BRAIN RESEARCH BULLETIN
·
2021
·
IF 4.079
Hongzhi Chen,Haichao Chu,Qian Jiang,Cong Wang,Yue Tian
Perioperative neurocognitive disorder (PND) frequently occurs in elderly patients following anesthesia, and is associated with pro-inflammatory activation of microglia in hippocampus. In this study, sevoflurane , a commonly used inhaled anesthetic in clinic, was used to induce PND-like symptoms in aged SD rats (18–20 months). Data from novel object recognition and Y-maze tests first confirmed that aged SD rats exposed to 2% sevoflurane for 5 h developed cognitive impairment . Microglia preferred to polarizing towards pro-inflammatory M1 subtype (iNOS+Iba-1 +) in rat hippocampus post sevoflurane exposure, but not anti-inflammatory M2 subtype (Arg-1 +Iba-1 +). Microarray data identified interferon regulatory factor 6 (Irf6) as one (Fold change = −2.52, p = 0.006) of the 15 downregulated genes in hippocampus of the rats exposed to sevoflurane. Co-immunofluorescence data further illustrated that sevoflurane decreased Irf6 expression in hippocampal microglia. In vitro, sevoflurane enhanced lipopolysaccharide-induced M1 polarization of BV-2 cells and inhibited interleukin-4 induced M2 polarization. Interestingly, manipulation of Irf6 expression hardly affected M1 polarization. However, Irf6 overexpression further augmented the inhibitory effects on M2 polarization, and its silencing showed opposite effects. In addition, such M2 polarization-promoting effects of Irf6 knockdown may be associated with induction of peroxisome proliferator activated receptor gamma expression. Collectively, these findings suggest that Irf6 downregulation in hippocampal microglia may be a compensatory mechanism against sevoflurane-induced PND in the elderly.
研究领域:
神经科学
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麻醉学
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免疫学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
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.
研究领域:
神经科学
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分子生物学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
Biomaterials Research
·
2024
·
IF 8.1
Dongming Lv,Zhongye Xu,Hao Yang,Yanchao Rong,Zirui Zhao,Zhicheng Hu,Rong Yin,Rui Guo,Xiaoling Cao,Bing Tang
Open wounds face severe bacterial infection, which affects the quality of healing. Photothermal antimicrobial therapy has received increasing attention as a broad-spectrum antimicrobial treatment that can avoid drug resistance. A variety of metallic materials have been used in the development of photothermal agents. However, there are few studies on bismuth as a photothermal agent and its use in tissue repair, so there is still a lack of clear understanding of its biomedical function. Here, a hollow bismuth nanosphere prepared from bismuth metal was developed for drug loading and photothermal antibacterial effect. The photothermal conversion efficiency of the hollow bismuth spheres reached 16.1%, and the bismuth-loaded gelatin-oxidized dextran (ODex)-based hydrogel achieves good antibacterial effects both in vivo and in vitro. The bismuth-loaded hydrogel can also promote the angiogenesis of human umbilical vein endothelial cells (HUVECs) and improve the proliferation of human keratinocytes cells (HaCaT) and the quality of wound healing. This discovery provides a new idea for the application of metal bismuth in the field of tissue repair and regeneration.
研究领域:
生物医学工程
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材料科学
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伤口愈合
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传染病学
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组织工程
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
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2022
·Vol. 41
·期 1
·1-15
·
IF 12.658
Cao Yi,Tu Yi,Xiong Jianbo,Tan Shengxing,Luo Lianghua,Wu Ahao,Shu Xufeng,Jie Zhigang,Li Zhengrong
Background Extracellular vesicles (EVs) derived from tumor-associated macrophages are implicated in the progression and metastasis of gastric cancer (GC) via the transfer of molecular cargo RNAs. We aimed to decipher the impact of microRNA (miR)-15b-5p transferred by M2 macrophage-derived EVs in the metastasis of GC.Methods Expression of miR-15b-5p was assessed and the downstream genes of miR-15b-5p were analyzed. GC cells were subjected to gain- and loss-of function experiments for miR-15b-5p, BRMS1, and DAPK1. M2 macrophage-derived EVs were extracted, identified, and subjected to co-culture with GC cells and their biological behaviors were analyzed. A lung metastasis model in nude mice was established to determine the effects of miR-15b-5p on tumor metastasis in vivo.Results miR-15b-5p was upregulated in GC tissues and cells as well as in M2 macrophage-derived EVs. miR-15b-5p promoted the proliferative and invasive potentials, and epithelial-mesenchymal transition (EMT) of GC cells. M2 macrophage-derived EVs could transfer miR-15b-5p into GC cells where it targeted BRMS1 by binding to its 3’UTR. BRMS1 was enriched in the DAPK1 promoter region and promoted its transcription, thereby arresting the proliferative and invasive potentials, and EMT of GC cells. In vivo experiments demonstrated that orthotopic implantation of miR-15b-5p overexpressing GC cells in nude mice displayed led to enhanced tumor metastasis by inhibiting the BRMS1/DAPK1 axis.Conclusion sOverall, miR-15b-5p delivered by M2 macrophage-derived EVs constitutes a molecular mechanism implicated in the metastasis of GC, and may thus be considered as a novel therapeutic target for its treatment.
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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产品关联
DOI
PubMed
高影响因子
CNS Neuroscience & Therapeutics
·
2023
·
IF 5.5
Xin Li,Huimei Shi,Di Zhang,Bei Jing,Zhenni Chen,Yachun Zheng,Shiquan Chang,Li Gao,Guoping Zhao
Background This study aimed to investigate the potential mechanism of paeonol in the treatment of neuropathic pain. Methods Relevant mechanisms were explored through microglial pseudotime analysis and the use of specific inhibitors in cell experiments. In animal experiments, 32 SD rats were randomly divided into the sham operation group, the chronic constrictive injury (CCI) group, the ibuprofen group, and the paeonol group. We performed behavioral testing, ELISA, PCR, Western blotting, immunohistochemistry, and immunofluorescence analysis. Results The pseudotime analysis of microglia found that RhoA, Rock1, and p38MAPK were highly expressed in activated microglia, and the expression patterns of these genes were consistent with the expression trends of the M1 markers CD32 and CD86. Paeonol decreased the levels of M1 markers (IL1β, iNOS, CD32, IL6) and increased the levels of M2 markers (IL10, CD206, ARG-1) in LPS-induced microglia. The expression of iNOS, IL1β, RhoA, and Rock1 was significantly increased in LPS-treated microglia, while paeonol decreased the expression of these proteins. Thermal hyperalgesia occurred after CCI surgery, and paeonol provided relief. In addition, paeonol decreased the levels of IL1β and IL8 and increased the levels of IL4 and TGF-β in the serum of CCI rats. Paeonol decreased expression levels of M1 markers and increased expression levels of M2 markers in the spinal cord. Paeonol decreased IBA-1, IL1β, RhoA, RhoA-GTP, COX2, Rock1, and p-p38MAPK levels in the spinal dorsal horn. Conclusion Paeonol relieves neuropathic pain by modulating microglial M1 and M2 phenotypes through the RhoA/p38 MAPK pathway.
研究领域:
药理学
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神经科学
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免疫学
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产品关联
DOI
PubMed
高影响因子
Journal of Orthopaedic Surgery and Research
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2022
·Vol. 17
·期 1
·1-10
·
IF 2.677
Bin-bin Zhang,Da-wa Zha Xi,Chao Li,Lan-tao Zhang,Tao Wu,Chuan Lu,Chao-zheng Liu,De-chun Li,Chang Feng,Shu-qing Wei,Zu-nan Dong,Xian-wei Pei,Zhang Zhi-xia,Ke-wen Li
Background Bone marrow mesenchymal stem cells have always been a heated research topic in bone tissue regeneration and repair because of their self-renewal and multi-differentiation potential. A large number of studies have been focused on finding the inducing factors that will promote the osteogenic differentiation of bone marrow mesenchymal stem cells. Previous studies have shown that macrophage exosomes or miRNA-26a-5p can make it work, but the function of this kind of substance on cell osteogenic differentiation has not been public.Methods M2 macrophages are obtained from IL-4 polarized bone marrow-derived macrophages. Exosomes were isolated from the supernatant of M2 macrophages and identified via transmission electron microscopy (TEM), western blotting, and DLS. Chondrogenic differentiation potential was detected by Alcian blue staining. Oil red O staining was used to detect the potential for lipogenic differentiation. And MTT would detect the proliferative capacity of cells. Western blot was performed to detect differential expression of osteogenic differentiation-related proteins.Results The results showed that M2 macrophage exosomes will promote bone differentiation and at the same time inhibit lipid differentiation. In addition, M2 macrophage-derived exosomes have the function of promoting the expression of SOX and Aggrecan suppressing the level of MMP13. The exosome inhibitor GW4689 suppresses miRNA-26a-5p in M2 macrophage exosomes, and the treated exosomes do not play an important role in promoting bone differentiation. Moreover, miRNA-26a-5p can enable to promote bone differentiation and inhibit lipid differentiation. miRNA-26a-5p can promote the expression of ALP (alkaline phosphatase), RUNX-2 (Runt-related transcription factor 2), OPN(osteopontin), and Col-2(collagen type II). Therefore, it is speculated that exosomal miRNA-26a-5p is indispensable in osteogenic differentiation.Conclusion sThe present study indicated that M2 macrophage exosomes carrying miRNA-26a-5p can induce osteogenic differentiation of bone marrow-derived stem cells to inhibit lipogenic differentiation, and miRNA-26a-5p will also promote the expression of osteogenic differentiation-related proteins ALP, RUNX-2, OPN, and Col-2.
研究领域:
干细胞生物学
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骨组织工程
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外泌体研究
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微小RNA功能
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DOI
PubMed
高影响因子
Acta Biomaterialia
·
2025
·
IF 9.6
Pengtong Li,Chenxi Huang,Yijie He,Xinyu Lei,Xiaoyan Shen,Jialin Xu,Yunfei Mo,Xiuhong Sun,Ling Zheng,Yuqing Niu
The earliest tissue-engineered vascular grafts (TEVGs) applied clinically are biodegradable scaffolds laden with bone marrow mononuclear cells (BMCs). However, the inability to control BMCs fate after transplantation severely restricts their clinical use. To overcome this limitation, we developed a regenerative TEVG and investigated its role in modulating the immune microenvironment at arterial defects sites to enhance tissue regeneration. This TEVG was fabricated from a degradable elastomeric nanofiber scaffold combined with rBMCs, which had been induced to differentiate into regenerative M2 macrophages through in vitro culture. The resulting M2-derived extracellular matrix (ECM) dynamically modulated scaffold elasticity to match the biomechanical environment of the implantation site. When implanted into a rat abdominal aortic (rAA) defect model, the TEVGs, serving as interpositional artery grafts, could maintain the patency of abdominal artery blood circulation in rats and gradually transform into mature abdominal arteries within 12 months. However, the implanted rBMCs migrated away shortly after implantation. Instead, the scaffolds were initially repopulated by rat monocytes and subsequently gradually replaced by rat endothelial cells (ECs) and smooth muscle cells (SMCs). Further research revealed that the implanted M2 macrophages secrete IL-10 and IL-4, activating CD4 + T cells and initiating the Th2 pathway. IL-4 derived from Th2 cells sustained the M2 macrophages phenotype, forming a positive feedback loop that boosted the regenerative microenvironment-key to restoring arterial function. These findings suggest that integrating BMCs into vascular grafts and regulating the extracellular microenvironment may offers a practical and efficient strategy for treating damaged and diseased arteries. Statement of Significance The earliest clinically applied tissue-engineered vascular grafts (TEVGs) are biodegradable scaffolds seeded with bone marrow mononuclear cells (BMCs), but the uncontrolled fate of BMCs after transplantation restricts their clinical use. This study developed a regenerative TEVG combining a degradable elastic nanofiber scaffold with in vitro -induced M2 macrophages. In a rat model, the TEVG maintained arterial patency and transformed into mature arteries within 12 months by activating an M2/Th2 immune positive feedback loop, offering a new strategy for arterial injury treatment.
研究领域:
生物医学工程
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组织工程
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免疫学
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再生医学
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血管生物学
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产品关联
DOI
PubMed
高影响因子
Stem Cell Research & Therapy
·
2025
·Vol. 16
·期 1
·1-18
·
IF 7.3
Mao Shihui,Lan Ting,Sun Yimei,Li Lin,Jiang Weifeng,Xu Jiadong,Feng Yan,Hu Huiqin,Fang Yan,Xu Lanxi,Chu Lisheng
Background Bone marrow mesenchymal stem cell-derived extracellular vesicles (BMSC-EVs) show therapeutic promise for ischemic stroke (IS). Preconditioning MSCs with drugs can modulate the cargo composition and function of their derived EVs. This study investigated the therapeutic effects and underlying mechanisms of EVs derived from tetramethylpyrazine (TMP)-preconditioned BMSCs (TMP-BMSC-EVs) in IS.Methods EVs were isolated from BMSCs pretreated with or without TMP by differential centrifugation. The therapeutic efficacy of EVs was evaluated in a rat model of middle cerebral artery occlusion (MCAO) through neurological function assessments and infarct volume quantification. The expression of miR-486 and its roles in regulating microglia/macrophage polarization and neurogenesis, as well as the mechanistic targets, were examined by real-time quantitative polymerase chain reaction (RT-qPCR), immunofluorescence staining, and Western blotting.Results TMP-BMSC-EVs exerted superior therapeutic efficacy compared to BMSC-EVs. Mechanistically, TMP-BMSC-EVs were enriched with miR-486, which promoted microglia/macrophage M2 polarization and neurogenesis, while downregulating phosphatase and tensin homolog (PTEN) and phosphorylated NF-κB (p-NF-κB) protein levels, and upregulating phosphorylated Akt (p-Akt) expression. Transfection with a miR-486 inhibitor abolished the beneficial effects of TMP-BMSC-EVs, which could be counteracted by the PTEN inhibitor bisperoxovanadium (bpV).Conclusion sTMP-BMSC-EVs could significantly promote neural repair by driving microglia/macrophage M2 polarization and enhancing neurogenesis through miR-486-mediated PTEN inhibition, thereby offering a promising treatment strategy for IS.
研究领域:
神经科学
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干细胞研究
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分子生物学
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2023
·
IF 5.6
Ling Tang,Liyuan Wang,Feng Jin,Yuehan Hao,Tianming Zhao,Wenxu Zheng,Zhiyi He
Intracerebral hemorrhage (ICH) is a cerebrovascular disease. Kallikrein-related peptidase 8 (KLK8) is a serine peptidase, while its role in ICH remains unclarified. Western blot (WB) showed that KLK8 was upregulated in rat perihematomal tissues 24 h following autologous blood injection. KLK8 overexpression aggravated behavioral deficits and increased water content and Fluoro-Jade B (FJB)-positive neuron numbers in brain tissue of rats. Immunofluorescence (IF) assay showed that overexpressed-KLK8 promoted Iba-1 and iNOS expression in perihematomal tissue of rats. Overexpressed-KLK8 increased COX-2, iNOS, and Arg-1 expression and the content of IL-6, IL-1β, and TNF-α in perihematomal tissue of rats, confirmed by WB and ELISA. IF staining confirmed the expression of CCR5 was co-expressed with Iba-1, and the WB results shown increased CCR5 expression and decreased p-PKA and p-CREB expression in perihematomal tissue. Maraviroc (MVC, CCR5 inhibitor) administration rescued KLK8-induced behavioral deficits and brain injury (decreased water content and FJB-positive neuron numbers) in rats. Additionally, MVC suppressed p-PKA and p-CREB expression and the content of IL-6, IL-1β, and TNF-α in perihematomal tissue, induced by overexpressed-KLK8. Co-IP confirmed the binding of CCR5 and CCL14 in HMC3 cells. Transwell assay shown that KLK8 plus CCL4 promoted the chemotactic activity of cells, which was rescued by MVC. The biological function of KLK8/CCL14/CCR5 axis in ICH injury was also proved by MVC administration in HMC3 cells. Overall, our work revealed that KLK8 overexpression aggravated ICH process and involved in microglial activation. KLK8 might activate CCL14 thereby turning on downstream CCR5/PKA/CREB pathway, providing a theoretical basis for future therapy.
研究领域:
神经科学
·
分子生物学
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药理学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2021
·
IF 13.273
Zhaohan Wei,Xiaoqiong Zhang,Zelong Zhang,Tuying Yong,Guiting Zhan,Weilin Lv,Ziqiao Ding,Kaili Sun,Xiangliang Yang,Lu Gan
Resetting M2-like tumor-associated macrophages (TAMs) to antitumor M1 phenotype is a promising strategy in cancer immunotherapy. Although iron-based nanoparticles exhibit the potential of M2-to-M1 macrophage repolarization, the efficient M2-like TAM targeting and the subsequent intracellular iron retention remains a big challenge. Here, M2 macrophage-targeting peptide-conjugated iron-based metal–organic frameworks are developed to load diclofenac ( [email protected] ) for enhanced cancer immunotherapy. [email protected] efficiently targets M2-like TAMs and decreases the efflux by hepcidin/ferroportin signaling pathway, enabling enhanced intracellular accumulation for improved M2-to-M1 macrophage repolarization. [email protected] M2-like TAMs efficiently kill and phagocytose tumor cells, and importantly remodel tumor immune microenvironment to generate long-term antitumor immune memory, eliciting strong anticancer efficacy with tumor recurrence inhibition. Our results support [email protected] as a potential drug for cancer immunotherapy.
研究领域:
纳米技术
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免疫学
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癌症研究
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药理学
✓ 已验证
产品关联
DOI
高影响因子
PHYTOTHERAPY RESEARCH
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2023
·
IF 7.2
Waimei Si,Xin Li,Bei Jing,Shiquan Chang,Yachun Zheng,Zhenni Chen,Guoping Zhao,Di Zhang
(Switching from the microglial M1 phenotype to the M2 phenotype is a promising therapeutic strategy for neuropathic pain (NP). This study aimed to investigate the potential use of stigmasterol for treating NP. In animal experiments, 32 male Sprague–Dawley rats were randomly divided into the sham operation group, chronic constriction injury (CCI) group, CCI + ibuprofen group, and CCI + stigmasterol group. We performed behavioral tests, enzyme-linked immunosorbent assay, hematoxylin-esoin staining (H&E) staining and immunohistochemistry, immunofluorescence, and Western blotting. In cell experiments, we performed flow cytometry, immunofluorescence, Western blotting, and qRT-PCR. Stigmasterol reduced thermal and mechanical hyperalgesia and serum IL-1β and IL-8 levels and increased serum IL-4 and TGF-β levels in CCI rats. Stigmasterol reduced IL-1β, COX-2, and TLR4 expression in the right sciatic nerve and IL-1β expression in the spinal cord. Stigmasterol reduced the expression of Iba-1, TLR4, MyD88, pNF-κB, pP38 MAPK, pJNK, pERK, COX-2, IL-1β, and CD32 in the spinal cord of CCI rats while increasing the expression of IL-10 and CD206. Stigmasterol decreased M1 polarization markers and increased M2 polarization markers in lipopolysaccharide (LPS)-induced microglia and decreased the expression of Iba-1, TLR4, MyD88, pNF-κB, pP38 MAPK, pJNK, pERK, iNOS, COX-2, and IL-1β in LPS-treated microglia while increasing the expression of Arg-1 and IL-10. Stigmasterol regulates microglial M1/M2 polarization via the TLR4/NF-κB pathway to alleviate NP.
研究领域:
药理学
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神经科学
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免疫学
·
疼痛研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2025
·
IF 13.2
Yang Chen,Wenting Cheng,Hailong Tian,Yilin Wang,Weifeng He,Canhua Huang
Burns catastrophically compromise the skin barrier, driving impaired healing, infection susceptibility, and regenerative failure, primarily through dysregulated inflammation, immune dysfunction, and overwhelming oxidative stress. While reactive oxygen species (ROS) mediate essential host defense, their pathological excess necessitates targeted modulation for burn repair. We engineered a ROS-responsive nanoassembly (PTC@Cu NPs) for co-delivering chlorogenic acid (CGA) and copper ions (Cu 2+ ). Synthesizing the amphiphilic polymer mPEG-TK-CGA (PTC) via a ROS-cleavable thioketal linker enabled self-assembly with Cu 2+ into NPs. This system achieves triggered release specifically within high-ROS burn sites. CGA and Cu 2+ act synergistically to potently scavenge ROS, polarize macrophages to a pro-regenerative M2 phenotype, and thereby ameliorate oxidative damage, infection, and healing deficits in deep partial-thickness burns. In vitro and in vivo studies demonstrate PTC@Cu NPs significantly suppress apoptosis, enhance cell migration, exert potent antibacterial effects, and markedly accelerate healing. These comprehensive therapeutic benefits are mechanistically underpinned by dual ROS reduction and macrophage M2 polarization. Collectively, this platform presents a promising strategy for infected deep burn wounds by simultaneously targeting oxidative damage, microbial infection, and impaired tissue repair.
研究领域:
纳米医学
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烧伤修复
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炎症调控
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氧化应激
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免疫调节
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药物递送
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生物化学
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生物医学工程
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产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）