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
PHYTOMEDICINE
·
2024
·
IF 6.7
Li An,Qianwen Zhai,Keyu Tao,Yingcai Xiong,Weiying Ou,Ziwei Yu,Xingyu Yang,Jianjian Ji,Mengjiang Lu
Background Quercetin has received extensive attention for its therapeutic potential treating respiratory syncytial virus (RSV) infection diseases. Recent studies have highlighted quercetin's ability of suppressing alveolar macrophages (AMs)-derived lung inflammation. However, the anti-inflammatory mechanism of quercetin against RSV infection still remains elusive. Purpose This study aims to elucidate the mechanism about quercetin anti-inflammatory effect on RSV infection. Methods BALB/c mice were intranasally infected with RSV and received quercetin (30, 60, 120 mg/kg/d) orally for 3 days. Additionally, an in vitro infection model utilizing mouse alveolar macrophages (MH-S cells) was employed to validate the proposed mechanism. Results Quercetin exhibited a downregulatory effect on glycolysis and tricarboxylic acid (TCA) cycle metabolism in RSV-infected AMs. However, it increased itaconic acid production, a metabolite derived from citrate through activating immune responsive gene 1 (IRG1), and further inhibiting succinate dehydrogenase (SDH) activity. While the suppression of SDH activity orchestrated a cascading downregulation of Hif-1α/NLRP3 signaling, ultimately causing AMs polarization from M1 to M2 phenotypes. Conclusion Our study demonstrated quercetin stimulated IRG1-mediated itaconic acid anabolism and further inhibited SDH/Hif-1α/NLRP3 signaling pathway, which led to M1 to M2 polarization of AMs so as to ameliorate RSV-induced lung inflammation.
研究领域:
免疫学
·
药理学
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病毒学
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代谢组学
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产品关联
DOI
PubMed
高影响因子
HUMAN REPRODUCTION
·
2016
·Vol. 32
·期 1
·94-102
·
IF 4.621
Yuan Ming,Li Dong,An Min,Li Qiuju,Zhang Lu,Wang Guoyun
STUDY QUESTIONWhat are the features of peritoneal macrophage subgroups and T helper cells in the development of murine endometriosis?SUMMARY ANSWERDuring the development of endometriosis in a murine model, large peritoneal macrophages (LPMs) and small peritoneal macrophages (SPMs) are polarized into M1 and M2 cells, respectively, and the proportions of T helper (Th) 1, Th17 and T regulatory (Treg) cells are increased.WHAT IS KNOWN ALREADYNumerous studies investigating the etiology and pathogenesis of endometriosis have focused on the polarization states of peritoneal macrophages in endometriosis models and patients, but the results are inconclusive. Further studies indicate that peritoneal macrophages are composed of two distinct subsets: LPMs and SPMs, although their roles in endometriosis are unknown.STUDY DESIGN, SIZE, DURATIONThis study involves a prospective and randomized experiment. Fifty C57BL/6 female mice were randomly allocated to five control and five experimental groups (n = 5/group) according to the presence or absence of transplantation. The transplant periods are 0.25, 3, 14, 28 and 42 days.PARTICIPANTS/MATERIALS, SETTING, METHODSC57BL/6 mice were utilized to establish an endometriosis model by i.p. injection of allogeneic endometrial segments. Dynamic changes of peritoneal macrophage subsets and polarization profiles were evaluated by flow cytometry (FCM). Macrophage morphology and density were assessed by cell counting under a microscope. Dynamic changes of Th1, Th2, Th17 and Treg cells were estimated by FCM.MAIN RESULTS AND THE ROLE OF CHANCEPeritoneal macrophages are composed of two distinct subsets: LPMs and SPMs. The proportion of SPMs increased immediately after peritoneal injection of endometrial tissues, whereas LPMs showed an opposite trend. Peritoneal macrophages differentiated into both M1 and M2 macrophages. The bidirectional polarization of macrophages was caused by the inverse trends of polarization of LPMs and SPMs. Consistently, the proportions of Th1, Th17 and Treg cells were all increased in mice with endometriosis.LARGE SCALE DATAN/A.LIMITATIONS, REASONS FOR CAUTIONIn this study, detection was only performed in a murine endometriosis model. Clinical data and more intervention experiments are required in understanding the roles of LPMs and SPMs in endometriosis.WIDER IMPLICATIONS OF THE FINDINGSThe dramatic changes of LPMs and SPMs in proportion and polarization profiles clarified the varying differentiation states of peritoneal macrophages. In addition, LPMs and SPMs may play different roles in the pathogenesis of endometriosis in different stages of endometriosis. Therefore, the new classification should be included in future relevant basic and clinical studies on endometriosis.STUDY FUNDING/COMPETING INTEREST(S)This research was supported totally by grant 81270671 from the National Natural Science Foundation of China. The authors report no conflict of interest.
研究领域:
免疫学
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生殖医学
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病理学
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产品关联
DOI
PubMed
高影响因子
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
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
EXPERIMENTAL CELL RESEARCH
·
2022
·
IF 4.145
Yanling Zhang,Zhiyun Du,Dan Li,Zhuo Wan,Tianyi Zheng,Xuehui Zhang,Yingjie Yu,Xiaoping Yang,Qing Cai
Due to the inflammatory responses associated with defect occurrence and materials implantation, immunoregulation has emerged as a promising strategy to enhance bone regeneration . It has been widely reported that a material could facilitate osteogenesis if it can guide macrophages to anti-inflammatory M2 phenotype, vice versa, a substrate will influence macrophage phenotype if it is osteoinductive. However, few studies have looked into the intercellular crosstalking directly. Herein, the compound catalpol was selected for its multiple functions to study the interactions between bone marrow mesenchymal stromal cells (BMSCs) and macrophages. This iridoid glucoside exhibits excellent anti-inflammatory and osteoinductive activities. The effects of catalpol on mediating M1/M2 polarization of macrophages, inhibiting osteoclast differentiation , promoting osteogenesis and angiogenesis were systematically investigated to correlate the biological responses of BMSCs and macrophages. To extend its in vivo application, the catalpol was then loaded onto an electrospun polylactide/gelatin composite fibrous mesh and subcutaneously implanted to evaluate the local inflammation and ectopic osteogenesis. The results revealed that the functions of catalpol displayed in modulating cellular behaviors are via cell paracrine to strengthen intercellular crosstalking, hence demonstrating that catalpol itself could serve as a promising bioactive stimulator for bone tissue engineering.
研究领域:
组织工程
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生物材料
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免疫学
·
细胞生物学
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再生医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
NEUROSCIENCE
·
2022
·
IF 3.708
Hanshu Zhao,Yushuang Liu,Nan Chen,Hongyi Yu,Sihan Liu,Meihe Qian,Zhongling Zhang
Cerebral ischemia/reperfusion injury is the main cause of neurological deficit following stroke. Pleckstrin homology-like domain, family A, member 1 (PHLDA1) is increasingly recognized as a critical determinant in immunological regulation and cell apoptosis, but its role in neuroinflammation during cerebral ischemia/reperfusion injury remains to be elucidated. In this study, middle cerebral artery occlusion/reperfusion (MCAO/R) in C57BL/6 mice and oxygen-glucose deprivation/reoxygenation (OGD/R) in BV-2 cells were used as models in vivo and in vitro , respectively. MACO/R mice and OGD/R cells were treated with scramble or PHLDA1 small interfering RNAs (siRNAs) to achieve the goal of PHLDA1 knockdown. The results showed that the expression of PHLDA1 was significantly increased in MCAO/R mice and OGD/R cells compared to their normal controls, respectively. Mice treated with PHLDA1 siRNA exhibited a lower degree of infarct volume and brain water content compared to the NC siRNA-treated mice. Notably, PHLDA1 knockdown switched the M1 pro-inflammatory phenotype to the M2 anti-inflammatory phenotype by decreasing the expression of M1 markers (i.e., CD16, TNF-α, IL-6 and IFN-γ, and iNOS) and elevating the expression of M2 markers (i.e., CD206, IL-4, IL-10, and Arg-1). Moreover, PHLDA1 knockdown suppressed the NLRP3 inflammasome activation by reducing NLRP3, ASC, cleaved caspase 1 and cleaved IL-1β expression. In summary, these results suggest that PHLDA1 blockade effectively alleviates the ischemia/reperfusion-induced cerebral injury by switching microglial M1/M2 polarization and inhibiting NLRP3 inflammasome activation. Targeting PHLDA1 could be considered as a novel strategy in the treatment against post-ischemic brain injury.
研究领域:
神经科学
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免疫学
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分子生物学
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细胞生物学
✓ 已验证
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
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
·
2022
·
IF 15.304
Yichang Xu,Liang Wu,Yunkai Tang,Feng Cai,Kun Xi,Jincheng Tang,Zonghan Xu,Yong Gu,Wenguo Cui,Liang Chen
Organic/inorganic composites have advantages in promoting bone repair ; however, early changes in the local immune response after material implantation and the mechanisms that affect the late osteogenesis have not been revealed systematically. Herein, we prepared injectable composite poly ( l -lactic acid)/nano hydroxyapatite (PLLA/nHA) porous microspheres ( [email protected] @nHA) using a microfluidic technology to explore the changes in the osteo-immune microenvironment and potential mechanisms using immunology and bioinformatics. Immunological analysis revealed that macrophages (Mφ) phagocytosed the nHA released from the composite microspheres, increased the proportion of M2 Mφ, regulated the early inflammatory response, exerted strong paracrine effects, and improved the osteo-immune microenvironment. Bioinformatics analysis showed that the signal transduction and adhesion ability were enhanced after Mφ activation, the inflammatory signaling pathways were inhibited, regulating the polarization direction , and the expression of cell growth factors was up-regulated to promote late osteogenesis. In vivo studies demonstrated that the composite microspheres effectively regulated Mφ polarization, and the paracrine secreted growth factors created a microsphere-centered osteogenesis pattern at the defect site . In conclusion, we successfully prepared injectable composite PLLA/nHA porous microspheres and systematically explored the osteogenesis-related mechanisms using immunological and bioinformatics analysis to provide theoretical evidence for bone repair materials that contribute to bone differentiation.
研究领域:
免疫学
·
生物信息学
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生物材料
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组织工程
·
骨再生
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2022
·
IF 10.383
Siyu Wu,Jiayi Ma,Jun Liu,Chun Liu,Su Ni,Ting Dai,Yan Wang,Yiping Weng,Hongbin Zhao,Dong Zhou,Xiubo Zhao
Biomaterial–immune system interactions play an important role in postimplantation osseointegration to retain the functionality of healthy and intact bones. Therefore, appropriate osteoimmunomodulation of implants has been considered and validated as an efficient strategy to alleviate inflammation and enhance new bone formation. Here, we fabricated a nanostructured PCL/PVP (polycaprolactone/polyvinylpyrrolidone) electrospinning scaffold for cell adhesion, tissue ingrowth, and bone defect padding. In addition, telmisartan, an angiotensin 2 receptor blocker with distinct immune bioactivity, was doped into PCL-/PVP-electrospun scaffolds at different proportions [1% (TPP-1), 5% (TPP-5), and 10% (TPP-10)] to investigate its immunomodulatory effects and osteoinductivity/conductivity. Telmisartan-loaded scaffolds displayed in vitro anti-inflammatory bioactivity on lipopolysaccharide-induced M1 macrophages by polarizing them to an M2-like phenotype and exhibited pro-osteogenic properties on bone marrow-derived mesenchymal stem cells (BMSCs). Histological analysis and micro-CT results of a rat skull defect model also showed that the telmisartan-loaded scaffolds induced a higher M2/M1 ratio, less inflammatory infiltration, and better bone regenerative patterns. Furthermore, activation of the BMP2 (bone morphogenetic protein-2)-Smad signaling pathway was found to be dominant in telmisartan-loaded scaffold-mediated macrophage–BMSC interactions. These findings indicate that telmisartan incorporation with PCL/PVP nanofibrous scaffolds is a potential therapeutic strategy for promoting bone healing by modulating M1 macrophages to a more M2 phenotype at early stages of postimplantation.
研究领域:
生物材料
·
免疫学
·
组织工程
·
再生医学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CARBOHYDRATE POLYMERS
·
2023
·
IF 11.2
Ying Zhang,Ruirui Ma,Cuiyu You,Xue Leng,Danyang Wang,Shujing Deng,Binyang He,Ziyang Guo,Zelin Guan,Hengyu Lei,Jie Yu,Qinyuan Zhou,Jianfeng Xing,Yalin Dong
Based on the biocompatibility and macrophage targeting of natural polysaccharides , combined with the physiological and pathological characteristics of the gastrointestinal tract and colonic mucosa of ulcerative colitis (UC), we prepare dexamethasone (Dex)-loaded oral colon-targeted nano-in-micro drug delivery systems coated with multilayers of chitosan (CS), hyaluronic acid (HA), and finally Eudragit S100 (ECHCD MPs) using a layer-by-layer coating technique for UC treatment through regulating the M1/M2 polarization of intestinal macrophages. HA/CS/Dex nanoparticles (HCD NPs) are ingested by macrophages via CD44 receptor-mediated endocytosis to regulate M1-to-M2 macrophage polarization and exert anti-inflammatory effects. Moreover, ECHCD MPs show better colon-targeting properties than Dex-loaded chitosan nanoparticles (CD NPs) and HCD NPs which is demonstrated by stronger mucoadhesion to inflamed colon tissues. After oral administration, ECHCD MPs exert significant anti-UC effects. Therefore, ECHCD MPs are proven to be as promising oral colon-targeting drug delivery systems for Dex and have potential application in UC treatment.
研究领域:
药学
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药物递送系统
·
炎症
·
胃肠病学
·
巨噬细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Science
·
2024
·
IF 14.3
Huirong Huang,Shimin Zheng,Jianing Wu,Xindan Liang,Shengjie Li,Pengfei Mao,Zhinan He,Yahui Chen,Lining Sun,Xinyu Zhao,Aimin Cai,Luhui Wang,Huixiang Sheng,Qing Yao,Ruijie Chen,Ying-Zheng Zhao,Longfa Kou
Osteoarthritis (OA) is a chronic inflammatory disease characterized by cartilage destruction, synovitis, and osteophyte formation. Disease-modifying treatments for OA are currently lacking. Because inflammation mediated by an imbalance of M1/M2 macrophages in the synovial cavities contributes to OA progression, regulating the M1 to M2 polarization of macrophages can be a potential therapeutic strategy. Basing on the inherent immune mechanism and pathological environment of OA, an immunoglobulin G-conjugated bilirubin/JPH203 self-assembled nanoparticle (IgG/BRJ) is developed, and its therapeutic potential for OA is evaluated. After intra-articular administration, IgG conjugation facilitates the recognition and engulfment of nanoparticles by the M1 macrophages. The internalized nanoparticles disassemble in response to the increased oxidative stress, and the released bilirubin (BR) and JPH203 scavenge reactive oxygen species (ROS), inhibit the nuclear factor kappa-B pathway, and suppress the activated mammalian target of rapamycin pathway, result in the repolarization of macrophages and enhance M2/M1 ratios. Suppression of the inflammatory environment by IgG/BRJ promotes cartilage protection and repair in an OA rat model, thereby improving therapeutic outcomes. This strategy of opsonization involving M1 macrophages to engulf carrier-free BR/JPH203 nanoparticles to suppress inflammation for OA therapy holds great potential for OA intervention and treatment.
CAS / MDL:
研究领域:
风湿病学
·
纳米技术
·
免疫学
·
药理学
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生物医学工程
✓ 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）