INTERNATIONAL IMMUNOPHARMACOLOGY
·
2023
·
IF 5.6
Aihua Xu,Yang Yang,Yang Shao,Manyu Jiang,Yongxin Sun,Bo Feng
Neuronal apoptosis and inflammation exacerbate the secondary injury after spinal cord injury (SCI). Four and a half domains 2 (FHL2) is a multifunctional scaffold protein with tissue- and cell-type specific effects on the regulation of inflammation, but its role in SCI remains unclear. The T10 mouse spinal cord contusion model was established, and the mice were immediately injected with lentiviruses carrying FHL2 shRNA after SCI. The results showed that FHL2 expression was increased following SCI, and then gradually decreased. Moreover, FHL2 depletion aggravated functional impairment, neuronal necrosis, and enlarged lesion cavity areas in the injured spinal cord. FHL2 deficiency facilitated neuronal apoptosis by elevating cleaved caspase 3/9 expression, neuroinflammation by regulating microglia polarization, and bone loss. Indeed, FHL2 deficiency increased the secretion of TNF-α and IL-6, M1 microglia polarization, and the activation of STAT1 pathway but decreased the secretion of IL-10 and IL-4, M2 microglia polarization, and the activation of the STAT6 pathway in the spinal cord. In vitro , FHL2 silencing promoted LPS + IFN-γ-induced microglia M1 polarization through activating the STAT1 pathway and alleviated IL-4-induced microglia M2 polarization via inhibiting the STAT6 pathway. FHL2 positively regulated the expression of poly (ADP-ribose) polymerase family member 14 (PARP14) by promoting its transcription. PARP14 overexpression inhibited FHL2 silencing-induced microglia M1 polarization and relieved the inhibitory effect of FHL2 silencing on microglia M2 polarization. Collectively, the study suggests that FHL2 reduces the microglia M1/M2 polarization-mediated inflammation via PARP14-dependent STAT1/6 pathway and thereby improves functional recovery after SCI.
研究领域:
神经科学
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炎症
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细胞生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Human Cell
·
2025
·Vol. 38
·期 4
·1-13
·
IF 3.1
Lian Hongyu,Yu Miao,Li Qi,Xiao Jiayi,Tang Xin,Zhang Bin,Liu Dongxue,Xu Yongliang,Dong Mo,Li Zitao,Yao Lihong,Li Caijuan
Hypoxia is a critical mechanism within the microenvironment of tumors. Exosomes, serve as conduits for intercellular communication and transport the biomolecule miRNA by facilitating intercellular signal exchange, which partially regulate cancer metastasis. Our research investigated whether the role of hypoxic breast cancer cell-derived exosomal miR-143-3p in cancer progression. Real-time PCR explored miR-143-3p expression in hypoxia breast cancer cell-derived exosomes. Co-culturing of breast cancer with hypoxia exosome-primed M0 macrophages, transwell detected the invasiveness of breast cancer cells. Western blot showed the effect of hypoxia exosomes on the levels of M2 makers in macrophages and the epithelial-mesenchymal transition (EMT) indicators in breast cancer cells. Bioinformatics prediction and dual luciferase reporter assay determined the interaction between miR-143-3p and RICTOR. We found that exosomal miR-143-3p expression was downregulated in hypoxic conditions. Hypoxia breast cancer cell-derived exosomal miR-143-3p negatively correlated with the presentation of the M2 macrophage marker CD206 and regulated the levels of Arg-1, CD206 and CD163 mRNA levels. In addition, hypoxia exosome-mediated polarization of M2 macrophages promotes breast cancer cell migration and invasion. Mechanistically, miR-143-3p acted antagonistically with RICTOR, thereby suppressing macrophage M2 polarization. In summary, our study reveals that the hypoxia downregulates the exosomal miR-143-3p derived from breast cancer cells to increase macrophage RICTOR expression, thereby promoting M2 macrophage polarization to enhance breast cancer cell invasiveness, suggesting that miR-143-3p may be a candidate molecule for microRNA alternative therapy in breast cancer.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
MOLECULAR MEDICINE
·
2025
·Vol. 31
·期 1
·1-20
·
IF 6.4
Peng Shuaijun,Su Pan,Liu Liming,Li Zibo,Liu Yuan,Tian Lei,Bai Ming,Xu Erping,Li Yucheng
Background The dysregulation of neuroinflammation triggered by imbalance of microglia M1/M2 polarization is a key pathogenic factor and closely associated with occurrence of depression. Formononetin (FMN), a natural non-steroidal isoflavonoid, has been confirmed to exhibit remarkable anti-inflammatory efficacy, but the impact of FMN on depression and the underlying antidepressant mechanisms are still not fully understood. This study aimed to investigate whether the antidepressant effect of FMN is involved in modulating microglia polarization, and if so, what are the underlying mechanisms.Methods Lipopolysaccharide (LPS)-induced depressive mice were used to study antidepressant mechanisms of FMN. Microglia cell line BV2 stimulated by LPS was employed to investigate pharmacological mechanisms of FMN. Effects of FMN on neuronal damage were detected by H&E, Nissl and Golgi staining. The efficacy of FMN were evaluated by immunostaining and western blots in vivo and vitro. In addition, molecular docking, luciferase reporter assay, cellular thermal shift assay (CETSA) and drug affinity responsive target stability (DARTS) were used to confirm the direct target of FMN.Results Our results showed that FMN significantly reverses depression-like behaviors, alleviates neuroinflammation and neuronal damage, rebalances M1/M2 polarization, inhibits NLRP3 inflammasome and enhances microglial autophagy level in prefrontal cortex of LPS-induced depressive mice. In vitro assays, results unraveled that autophagy inhibitor chloroquine (CQ) blocks effects of FMN on inhibiting NLRP3 inflammasome and rebalancing M1/M2 polarization. Moreover, PPARα is identified as a direct target of FMN and FMN can activate PPARα-mediated autophagy. Furtherly, combination PPARα agonist (WY14643) with FMN had no significant additive effects on inhibiting NLRP3 inflammasome and rebalancing M1/M2 polarization, whereas PPARα antagonist (GW6471) abrogated these pharmacologic effects of FMN in BV2. Importantly, GW6471 exhibited similar pharmacologic effects to abolish antidepressant effect of FMN in LPS-induced depressive mice.Conclusion Our study firstly demonstrated that FMN can rebalance microglia M1/M2 polarization and inhibit NLRP3 inflammasome, with the involvement of activating PPARα-mediated autophagy to ameliorate depression-like behaviors, which provides a novel view to elucidate antidepressant mechanisms of FMN and also offers a potential therapeutic target for depression.
研究领域:
神经科学
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药理学
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免疫学
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产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
·
2022
·
IF 15.304
Yaping Wang,Jingrong Wang,Rui Gao,Xiang Liu,Zujian Feng,Chuangnian Zhang,Pingsheng Huang,Anjie Dong,Deling Kong,Weiwei Wang
The reconstruction of large cranial bone defects by bioactive materials without exogenous cells or growth factors remains a substantial clinical challenge. Here, synthetic fibrous glycopeptide hydrogel (GR gel ) self-assembled by β-sheet RADA16-grafted glucomannan was designed to mimic the glycoprotein composition and the fibrillar architecture of natural extracellular matrix (ECM), which was non-covalently composited with 3D-printed polycaprolactone/nano hydroxyapatite (PCL/nHA) scaffold for cranial bone regeneration . The glycopeptide hydrogel significantly promoted the proliferation, osteogenic differentiation of bone mesenchymal stem cells (BMSCs), which was further augmented by GR gel -induced macrophage M2-phonotype polarization and the effective M2 macrophage-BMSC crosstalk . The repair of critical-size skull bone defect in rat indicated a superior efficacy of PCL/ [email protected] gel implant on bone regeneration and osseointegration , with an average bone area of 83.3% throughout the defect location at 12 weeks post treatment. Furthermore, the osteo-immunomodulatory GR gel induced a reparative microenvironment similar with that in normal cranium, as characterized by an increased percentage of anti-inflammatory M2 macrophages and osteoblasts, and high-level vascularization . Collectively, the composite scaffold developed here with macrophage polarization-mediated osteo-immunomodulation may represent a promising implant for expediting in situ bone regeneration by providing biochemical and osteoinductive cues at the injured tissue.
研究领域:
生物材料学
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组织工程学
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再生医学
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DOI
PubMed
高影响因子
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
·
2025
·
IF 3
Chengxiang Yan,Haijiang Dong,Zhibin Li,Xinhao Cheng,Ximei Wang
Keloid are characterized by fibroblastic proliferation and excessive collagen deposition. Nicotinamide N-methyltransferase (NNMT) belongs to the methyltransferase family and plays an important role in various physiological processes, including keloid formation. However, the role of NNMT in keloid development remains poorly understood. In this study, we investigated the role of NNMT in keloids using a bleomycin (BLM)-induced fibrosis model in vivo and primary human keloid fibroblast (HPKF) in vitro. NNMT expression was upregulated in keloid tissues, and M2 macrophages were significantly increased in keloid tissue. NNMT overexpression reduced the SAM content, while NNMT knockdown increased it. Moreover, overexpression of NNMT enhanced the cell viability of HPKFs, while knockdown of NNMT promoted apoptosis. Additionally, NNMT overexpression promoted HPKF invasion and migration, whereas knockdown effectively inhibited these processes. Overexpression of NNMT also increased the expression of fibrosis-related markers, including FN1, COL1A1, COL3A1, Vimentin, and α-SMA, while NNMT knockdown reversed it. THP-1 cells were induced into THP1-M0 macrophages using PMA and co-cultured with HPKFs. Co-culturing with NNMT-overexpressing HPKFs promoted M2 polarization in M0 cells, while NNMT knockdown inhibited M2 polarization and reduced TGFB1 and Arg-1 expression in M0 cells. Furthermore, NNMT overexpression promoted IGF-1 expression, and treatment with AG1024 (an IGF1R inhibitor) suppressed NNMT-induced M2 polarization and inhibited IGF1B and Arg-1 expression. Taken together, our findings suggest that NNMT enhances the invasive and migratory capacity of keloid fibroblasts and regulates M2 macrophage polarization in keloids through IGF-1 modulation. These results highlight NNMT as a potential therapeutic target for keloid treatment.
研究领域:
皮肤病学
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细胞生物学
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免疫学
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分子生物学
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病理学
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产品关联
DOI
PubMed
高影响因子
ADVANCED MATERIALS
·
2025
·
IF 26.8
Shengjie Cui,Xiaowei Wu,Xiaotong Yu,Yiqian Huang,Daixing Zhang,Haotian Chen,Boon Chin Heng,Qing Cai,Yixiang Wang,Yan Gu,Xuliang Deng
Targeted siRNA delivery has been widely used to regulate cell function. However, the rapid degradation of siRNA within macrophages upon delivery severely limits its utility for regulating macrophage function. Here, a novel technique is developed to compact large amounts of siAkt2 strands into delivery nanoparticles, to achieve massive and sustained intracellular release of siAkt2 that overwhelms the degradation capacity of macrophages. Microspheres of RNA complexes are prepared by rolling circle transcription. For better deliverability, siAkt2 microspheres are compacted by cholesterol-modified DNA, and encapsulated by Poly-(L-lactic acid) (PLLA). These PLLA-encapsulated siAkt2-compacted nanoparticles (siAkt2 RNP@PLLA NPs), each containing multiple repeated siAkt2 sequences, displayed long-term stability and maintenance of integrity within body fluids and acidic environments. Extensive endocytosis by RAW 264.7 is followed by continuous massive siAkt2 release into the cytosol, which significantly increased Akt2 gene silencing, metabolic reprogramming, as well as enhanced macrophage alternative polarization to the pro-regenerative M2 phenotype. Local administration of siAkt2 RNP@PLLA NPs in bone defects caused by periodontitis markedly induced macrophage alternative M2 polarization and enhanced bone regeneration. Therefore, the study provides a novel and highly efficient siRNA delivery system for regulating macrophage function, which can be a promising therapeutic strategy for enhancing tissue regeneration.
研究领域:
纳米医学
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免疫治疗
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组织工程
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基因递送
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再生医学
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产品关联
DOI
PubMed
高影响因子
PHARMACEUTICAL BIOLOGY
·
2021
·
IF 3.503
Chun Li,Xin-You Pan,Mingyun Ma,Jun Zhao,Fengda Zhao,Ya-Ping Lv
Context Astragalus polysaccharin (APS), an extract of Astragalus propinquus Schischk, exerts antitumor effects in hepatocellular carcinoma (HCC).Objective This study investigated the mechanism of action of APS in HCC.Materials and methods Tumour-associated macrophages (TAMs) were treated with APS (0, 8, 16 mg/mL) for 24 h. APS (16 mg/mL)-treated TAMs were co-cultured with MHCC97H/Huh7 cells for 24 h. Finally, BALB/c nude mice were divided into PBS, APS (50 mg/kg), APS (100 mg/kg), APS (200 mg/kg) groups: mice were inoculated with Huh7 cells to construct tumour xenograft model, followed by administration of APS (50, 100, 200 mg/kg) or PBS daily for 30 days. Cell proliferation, migration, invasion, tumour growth, macrophage markers and proportions were measured.Results APS 16 mg/mL treatment enhanced the expression of M1 macrophage markers (iNOS, IL-1β and TNF-α) and M1 macrophage proportions, while reducing the expression of M2 macrophage markers (IL-10, Arg-1) and M2 macrophage proportions in TAMs. Moreover, the APS-mediated M1 phenotype of TAMs significantly repressed cell proliferation, migration and invasion of MHCC97H and Huh7 cells. Moreover, APS (50, 100, 200 mg/kg) enhanced M1 macrophage proportions and reduced M2 macrophage proportions in the tumour tissues, and thus inhibited tumour growth of HCC.Discussion and conclusions APS inhibits HCC-like phenotypes in a murine HCC model through repression of M2 polarization of TAMs. This work provides a novel theoretical basis for the application of APS in the clinical treatment of HCC.
研究领域:
肿瘤学
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免疫学
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药理学
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产品关联
DOI
PubMed
高影响因子
ENVIRONMENTAL POLLUTION
·
2016
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IF 4.839
Naling Bai,Rexiding Abuduaini,Sheng Wang,Meinan Zhang,Xufen Zhu,Yuhua Zhao
Nonylphenol (NP), ubiquitously detected as the degradation product of nonionic surfactants nonylphenol polyethoxylates, has been reported as an endocrine disrupter . However, most pure microorganisms can degrade only limited species of NP with low degradation efficiencies. To establish a microbial consortium that can effectively degrade different forms of NP, in this study, we isolated a facultative microbial consortium NP-M2 and characterized the biodegradation of NP by it. NP-M2 could degrade 75.61% and 89.75% of 1000 mg/L NP within 48 h and 8 days, respectively; an efficiency higher than that of any other consortium or pure microorganism reported so far. The addition of yeast extract promoted the biodegradation more significantly than that of glucose. Moreover, surface-active compounds secreted into the extracellular environment were hypothesized to promote high-efficiency metabolism of NP. The detoxification of NP by this consortium was determined. The degradation pathway was hypothesized to be initiated by oxidization of the benzene ring, followed by step-wise side-chain biodegradation. The bacterial composition of NP-M2 was determined using 16S rDNA library, and the consortium was found to mainly comprise members of the Sphingomonas , Pseudomonas , Alicycliphilus , and Acidovorax genera, with the former two accounting for 86.86% of the consortium. The high degradation efficiency of NP-M2 indicated that it could be a promising candidate for NP bioremediation in situ .
研究领域:
环境微生物学
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生物修复
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微生物生态学
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产品关联
DOI
PubMed
高影响因子
ANNALS OF CLINICAL AND LABORATORY SCIENCE
·
2017
·Vol. 47
·期 6
·676-686
·
IF 0.727
Mingxiu Guan,Yingna Tong,Xiaobin Liu,Dong Dong,Yunli Zhou
Background M2 type Pyruvate kinase (PKM2) is the key rate-limiting enzyme of glycolysis, and it mainly exists as a dimer in tumor cells.This study aims to establish an enzyme kinetic assay for serum tumor M2 pyruvate kinase (TuM2-PK), and to evaluate its diagnosticvalue in breast cancer. Methods The catalytic kinetics of Pyruvate Kinase (PK) was examined. Its allosteric regulation property and Michaelis constant werethen measured. Next, the levels of TuM2-PK in serum were detected and compared with results from an enzyme-linked immunosorbentassay (ELISA). Finally, the levels of TuM2-PK among breast cancer patients, post-mastectomy patients, patients with benignbreast diseases, and healthy controls were compared. Results A PK kinetic assay was established in this study. The assay reaction time is 108 seconds, and the optimum pH level is 8.0.In the presence of the allosteric activator fructose 1, 6-bisphosphate (FBP), the Km of PK for phosphoenolpyruvate (PEP) is0.15 mmol/L and the Vmax is 330 μmol/min. The levels of TuM2-PK in serum obtained by enzyme kinetics are comparable to theELISA results. Both assays showed that TuM2-PK in breast cancer patients was increased from stage I to IV. Importantly, TuM2-PKlevels were significantly different between early and late-stage breast cancer patients (stage I and stage II vs. stage IIIand IV), as well as between late-stage and non-malignant patients (p<0.05). No statistical difference was found between benign breast disease patients and healthy controls. Conclusions An enzyme kinetic assay of serum TuM2-PK was successfully established and may be useful for breast cancer diagnosis.
研究领域:
肿瘤学
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生物化学
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癌症诊断
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酶学
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产品关联
DOI
PubMed
高影响因子
Scientific Reports
·
2015
·Vol. 5
·期 1
·1-16
·
IF 5.578
Wan Min,Zhang Wenhua,Tian Yangli,Xu Chanjuan,Xu Tao,Liu Jianfeng,Zhang Rongying
Endocytosis and postendocytic sorting of G-protein-coupled receptors (GPCRs) is important for the regulation of both their cell surface density and signaling profile. Unlike the mechanisms of clathrin-dependent endocytosis (CDE), the mechanisms underlying the control of GPCR signaling by clathrin-independent endocytosis (CIE) remain largely unknown. Among the muscarinic acetylcholine receptors (mAChRs), the M4 mAChR undergoes CDE and recycling, whereas the M2 mAChR is internalized through CIE and targeted to lysosomes. Here we investigated the endocytosis and postendocytic trafficking of M2 mAChR based on a comparative analysis of the third cytoplasmic domain in M2 and M4 mAChRs. For the first time, we identified that the sequence 374 KKKPPPS 380 servers as a sorting signal for the clathrin-independent internalization of M2 mAChR. Switching 374 KKKPPPS 380 to the i3 loop of the M4 mAChR shifted the receptor into lysosomes through the CIE pathway; and therefore away from CDE and recycling. We also found another previously unidentified sequence that guides CDE of the M2 mAChR, 361 VARKIVKMTKQPA 373 , which is normally masked in the presence of the downstream sequence 374 KKKPPPS 380 . Taken together, our data indicate that endocytosis and postendocytic sorting of GPCRs that undergo CIE could be sequence-dependent.
研究领域:
细胞生物学
·
分子生物学
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神经科学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2022
·
IF 11.467
Jianing Zhao,Longbing Ling,Wei Zhu,Tianhao Ying,Tao Yu,Mengmeng Sun,Xuan Zhu,Yuan Du,Leiming Zhang
Atherosclerosis (AS), a leading cause of death worldwide, involves chronic macrophage inflammation from its initiation to the emergence of complications. Targeting plaque inflammation by re-polarizing pro-inflammatory M1 to anti-inflammatory M2 could therefore provide a promising strategy to treat AS, but currently available anti-inflammatory drugs limit clinical outcomes. In this study, we found that kaempferol (KPF) is capable of potential anti-inflammation as a novel drug candidate, which has been scarcely reported. Building upon these findings, we fabricated a macrophage-biomimetic KPF delivery platform, abbreviated as [email protected] to potentiate therapeutic payloads, wherein the designed ROS-responsive Dextran- g -PBMEO NPs with π-π stacking were coated with macrophage membrane (MM) for effective target and accumulation in atherosclerotic lesions. Therapy of [email protected] afforded significant decrease in proliferating macrophage inflammation while went with the reduction of key pro-inflammatory cytokines and re-polarization M1 to M2 phenotype, inducing excellent anti-AS responses in ApoE −/− mice after i.p. delivery. The mechanism of [email protected] was further investigated and found it related to block the ROS/NF-κB signaling pathways. Together with as well demonstrated biosafety profiles, this proof-of-concept opens an instructive door for the study of KPF-mediated nanodrugs in treatment of AS based on biomimetic NPs.
研究领域:
药理学
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纳米技术
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心血管疾病
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炎症
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药物递送系统
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产品关联
DOI
PubMed
高影响因子
Acta Biomaterialia
·
2020
·
IF 7.242
Ying-Zheng Zhao,Zhi-Wei Huang,Yuan-Yuan Zhai,Yannan Shi,Chu-Chu Du,Jiaoyuan Zhai,He-Lin Xu,Jian Xiao,Longfa Kou,Qing Yao
Macrophage polarization is one of the main factors contributing to the proinflammatory milieu of transplanted islets. It causes significant islet loss. Bilirubin exhibits protective effects during the islet transplantation process, but the mode of delivering drugs along with the islet graft has not yet been developed. In addition, it remains unclear whether bilirubin or its derivatives can modulate macrophage polarization during islet transplantation. Therefore, this study aimed to develop an ε-polylysine-bilirubin conjugate (PLL-BR) to encapsulate the islets for protection and to explore its macrophage modulation activities. In in vitro studies, the PLL-BR was shown to tightly adhere to the islet surface. It also exhibited enhanced cytoprotective effects against oxidative and inflammatory conditions by promoting M2-type macrophage polarization. In i n vivo studies, the PLL-BR-protected islets successfully prolonged the euglycemia period in diabetic mice and accelerated the blood glucose clearance rate by maintaining the insulin secretion function. Compared to the untreated islets, the PLL-BR-encapsulated islets induced anti-inflammatory responses that were characterized by elevated levels of M2 macrophage markers and local vascularization . In conclusion, PLL-BR can be used as a tool for reprograming macrophage polarization while providing a more efficient immune protection for transplanted islets. Statement of significance Macrophage polarization is one main factor that caused significant loss of transplanted islets. Bilirubin possesses protective effects toward pancreatic islet, but how to deliver the drug along with the islet graft has not yet been harnessed. More importantly, whether bilirubin or its derivatives could modulate macrophage polarization during the host rejections has also not been answered. In this study, we developed an ε-polylysine-bilirubin conjugate (PLL-BR) to encapsulate the islets and explore its role in macrophage modulation activities. PLL-BR could attach to the surface of islets and exerted high oxidation resistance and anti-inflammatory effect. For the first time, we demonstrate that bilirubin and its derivatives effectively promoted the M2-type macrophage polarization, and optimize the immune microenvironment for islets survival and function.
研究领域:
移植免疫学
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药学
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糖尿病研究
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免疫学
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）