ACS Applied Materials & Interfaces
·
2021
·
IF 9.229
Jiang Wu,Junyi Zhu,Qiuji Wu,Ying An,Kangning Wang,Tengxiao Xuan,Junwen Zhang,Wenxiang Song,Huacheng He,Liwan Song,Jie Zheng,Jian Xiao
Efficient reconstruction of a fully functional skin after wounds requires multiple functionalities of wound dressing due to the complexity of healing. In these regards, topical administration of functionalized nanoparticles capable of sustainably releasing bioactive agents to the wound site may significantly accelerate wound repair. Among the various nanoparticles, superparamagnetic iron oxide (Fe3O4) nanoparticles gain increasing attractiveness due to their intrinsic response to an external magnetic field (eMF). Herein, based on the Fe3O4 nanoparticle, we developed a fibroblast growth factor (bFGF)-loaded Fe3O4 nanoparticle using a simple mussel-inspired surface immobilization method. This nanoparticle, named as bFGF-HDC@Fe3O4, could stabilize bFGF in various conditions and exhibited sustained release of bFGF. In addition, an in vitro study discovered that bFGF-HDC@Fe3O4 could promote macrophage polarization toward an anti-inflammatory (pro-healing) M2 phenotype especially under eMF. Further, in vivo full-thickness wound animal models demonstrated that bFGF-HDC@Fe3O4 could significantly accelerate wound healing through M2 macrophage polarization and increased cell proliferation. Therefore, this approach of realizing sustained the release of the growth factor with magnetically macrophage regulating behavior through modification of Fe3O4 nanoparticles offers promising potential to tissue-regenerative applications.
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BMC Complementary Medicine and Therapies
·
2023
·Vol. 23
·期 1
·1-11
·
IF 3.9
Yi Zhirong,Jia Qingling,Wang Yujiao,Zhang Yuqin,Xie Tianyi,Ling Jianghong
Background Precancerous lesions of gastric cancer (PLGC) refer to a kind of histopathological changes in the gastric mucosa that can progress to gastric cancer. Elian granules (ELG), a Chinese medicinal prescription, have achieved satisfactory results in the treatment of PLGC. However, the exact mechanism underlying the therapeutic effect of ELG remains unclear. Here, this study aims to explore the mechanism of ELG alleviating PLGC in rats.Methods The chemical ingredients of ELG were analyzed using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS). Specific Pathogen Free SD rats were randomly assigned to 3 groups: the control, model, and ELG groups. The 1-Methyl-3-nitro-1-nitrosoguanidine (MNNG) integrated modeling method was adopted to construct the PLGC rat model in groups except for the control group. Meanwhile, normal saline was used as an intervention for the control and model groups, and ELG aqueous solution for the ELG group, lasting 40 weeks. Subsequently, the stomach of rats was harvested for further analysis. Hematoxylin-eosin staining of the gastric tissue was conducted to assess the pathological changes. Immunofluorescence was carried out for the expression of CD68, and CD206 proteins. Real-time quantitative PCR combined with Western blot was conducted to analyze the expression of arginase-1(Arg-1), inducible nitric oxide synthase (iNOS), p65, p-p65, nuclear factor inhibitor protein-α (IκBα), and p-IκBα in gastric antrum tissue.Results Five chemical ingredients including Curcumol, Curzerenone, Berberine, Ferulic Acid, and 2-Hydroxy-3-Methylanthraquine were identified in ELG. The gastric mucosal glands of rats treated with ELG were orderly arranged, with no intestinal metaplasia and no dysplasia. Furthermore, ELG decreased the percentage of M2-type TAMs marked with CD68 and CD206 proteins, and the ratio of Arg-1 to iNOS in the gastric antrum tissue of rats with PLGC. In addition, ELG could also down-regulate the protein and mRNA expression of p-p65, p65, and p-IκBα, but up-regulate the expression of IκBα mRNA in rats with PLGC.Conclusion sThe results showed that ELG attenuates PLGC in rats by suppressing the M2-type polarization of tumor-associated macrophages (TAMs) through NF-κB signaling pathway.
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JOURNAL OF ETHNOPHARMACOLOGY
·
2023
·
IF 5.4
Lei Lei,Guoguo Wan,Xiaoyu Geng,Jianguo Sun,Yi Zhang,Jianwei Wang,Congwen Yang,Zheng Pan
Ethnopharmacological relevance Lamiophlomis rotata (Benth.) Kudo ( L . rotata ), a Tibetan medicinal plant , is used to treat “yellow-water diseases”, such as skin disease, jaundice and rheumatism . Our previous study showed that the iridoid glycoside extract of L. rotata (IGLR) is the major constituent of skin wound healing. However, the role of IGLR in the biological process of trauma repair and the probable mechanism of the action remain largely unknown. Aim of the study To investigate the role of IGLR in the biological process of trauma repair and the probable mechanism of the action. Materials and methods The role of IGLR in wound healing was investigated by overall skin wound in mice with Hematoxylin and Eosin (H&E) and Masson trichrome staining. The anti-inflammatory, angiogenesis-promoting and fibril formation effects of IGLR were visualized in wound skin tissue by immunofluorescence staining, and the proinflammatory factors and growth factors were assayed by real-time polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). Macrophages, dermal fibroblasts, and endothelial cells were cultured to measure the direct/indirect interaction effects of IGLR on the proliferation and migration of cells, and flow cytometry was employed to assess the role of IGLR on macrophage phenotype. Network pharmacology combined with Western blot experiments were conducted to explore possible mechanisms of the actions. Results IGLR increased the expression of CD206 (M2 markers) through the RAS/p38 MAPK/NF-κB signaling pathway during wound injury in vivo and in vitro . IGLR suppressed the inflammatory cytokines iNOS, IL-1β and TNF-α in the early stage of wound healing . During the proliferation step of wound repair, IGLR promoted angiogenesis and fibril formation by increasing the expression of VEGF, CD31, TGF-β and α-SMA in wound tissue, and similar results were verified by RT-PCR and ELISA. In a paracrine mechanism, the extract promoted the proliferation of dermal fibroblasts, and endothelial cells were founded by the conditioned medium (CM). Conclusion IGLR induced M2 macrophage polarization in the early stage of wound healing; in turn, IGLR played a key role in the transition from inflammation to cell proliferation during the biological process of wound healing.
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CHEMICAL ENGINEERING JOURNAL
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2022
·
IF 16.744
Faxing Zou,Yansen Wang,Tao Tang,Yudong Zheng,Yajie Xie,Shihui Zhu,Huiyi Yang,Haoye Meng,Xudong Liu,Jiayu Yang
Chronic wound healing is a major and unmet challenge, due to contamination of exudate, bacterial infection and non-healing symptoms, having become urgent an problem to be solved. Developing multifunctional dressings capable of efficiently absorbing exudate by forming self-micro-negative pressure, effectively antibacterial and inducing immune regulation, would be a promising strategy for wound healing. Herein, the hydrogel-aerogel biphase gel (HAB-gel) dressing consisted of PVA grafted with PAM and bio-based polyurethane was prepared to generate synergistic therapeutic effects through removing exudates, antibacterial properties and immune regulation. The PVA grafted with PAMs features generating self-negative pressure to absorb deep exudate by aerogel phase, providing a comfortable microenvironment for wound healing, moreover, the capacities of liquid absorption and retention are enhanced by hydrogel phase, preventing wounds from exudate contamination. The incorporation of β-cyclodextrin (β-CD) in the constructed polyurethane (LPU) endows the HAB-gel materials with excellent antibacterial properties after being loaded with polyhexamethylene biguanidine (PHMB). Furthermore, the HAB-gel dressing can accelerate the macrophage polarization into anti-inflammatory M2 via the hydrogen sulfide (H 2 S) generation, angiogenesis promotion and collagen deposition in periwound tissue. Overall, this novel strategy for synergistic treatment of chronic wounds, provides a promising method for the management of tissue regeneration disorders.
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INTERNATIONAL JOURNAL OF PHARMACEUTICS
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2022
·
IF 6.51
Zhengjie Meng,Bowen Fu,Zheng Yang,Yuhua Xu,Haixiao Huang,Yunhao Bai,Xue Fang,Shuilin Shen,Jing Yang,Jiahui Yong,Xinyue Tao,Chenyu Ma,Wenjun Miao,Hao Ren,Yonglu Wang,Hao Xu,Xueming Li
High levels of proinflammatory cytokines, macrophage polarization status and immune-mediated angiogenesis play pivotal roles in the pathogenesis of inflammatory bowel disease (IBD). Thalidomide, an anti-inflammatory, immunomodulatory and antiangiogenic agent, is used off-label for treatment of IBD. The therapeutic potential of thalidomide is limited by its poor solubility and side effects associated with its systemic exposure. To address these issues and promote its therapeutic effects on IBD, thalidomide nanocrystals (Thali NCs) were prepared and coated with polydopamine (PDA), a potential macrophage polarization modulator, to form PDA coated Thali NCs ( [email protected] ). [email protected] possessed a high drug loading and displayed average particle size of 764.7 ± 50.30 nm. It showed a better anti-colitis effect than bare thalidomide nanocrystals at the same dose of thalidomide. Synergistic effects of polydopamine on anti-inflammatory and anti-angiogenic activities of thalidomide were observed. Furthermore, PDA coating could direct polarization of macrophages towards M2 phenotype, which boosted therapeutic effects of [email protected] on IBD. Upon repeated dosing of [email protected] for one week, symptoms of IBD in mice were significantly relieved, and histomorphology of the colitis colons were normalized. Key proinflammatory cytokine levels in the inflamed intestines were significantly decreased. Toxicity study also revealed that [email protected] is a safe formulation.
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Neural Regeneration Research
·
2022
·Vol. 18
·期 8
·1809
·
IF 6.058
Xu Ai-Hua,Yang Yang,Shao Yang,Jiang Man-Yu,Sun Yong-Xin
Poly(ADP-ribose)polymerase family member 14 ( PARP14 ), which is an intracellular mono(ADP-ribosyl) transferase, has been reported to promote post-stroke functional recovery, but its role in spinal cord injury (SCI) remains unclear. To investigate this, a T10 spinal cord contusion model was established in C57BL/6 mice, and immediately after the injury PARP14 shRNA-carrying lentivirus was injected 1 mm from the injury site to silence PARP14 expression. We found that PARP14 was up-regulated in the injured spinal cord and that lentivirus-mediated downregulation of PARP14 aggravated functional impairment after injury, accompanied by obvious neuronal apoptosis , severe neuroinflammation , and slight bone loss. Furthermore, PARP14 levels were elevated in microglia after SCI, PARP14 knockdown activated microglia in the spinal cord and promoted a shift from M2-polarized microglia (anti-inflammatory phenotype) to M1-polarized microglia (pro-inflammatory phenotype) that may have been mediated by the signal transducers and activators of transcription (STAT) 1/6 pathway. Next, microglia M1 and M2 polarization were induced in vitro using lipopolysaccharide/interferon-γ and interleukin-4, respectively. The results showed that PARP14 knockdown promoted microglia M1 polarization , accompanied by activation of the STAT1 pathway . In addition, PARP14 overexpression made microglia more prone to M2 polarization and further activated the STAT6 pathway . In conclusion, these findings suggest that PARP14 may improve functional recovery after SCI by regulating the phenotypic transformation of microglia via the STAT1/6 pathway.
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MEDICAL ONCOLOGY
·
2022
·Vol. 39
·期 7
·1-12
·
IF 3.738
Chen Zhuo,Wu Jing,Wang Liang,Zhao Hua,He Jie
Triple negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. More and more studies have shown that the tumor immune microenvironment (TME) of TNBC is closely related to its poor prognosis and early metastasis. We try to explain how tumor-associate macrophages (TAMs), an important component of the TME, function in the matrix of TNBC. Therefore, we induced THP-1 cells to become M1-TAMs and M2-TAMs, investigated their influence on breast cancer cells. 82 TNBC paraffin samples were made into tissue microarrays. The expression of macrophages makers were measured by immunohistochemistry. Scratch assay, Transwell assay, CCK-8 cell proliferation assay were performed in the co-culture system of breast cancer cells lines and macrophages to observe the invasion and proliferation ability of breast cancer cell lines. Western Blot (WB) was performed to detect the expression of E-cadherin (CDH1) and N-cadherin (CDH2). M2-TAMs were more numerous than M1-TAMs in the matrix of TNBC cancer nests and associated with poor prognosis. M2-TAMs promoted the invasion, migration, and proliferation of TNBC cells. M1-TAMs had inhibitory effects. In MCF-7 cells, WB showed a decrease in CDH1 and an increase in CDH2. In MDA-MB-231 cells and BT549 cells, CDH2 expression was reduced and CDH1 expression was increased. All of the above results were statistically significant, p < 0.001. M2-TAMs were more numerous in TNBC and associated with poor prognosis. M2-TAMs promoted the invasion, migration, and proliferation of breast cancer cells. The mechanism may be related to the epithelial-mesenchymal transition.
研究领域:
肿瘤学
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免疫学
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细胞生物学
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病理学
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Current Alzheimer Research
·
2020
·Vol. 17
·期 8
·735-752
·
IF 3.047
Qiao Peifeng,Ma Jingxi,Wang Yangyang,Huang Zhenting,Zou Qian,Cai Zhiyou,Tang Yong
Background: Neuroinflammation plays an important role in the pathophysiological process of various neurodegenerative diseases. It is well known that curcumin has obvious anti-inflammatory effects in various neuroinflammation models. However, its effect on the modulation of microglial
polarization is largely unknown. Objective: This study aimed to investigate whether curcumin changed microglia to an anti-inflammatory M2-phenotype by activating the AMP-activated protein kinase (AMPK) signaling pathway. Methods: LPS treatment was used to establish BV2 cells and
primary microglia neuroinflammation models. The neuroinflammation mouse model was established by an intracerebroventricular (ICV) injection of lipopolysaccharide (LPS) in the lateral septal complex region of the brain. TNF-α was measured by ELISA, and cell viability was measured by Cell
Counting Kit-8 (CCK-8). The expression of proinflammatory and anti-inflammatory cytokines was examined by Q-PCR and Western blot analysis. Phenotypic polarization of BV2 microglia was detected by immunofluorescence. Results: Curcumin enhanced AMPK activation in BV2 microglial cells in
the presence and absence of LPS. Upon LPS stimulation, the addition of curcumin promoted M2 polarization of BV2 cells, as evidenced by suppressed M1 and the elevated M2 signature protein and gene expression. The effects of curcumin were inhibited by an AMPK inhibitor or AMPK knockdown. Calmodulin-dependent
protein kinase kinase β (CaMKKβ) and liver kinase B1 (LKB1) are upstream kinases that activate AMPK. Curcumin can activate AMPK in Hela cells, which do not express LKB1. However, both the CaMKKβ inhibitor and siRNA blocked curcumin activation of AMPK in LPS-stimulated BV2 cells.
Moreover, the CaMKKβ inhibitor and siRNA weaken the effect of curcumin suppression on M1 and enhancement of M2 protein and gene expression in LPS-stimulated BV2 cells. Finally, curcumin enhanced AMPK activation in the brain area where microglia were over-activated upon LPS stimulation
in an in vivo neuroinflammation model. Moreover, curcumin also suppressed M1 and promoted M2 signature protein and gene expression in this in vivo model. Conclusion: Curcumin enhances microglia M2 polarization via the CaMKKβ-dependent AMPK signaling pathway. Additionally, curcumin
treatment was found to be neuroprotective and thus might be considered as a novel therapeutic agent to treat the neurodegenerative disease such as Alzheimer's disease, Parkinson's disease, etc.
研究领域:
神经科学
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药理学
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炎症生物学
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神经退行性疾病
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Hepatology International
·
2026
·
IF 7.8
Meng Hui,Wang Zeyuan,Wang Liye,Fang Xiaokun,Li Haonan,Ma Weiqian,Ding Yi,Nan Manman,Meng Yu,Li Ling,Li Yizhen,Chen Kuisheng,Zhang Mingzhi
Background Hepatocellular carcinoma (HCC) is a highly aggressive primary liver malignancy characterized by limited therapeutic options and poor prognosis. Within the tumor microenvironment (TME), tumor-associated macrophages (TAMs) predominantly exhibit an M2-like phenotype, contributing to immune escape and tumor progression. Zymogen granule protein 16 (ZG16) has been reported to be downregulated in HCC, but its precise biological function and molecular mechanisms remain poorly understood. Therefore, we aimed to investigate the impact of ZG16 on HCC cell metastasis and TAM infiltration, as well as to elucidate its molecular mechanism. Methods Gain- and loss-of-function assays were used to verify the effect of ZG16 on HCC cell metastasis, as well as the recruitment and M2 polarization of TAMs. The underlying mechanism of ZG16 was explored by immunoprecipitation–liquid chromatography–mass spectrometry (IP–LC/MS) analysis, co-immunoprecipitation (co-IP) assay, and GST pull-down assay. Results Our results demonstrated that ZG16 overexpression significantly inhibited metastasis of HCC cells while also suppressing the recruitment and M2 polarization of TAMs, suggesting its dual role in both tumor cell-intrinsic and microenvironmental regulation. Notably, sorting nexin 9 (SNX9), a facilitator of HCC, was identified as a downstream target of ZG16. Mechanistically, we uncovered that ZG16 physically interacted with SNX9 and promoted its protein degradation through the ubiquitin–proteasome pathway. Functional rescue experiments provided compelling evidence that SNX9 overexpression effectively counteracted ZG16-mediated suppression of both HCC progression and TAM M2 polarization. Further mechanism exploration confirmed that ZG16 promoted the ubiquitination and degradation of SNX9 by recruiting itchy E3 ubiquitin protein ligase (ITCH). Conclusions Our findings certify that ZG16 suppresses tumor progression and M2 polarization of TAMs in HCC through ITCH-mediated ubiquitination and subsequent degradation of SNX9. The ZG16/ITCH/SNX9 axis may represent an important regulatory pathway and potential therapeutic target for HCC.
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BIOORGANIC & MEDICINAL CHEMISTRY
·
2025
·
IF 3
Min Chen,Huifang Jiao,Dandan Lu,Wenhuan Chen,Zhen Yang,Xue Liang,Pengcheng Wei,Kunpeng Liu
Influenza viruses generate new strains or subtypes through antigenic drift and antigenic shift, leading to the failure of existing antiviral drugs and potentially causing widespread viral infection and influenza epidemics. However, during evolution, certain influenza virus proteins remain unchanged or undergo only minor mutations. Therefore, drugs targeting these evolutionarily conserved viral protein regions may exhibit broad-spectrum antiviral activity across subtypes and against mutations. The purpose of this study is to target the evolutionarily conserved domain of influenza A virus M2 protein and screen for drugs with cross-strain, mutation-resistant, and broad-spectrum antiviral activity. This study used AlphaFold3 to predict the M2 conserved domain structure and employed AutoDock to perform virtual screening of the NMPA database, identifying seven potential candidate drugs. Molecular dynamics simulations indicated that pamiparib exhibits strong affinity for the M2 conserved domain. It demonstrates excellent physiological activity in vitro in inhibiting the replication of H1N1 replication, while showing no effect on other viruses. CETSA experiments confirmed that pamiparib has the potential to bind to the M2 proteins of various influenza virus subtypes. In addition, pamiparib suppresses effectively viral infection in vivo. Ultimately, this study verifies that antiviral drugs designed to target the evolutionarily conserved regions of the influenza virus M2 protein indeed possess broad-spectrum antiviral activity across different strains.
研究领域:
病毒学
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药物发现
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计算生物学
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结构生物学
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抗病毒治疗
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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2025
·
IF 8.5
Yaning Ge,Xin Zhu,Zhengxian Zhang,Huanhuan Zhu,Tianqi Wang,Jingru Cui,Huahui Zeng,Xiangxiang Wu,Zhenqiang Zhang
Triptolide (TP) is a promising anti-tumor candidate derived from the herb Tripterygium wilfordii , but its poor water solubility and multi-organ toxicity limit its application. Here, we developed novel nanoparticles (TP-SP@NPs) modified with dextran sulfate and RGD peptide for double-targeted delivery of TP to both tumor cells and pro-tumor macrophages in pancreatic cancer treatment. TP-SP@NPs exhibited suitable particle size (about 98 nm), good stability and controlled release performance. TP-SP@NPs showed high cellular uptake in Pan02 cells and M2 macrophages through α v β 3 integrin-RGD interaction and SR-A-DS interaction, effectively inhibiting tumor growth by triggering apoptosis of these cells. In Pan02 tumor-bearing mice, TP-SP@NPs specifically accumulated at the tumor site and efficiently decreased the number of M2 macrophages, thereby exerting better curative effect on pancreatic cancer and lower systemic toxicity as compared with TP. As a result, TP-SP@NPs had achieved selective anti-tumor effect, good biosafety and great promise in clinical application.
研究领域:
药学
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肿瘤学
·
纳米医学
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Materials Today Bio
·
2026
·
IF 11
Chengbai Dai,Cheng Chen,Jun Zhu,Minghao Chao,Hanrong Yan,Pengjin Wei,Ming Guan,Bin Pan,Fenglei Gao,Rongze Tang
ZCM2 reprograms redox–inflammatory coupling by activating Nrf2/HO-1 signaling and suppressing NF-κB–driven responses in macrophages. • ZCM2 disrupts macrophage-mediated matrix degradation via downregulation of MMP-9, mitigating pathological bone resorption. • Calcium ion release from ZCM2 instructs osteogenic commitment through activation of the RUNX2-centered transcriptional network. • ZCM2 achieves immune modulation–coupled bone regeneration, enabling systemic restoration of bone homeostasis in osteoporosis. Osteoporosis is a systemic skeletal disorder characterized by bone loss and microstructural deterioration, and its pathogenesis is closely associated with dysregulation of the bone marrow immune microenvironment. In this study, bioinformatic analysis first revealed significant oxidative stress and mitochondrial metabolic dysfunction in macrophages within the osteoporotic microenvironment. Based on this, we constructed a biomimetic nanoplatform (ZCM2) composed of ZIF-8@CaCO 3 core–shell nanoparticles camouflaged with M2 macrophage membranes, designed to achieve comprehensive osteoporosis therapy through a triple synergistic mechanism: the ZIF-8 core scavenges reactive oxygen species to exert antioxidant and anti-inflammatory effects, inhibits MMP-9 secretion to reduce pathological bone resorption, and the CaCO 3 shell releases calcium ions to promote osteogenic differentiation. ZCM2 exhibited favorable biosafety, high cellular uptake efficiency, and excellent bone-targeting capability. Mechanistic studies demonstrated that ZCM2 upregulates the expression of Nrf2 and HO-1, downregulates the expression of NF-κB p65, and significantly reduces the secretion of matrix metalloproteinase-9 (MMP-9) by macrophages, thereby attenuating bone resorption. Meanwhile, calcium ions released from the CaCO 3 shell activate the RUNX2/OSX/OPN signaling axis, promoting osteogenic differentiation of bone marrow mesenchymal stem cells. In an ovariectomized mouse model of osteoporosis, ZCM2 markedly improved bone microarchitecture, promoted new bone formation, and effectively inhibited bone resorption activity. Collectively, this biomimetic nanoplatform integrates anti-inflammatory, anti-resorptive, and pro-osteogenic functions, offering a multifaceted synergistic therapeutic strategy for osteoporosis. M2 macrophage membrane–biomimetic nanoparticles activates the Nrf2/HO-1 antioxidant pathway in macrophages, thereby inhibiting NF-κB activation and MMP-9 secretion, which suppresses pathological bone resorption. Download: Download high-res image (327KB) Download: Download full-size image
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