RESPIRATORY RESEARCH
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2026
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IF 5
Zhang Jia,Liu Jin,Chen Yuqian,Chen Huan,Meng Yihan,Wang Yan,Qiu Yuanjie,Hu Huizhong,Shi Wenhua,Li Manxiang,Li Man-xiang
Background Galactose lectin-3 (Gal-3) has been shown to promote the progression of pulmonary arterial hypertension (PAH), yet the intricate molecular mechanisms are still unclear. Methods Primary cultured rat pulmonary arterial smooth muscle cells (PASMCs) and PAH rats were used in this study. Protein phosphorylation and expression levels were identified using Western blotting, while mRNA level was quantified through qRT-PCR. Hemodynamic measurements, hematoxylin-eosin and immunohistochemistry staining were employed to assess the PAH progression. Results Yes-associated protein 1 (YAP1) mediated Gal-3/toll-like receptor 4 (TLR4)-induced PDZ-binding kinase (PBK) upregulation. Furthermore, polo-like kinase 1 (PLK1)/cyclin-dependent kinase 1 (CDK1) mediated Gal-3/TLR4-induced PBK phosphorylation. Activated PBK further phosphorylated protein regulator of cytokinesis 1 (PRC1), which ultimately led to PASMC proliferation. In monocrotaline-induced PAH rat models, inhibition of Gal-3, TLR4, YAP1, CDK1 or silencing of PLK1, PBK, PRC1 attenuated PAH progression. Conclusion Our study presents novel evidence that Gal-3 promotes PASMC proliferation and pulmonary vascular remodeling by activating PBK/PRC1 through the TLR4/YAP1 and TLR4/PLK1/CDK1 signaling pathways, suggesting that this signaling pathway might be a promising target for the treatment of PAH.
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Advanced Science
·
2026
·
IF 14.1
Yuan Zhang,Shucheng Jin,Penghui Guo,Yuying Yin,Yichun Hua,Xiaosheng Ding,Zhe Zhang,Shuo Chen,Xu Han,Baowang Li,Yan Liu,Xiaoyan Li,Deling Li,Jing Jing,Wei Shi,Wang Jia
Meningeal lymphatic vessels (mLVs) contribute to brain immune surveillance; however, their structural and functional alterations in brain metastasis remain incompletely defined. Here, we optimized a magnetic resonance imaging protocol to quantitatively analyze mLV structure and drainage function. Using murine lung adenocarcinoma brain metastasis models and clinical imaging data, we reveal significant mLV disruption surrounding the superior sagittal sinus (SSS), which results in impaired drainage to deep cervical lymph nodes (dCLNs). Among ten cervical lymph-node levels assessed clinically, level IIA lymph nodes most accurately reflect mLV drainage efficiency. Functionally, mLV ablation compromised intrathecal chemotherapy efficacy in mice, while clinically, greater mLV structural and functional impairment correlates with disease progression in lung adenocarcinoma brain metastasis. Collectively, our findings demonstrate that lung adenocarcinoma brain metastases disrupt SSS-adjacent mLVs (mLVs-SSS), which potentially facilitates metastatic progression through compromised immune surveillance.
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Small Methods
·
2023
·
IF 12.4
Peng Wang,Zhangwen Peng,Liu Yu,Yiling Liu,Hanwen Wang,Ziheng Zhou,Hengdeng Liu,Sheng Hong,Yichu Nie,Yang Deng,Yang Liu,Julin Xie
Hypertrophic scarring (HS) is a common skin injury complication with unmet needs. Verteporfin (VP) should be an ideal HS-targeted therapeutic drug due to its efficient fibrosis and angiogenesis inhibitory abilities. However, its application is restricted by its side effects such as dose-dependent cytotoxicity on normal cells. Herein, the bioadhesive nanoparticles encapsulated VP (VP/BNPs) are successfully developed to attenuate the side effects of VP and enhance its HS inhibition effects by limiting VP releasing slowly and stably in the lesion site but not diffusing easily to normal tissues. VP/BNPs displayed significant inhibition on the proliferation, migration, collagen deposition, and vessel formation of human hypertrophic scar fibroblasts (HSFBs) and dermal vascular endothelial cells (HDVECs). In a rat tail HS model, VP/BNPs treated HS exhibits dramatic scar repression with almost no side effects compared with free VP or VP-loaded non-bioadhesive nanoparticles (VP/NNPs) administration. Further immunofluorescence analysis on scar tissue serial sections validated VP/BNPs effectively inhibited the collagen deposition and angiogenesis by firmly confined in the scar tissue and persistently releasing VP targeted to nucleus Yes-associated protein (nYAP) of HSFBs and HDVECs. These findings collectively suggest that VP/BNPs can be a promising and technically advantageous agent for HS therapies.
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Advanced Healthcare Materials
·
2022
·Vol. 11
·期 23
·2201878
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IF 11.092
Ze Li,Jinjian Huang,Yungang Jiang,Ye Liu,Guiwen Qu,Kang Chen,Yun Zhao,Peige Wang,Xiuwen Wu,Jianan Ren
Wound healing is a significant problem in clinical management. Various functional dressings are studied to promote wound healing through biochemical factors. They are generally expensive, complex to fabricate, and may adversely affect the wound. Mechanical forces are the critical regulators of tissue repair. Although contraction is shown to promote wound healing, the underlying mechanisms are not fully understood. In this study, a novel adhesive temperature-sensitive mechanically active hydrogel with a simple and inexpensive preparation process is developed. The dressing is able to adhere to the wound surface and actively contract the wound in response to body temperature. This mechanical contraction enhances the proliferative activity of basal cells, reduces the inflammatory response of the wound, and promotes wound healing. Furthermore, RNA-seq clarifies how the gene regulatory network is regulated by contraction. Finally, using pharmacological inhibitors, YAP and MEK are identified as the key signaling molecules for contraction-mediated tissue healing in vivo.
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Small
·
2022
·Vol. 18
·期 14
·2107656
·
IF 15.153
Liuyun Gong,Yujie Zhang,Jing Zhao,Yilei Zhang,Kangsheng Tu,Lianying Jiao,Qiuran Xu,Mingzhen Zhang,Suxia Han
Even though radiotherapy is the most important therapeutic strategy for colon cancer treatment, there is an enormous demand to improve radiosensitivity in solid tumor destruction. For this purpose, a biomimetic nanoplatform based on hollow polydopamine nanoparticles (HP) with homologous targeting and pH-responsive drug release properties is designed. In this work, HP is constructed by using a chelation competition-induced polymerization strategy and then modified with the cancer cell membrane. Hollow polydopamine integrated with Pt nanoparticles (Pt@HP) has a catalase-like activity, which can be used to trigger endogenous H 2 O 2 into O 2 , relieving hypoxia of the tumor microenvironment (TME). With mesoporous shells and large cavities, Pt@HP shows efficient apoptin 100–109 (AP) and verteporfin (VP) loading to form AVPt@HP@M. Under X-ray irradiation, AVPt@HP@M exerts a radiosensitization effect via multiple strategies, including relieving hypoxia (Pt NPs), enhancing tumor apoptosis (AP), and X-ray-induced photodynamic therapy (X-PDT) (VP). Further metabonomics analysis shows that the specific mechanism of the AVPt@HP@M is through influencing purine metabolism. Without appreciable systemic toxicity, this nanoplatform highlights a new strategy for effective radiosensitization and provides a reference for treating malignant tumors.
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Nature Communications
·
2021
·Vol. 12
·期 1
·1-18
·
IF 14.919
Gao Feng,Shao Tianyi,Yu Yunpeng,Xiong Yujie,Yang Lihua
Acting by producing reactive oxygen species (ROS) in situ, nanozymes are promising as antimicrobials. ROS’ intrinsic inability to distinguish bacteria from mammalian cells, however, deprives nanozymes of the selectivity necessary for an ideal antimicrobial. Here we report that nanozymes that generate surface-bound ROS selectively kill bacteria over mammalian cells. This result is robust across three distinct nanozymes that universally generate surface-bound ROS, with an oxidase-like silver-palladium bimetallic alloy nanocage, AgPd 0.38 , being the lead model. The selectivity is attributable to both the surface-bound nature of ROS these nanozymes generate and an unexpected antidote role of endocytosis. Though surface-bound, the ROS on AgPd 0.38 efficiently eliminated antibiotic-resistant bacteria and effectively delayed the onset of bacterial resistance emergence. When used as coating additives, AgPd 0.38 enabled an inert substrate to inhibit biofilm formation and suppress infection-related immune responses in mouse models. This work opens an avenue toward biocompatible nanozymes and may have implication in our fight against antimicrobial resistance.
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Journal of Neuroinflammation
·
2024
·Vol. 21
·期 1
·1-17
·
IF 9.3
Gao Dandan,Zou Bin,Zhu Kunyuan,Bi Shijun,Zhang Wenxu,Yang Xinyu,Lai Jieyu,Liang Guobiao,Pan Pengyu
Background Subarachnoid hemorrhage (SAH) is a severe cerebrovascular disorder primarily caused by the rupture of aneurysm, which results in a high mortality rate and consequently imposes a significant burden on society. The occurrence of SAH initiates an immune response that further exacerbates brain damage. The acute inflammatory reaction subsequent to SAH plays a crucial role in determining the prognosis. Th17 cells, a subset of T cells, are related to the brain injury following SAH, and it is unclear how Th17 cells are cleared in the brain. Meningeal lymphatic vessels are a newly discovered intracranial fluid transport system that has been shown to drain large molecules and immune cells to deep cervical lymph nodes. There is limited understanding of the role of the meningeal lymphatic system in SAH. The objective of this research is to explore the impact and underlying mechanism of drainage Th17 cells by meningeal lymphatics on SAH.Methods Treatments to manipulate meningeal lymphatic function and the CCR7-CCL21 pathway were administered, including laser ablation, injection of VEGF-C geneknockout, and protein injection. Mouse behavior was assessed using the balance beam experiment and the modified Garcia scoring system. Flow cytometry, enzyme-linked immunosorbent assays (ELISA), and immunofluorescence staining were used to study the impact of meningeal lymphatic on SAH drainage. Select patients with unruptured and ruptured aneurysms in our hospital as the control group and the SAH group, with 7 cases in each group. Peripheral blood and cerebrospinal fluid (CSF) samples were assessed by ELISA and flow cytometry.Results Mice with SAH showed substantial behavioral abnormalities and brain damage in which immune cells accumulated in the brain. Laser ablation of the meningeal lymphatic system or knockout of the CCR7 gene leads to Th17 cell aggregation in the meninges, resulting in a decreased neurological function score and increased levels of inflammatory factors. Injection of VEGF-C or CCL21 protein promotes Th17 cell drainage to lymph nodes, an increased neurological function score, and decreased levels of inflammatory factors. Clinical blood and CSF results showed that inflammatory factors in SAH group were significantly increased. The number of Th17 cells in the SAH group was significantly higher than the control group. Clinical results confirmed Th17 cells aggravated the level of neuroinflammation after SAH.Conclusion This study shows that improving the drainage of Th17 cells by meningeal lymphatics via the CCR7-CCL21 pathway can reduce brain damage and improve behavior in the SAH mouse model. This could lead to new treatment options for SAH.
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Nature Communications
·
2024
·Vol. 15
·期 1
·1-19
·
IF 14.7
Liu Tao,Chai Shuang,Li Mingyang,Chen Xu,Xie Yutao,Zhao Zehui,Xie Jingjing,Yu Yunpeng,Gao Feng,Zhu Feng,Yang Lihua
Infection by Helicobacter pylori , a prevalent global pathogen, currently requires antibiotic-based treatments, which often lead to antimicrobial resistance and gut microbiota dysbiosis. Here, we develop a non-antibiotic approach using sonodynamic therapy mediated by a lecithin bilayer-coated poly(lactic-co-glycolic) nanoparticle preloaded with verteporfin, Ver-PLGA@Lecithin, in conjunction with localized ultrasound exposure of a dosage permissible for ultrasound medical devices. This study reveals dual functionality of Ver-PLGA@Lecithin. It effectively neutralizes vacuolating cytotoxin A, a key virulence factor secreted by H. pylori , even in the absence of ultrasound. When coupled with ultrasound exposure, it inactivates H. pylori by generating reactive oxygen species, offering a potential solution to overcome antimicrobial resistance. In female mouse models bearing H. pylori infection, this sonodynamic therapy performs comparably to the standard triple therapy in reducing gastric infection. Significantly, unlike the antibiotic treatments, the sonodynamic therapy does not negatively disrupt gut microbiota, with the only major impact being upregulation of Lactobacillus , which is a bacterium widely used in yogurt products and probiotics. This study presents a promising alternative to the current antibiotic-based therapies for H. pylori infection, offering a reduced risk of antimicrobial resistance and minimal disturbance to the gut microbiota.
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Advanced Science
·
2025
·
IF 14.1
Ze Li,Jiayang Li,Kang Chen,Guiwen Qu,Shuanghong Yang,Sicheng Li,Ye Liu,Yitian Teng,Rui Ma,Jinjian Huang,Peige Wang,Jianan Ren,Xiuwen Wu
Intestinal fistula is a serious condition characterized by abnormal connections between the intestine and surrounding tissues. Despite advances in comprehensive management of intestinal fistulas, patients often need to undergo definitive surgery and face life-threatening complications due to ineffective closure measures. Herein, a mechanically active hydrogel (GNGP) that actively constricts intestinal fistulas in response to body temperature is presented. It possesses broad-spectrum antimicrobial properties, excellent adhesion, suitable degradation properties, and a balance between injectable properties and mechanical activity—which, together, enable the in situ sealing of intestinal fistulas. Moreover, GNGP hydrogel accelerates the re-epithelialization process of rabbit intestinal fistulas, ameliorates the inflammation of the fistula tract, and promotes the deposition of collagen into the damaged area to effectively facilitate intestinal fistula healing. Mechanistically, shear stress is found to promote the proliferation of intestinal epithelial cells via Yes-associated protein-mediated mechanosensitization, through finite element simulations and in vitro experiments. Together, this mechanically active hydrogel with injectable properties offers a promising strategy for the sealing treatment of intestinal fistulas.
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FASEB JOURNAL
·
2025
·Vol. 39
·期 10
·e70670
·
IF 4.2
Shushu Jiang,Shichen Bu,Xiang Kang,Yin Dong,Long Chen,Lin Yuan,Menghao Shi,Meng Du,Minglu Liang,Kai Huang,Liu Yang
Pathological cardiac hypertrophy leads to heart failure. In this study, we aimed to explore the role of transmembrane protein Tspan9 in the development of cardiac hypertrophy and failure. We found that Tspan9 was upregulated in the hearts of patients with hypertrophic cardiomyopathy (HCM), in the hearts of mice subjected to transverse aortic constriction (TAC), as well as in phenylephrine-induced hypertrophic neonatal rat cardiomyocytes (NRCMs). AAV9-mediated overexpression (OE) of Tspan9 in mouse hearts augmented TAC-induced cardiac hypertrophy and failure, while Tspan9 knockdown (KD) alleviated this effect. Tspan9-OE promotes PE-induced cardiomyocyte enlargement, whereas Tspan9-KD suppresses it. Mechanistically, we demonstrated that Tspan9 interacts with p62, a pivotal regulator of autophagy, impairs its cargo function, leading to autophagy suppression. Remarkably, the anti-hypertrophic effect of Tspan9-KD was impaired when autophagy was inactivated or p62 was knocked down. These findings suggest that Tspan9 exacerbates pressure overload-induced pathological cardiac hypertrophy and failure by suppressing cardiac autophagy through its interaction with p62. Graphical Upon pathological stimuli, Tspan9 is upregulated in the cardiomyocytes and interacts with p62. It impairs the binding of p62 to the ubiquitin chains of misfolded proteins and LC3 on phagophores. This leads to the inhibition of autophagy flux and accumulation of misfolded proteins, which ultimately results in cardiac hypertrophy and failure.
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Neurotherapeutics
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2025
·
IF 6.9
Yichen Cai,Yanxin Shao,Hui Yuan,Lina Feng,Jing Wang,Mingfeng Yang,Cong Li,Baoliang Sun,Leilei Mao
More than half of subarachnoid hemorrhage (SAH) survivors develop delayed cognitive dysfunction, but the underlying mechanisms remain elusive. This study investigated the role of meningeal lymphatic vessels (mLVs) in this complication by examining their structural integrity, drainage capacity, and association with cognitive deficits post-SAH. In adult male C57BL/6J mice in which SAH was induced by intracisternal injection of autologous blood, spatial learning and memory, and hippocampal CA1 neuronal activity were impaired as early as 1 month post-surgery, with a marked exacerbation of these deficits at 2 months. SAH induced mLV fragmentation and atrophy, subsequent cerebrospinal and interstitial fluid drainage impairment, metabolite accumulation, and ultimately delayed cognitive dysfunction. Notably, lymphatic vessel ablation exacerbated these pathologies. In vitro experiments confirmed that vascular endothelial growth factor C (VEGF-C) reduced oxyhemoglobin-induced lymphatic endothelial cell apoptosis. Furthermore, in vivo studies demonstrated that VEGF-C therapy inhibited amyloid-β (Aβ) deposition in the hippocampal CA1 region and ameliorated cognitive dysfunction. Additional studies revealed that VEGF-C's protective effect on mLVs may be mediated via PI3K-AKT pathway activation. Collectively, these findings indicate that disrupted mLV integrity and drainage contribute to post-SAH cognitive impairment. Activation of VEGF-C-mediated PI3K-AKT signaling may preserve mLV function and represent a potential therapeutic strategy for preventing delayed cognitive impairment after SAH.
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Acta Biomaterialia
·
2025
·
IF 9.6
Chaorong Wei,Lingke Feng,Jing Liu,Mingxia Xu,Yongsheng Cui,Fengyi Lin,Honglian Yu,Zhanzhan Feng,Hong Zhang,Changyang Gong,Peng Mi
X-ray-induced photodynamic therapy (X-PDT) shows significant promise in tumor treatments due to its unlimited tissue penetration but requires delivering sensitizers to tumors. Here, we engineered photosensitizer verteporfin (VP) and T-lymphokine-activated killer cell-originated protein kinase (TOPK) inhibitor OTS964-encapsulated polymeric nanocarriers (VP/OTS964@NPs) for effective tumor X-PDT, molecule-targeted therapy and inducing robust antitumor immunity for synergistic immunotherapy of low immunogenic breast tumors and their lung metastases when combined with PD-L1 blockade. The VP/OTS964@NPs are monodisperse and can be disassembled to release drugs in response to high reactive oxygen species (ROS) levels in the tumor microenvironment or generated during X-PDT. It can efficiently deliver drugs into the TOPK-high expression breast cancer cells, generate ROS and induce ICD effects. By i.v. injection, VP/OTS964@NPs efficiently accumulated in the breast tumors and effectively eradicated tumors upon X-PDT. Additionally, the VP/OTS964@NPs activated the systemic antitumor immune responses, significantly inhibited the distant breast tumors and the lung metastasis of breast tumors, and enhanced the survival rates in combination with PD-L1 blockade. This study presented a strategy for engineering nanocarriers for synergistic molecular therapy, tumor XDT and immunotherapy. Statement of Significance X-PDT is a promising therapeutic modality for cancer treatment. However, its clinical application is hindered by the limited availability of suitable sensitizers and their insufficient tumor-targeting capability. This work aims to construct ROS-sensitive nanocarriers co-loaded with the photosensitizer verteporfin and the TOPK inhibitor OTS964 to achieve synergistic X-PDT for triple-negative breast cancer. By further activating antitumor immune responses, this strategy is designed to suppress the distant and metastatic breast tumors. Overall, this work provides both a nanodrug platform and a therapeutic strategy for the treatment of poorly immunogenic solid tumors.
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