714 | Yang, Guiqian , Zhang, Lanbi , Xie, Song et al. Protonation State-Induced Unfolding of Protein Secondary Structure in the Gas Phase [J]. | JOURNAL OF PHYSICAL CHEMISTRY LETTERS , 2024 , 15 (37) : 9374-9379 . |
| MLA | Yang, Guiqian et al. "Protonation State-Induced Unfolding of Protein Secondary Structure in the Gas Phase" . | JOURNAL OF PHYSICAL CHEMISTRY LETTERS 15 . 37 (2024) : 9374-9379 . |
| APA | Yang, Guiqian , Zhang, Lanbi , Xie, Song , Wu, Juhong , Khan, Majid , Zhang, Yongqi et al. Protonation State-Induced Unfolding of Protein Secondary Structure in the Gas Phase . | JOURNAL OF PHYSICAL CHEMISTRY LETTERS , 2024 , 15 (37) , 9374-9379 . |
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The intracellular bacterial pathogen Legionella pneumophila modulates host cell functions by secreting multiple effectors with diverse biochemical activities. In particular, effectors of the SidE family interfere with host protein ubiquitination in a process that involves production of phosphoribosyl ubiquitin (PR-Ub). Here, we show that effector LnaB converts PR-Ub into ADP-ribosylated ubiquitin, which is further processed to ADP-ribose and functional ubiquitin by the (ADP-ribosyl)hydrolase MavL, thus maintaining ubiquitin homeostasis in infected cells. Upon being activated by actin, LnaB also undergoes self-AMPylation on tyrosine residues. The activity of LnaB requires a motif consisting of Ser, His and Glu (SHxxxE) present in a large family of toxins from diverse bacterial pathogens. Thus, our study sheds light on the mechanisms by which a pathogen maintains ubiquitin homeostasis and identifies a family of enzymes capable of protein AMPylation. The bacterial pathogen Legionella pneumophila secretes effectors that affect protein ubiquitination within host cells, involving production of phosphoribosyl ubiquitin (PR-Ub). Here, the authors identify additional effectors that convert PR-Ub back into functional ubiquitin, thus maintaining ubiquitin homeostasis in infected cells.
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| GB/T 7714 | Fu, Jiaqi , Li, Siying , Guan, Hongxin et al. Legionella maintains host cell ubiquitin homeostasis by effectors with unique catalytic mechanisms [J]. | NATURE COMMUNICATIONS , 2024 , 15 (1) . |
| MLA | Fu, Jiaqi et al. "Legionella maintains host cell ubiquitin homeostasis by effectors with unique catalytic mechanisms" . | NATURE COMMUNICATIONS 15 . 1 (2024) . |
| APA | Fu, Jiaqi , Li, Siying , Guan, Hongxin , Li, Chuang , Zhao, Yan-Bo , Chen, Tao-Tao et al. Legionella maintains host cell ubiquitin homeostasis by effectors with unique catalytic mechanisms . | NATURE COMMUNICATIONS , 2024 , 15 (1) . |
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