BIOMATERIALS
·
2024
·
IF 12.8
Yuhuan Li,Jiayin Lv,Shuchen Liu,Zhuoran Wang,Yu Gao,Zheyuan Fan,Lei Huang,Jing Cui,Boya Zhang,Xinchen Liu,Zhuo Zhang,Te Liu,Daowei Li,Modi Yang
The role of pro-inflammatory macrophages (M1) in rheumatoid arthritis (RA) is significant, as they produce excessive cytokines. Targeting efferocytosis is a potential manner to repolarize M1 macrophages into pro-resolving M2 phenotype, which restores immune homeostasis by releasing anti-inflammatory mediators. In this study, liquid nitrogen-treated dead macrophages (DM) are employed to act as a dead cell-derived active targeted drug carrier for shikonin (SHK) and induce efferocytosis in M1 macrophages with the enhancement of SHK as an AMP-activated protein kinase (AMPK)-activator. The synergistic activation of AMPK leads to uncoupled protein 2 (UCP2) upregulation and reprograms M1 macrophages into M2 phenotypes by promoting oxidative phosphorylation. In the mouse model of collagen-induced arthritis, the intravenous administration of DM/SHK leads to a consistent transformation of M1 macrophages into the M2 phenotype within the infiltrative synovium. This transformation of macrophages results in the restoration of immune homeostasis in the synovium through an increase in the production of pro-resolving mediators. Additionally, it inhibits synovial proliferation and infiltration and provides protection against erosion of cartilage and bone. In summary, LNT-based DM serves as an active targeting drug carrier to M1 macrophages and also acts synergistically with SHK to target immunometabolism.
研究领域:
免疫学
·
药理学
·
风湿病学
·
炎症
·
药物递送系统
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DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2025
·
IF 4.7
Xiu-ying Li,Feng-yuan Zhang,Xin Wang,Qin-qing Li,Yan-dong Li,Cai-xia Liu
Inflammation and bone damage are the primary factors contributing to poor quality of life in patients with rheumatoid arthritis (RA). Triptolide (TP), the main active component of Tripterygium wilfordii , exhibits a certain inhibitory effect on RA, however, its clinical application is hindered by systemic toxicity and poor spatiotemporal specificity in vivo . Based on the pathological features of RA, we designed and constructed a novel multifunctional TP-loaded micelle (Mul@MC) with acid sensitivity and particle size shrinkage properties. Specifically, Mul@MC first accumulates at inflammatory sites via passive targeting. In the acidic microenvironment of RA lesions, acid-sensitive bonds on the micelle surface are disrupted, exposing folate ligands. This process is accompanied by a significant reduction in particle size, which the penetration of the formulation into inflamed joints. Subsequently, the exposed folate ligands enable active targeting of folate receptors (FR) overexpressed on M1 macrophages. This targeted delivery inhibits M1 polarization of macrophages, promotes M1 macrophage repolarization, reduces the secretion of pro-inflammatory cytokines, and decreases the release of nitric oxide (NO) and reactive oxygen species (ROS). Consequently, the inflammatory microenvironment is rebalanced, chondrocytes are protected, and the toxicity of TP to normal tissues is effectively alleviated. In conclusion, the Mul@MC designed in this study exhibit excellent in vivo spatiotemporal selectivity for TP delivery. By integrating anti-inflammatory and chondroprotective effects, Mul@MC exerts a significant anti-RA effect, providing new prospects for the clinical application of TP in RA treatment
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DOI
PubMed
高影响因子
ADVANCED FUNCTIONAL MATERIALS
·
2025
·
IF 19
Wenxin Yang,Zhengrong Chen,Ying Qu,Peng Ye,Yong Tang,Qixiu Yu,Ziyang Zhang,Qijie Dai,Ce Dou,Fei Luo
In rheumatoid arthritis (RA), the complex interplay of inflammatory mediators and cellular mechanisms presents challenges for effective treatment. Current therapies, often targeting singular pathways, achieve limited clinical remission. This study introduces a multifunctional therapeutic strategy using a pollen-inspired aptamer delivery system (tk-Apt@pollen) designed for dual targeting of neutrophil extracellular traps (NETs) and tumor necrosis factor-alpha (TNFα). Engineered sunflower pollen grains, modified with methoxy polyethylene glycol (mPEG) and thioketal (TK), encapsulate aptamers that inhibit DEK protein activity and TNFα-mediated inflammation. This dual mechanism disrupts NETs formation, mitigates reactive oxygen species (ROS) levels, and inhibits osteoclastogenesis. In vitro assays demonstrated the system's ability to inhibit NET production, reduce osteoclast activation, and achieve controlled aptamer release in response to ROS. In vivo, tk-Apt@pollen significantly reduces joint inflammation and bone erosion in a collagen-induced arthritis mouse model, outperforming free aptamers. This study highlights tk-Apt@pollen as a promising approach to address the multifaceted pathology of RA, providing insights into designing multi-target therapies for chronic inflammatory diseases.
研究领域:
医学
·
免疫学
·
纳米医学
·
药理学
✓ 已验证
产品关联
DOI
高影响因子
Pharmaceutics
·
2022
·Vol. 14
·期 7
·1518
·
IF 6.525
Mengchen An,Mengxiao Shi,Jingjing Su,Yueru Wei,Rongrong Luo,Pengchao Sun,Yongxing Zhao
Although the inhibitors of the interleukin-6 receptor (IL-6R) and tumor necrosis factor-α (TNF-α) have achieved a certain success in the clinical treatment of rheumatoid arthritis (RA), great effort should be made to overcome side effects and to improve patient compliance. The present research aimed to address these problems by the co-delivery of tocilizumab (TCZ)—an inhibitor of IL-6R—and an aptamer Apt1-67, which specifically inhibits TNF receptor 1 via separable microneedles (MN). MN were featured with a sustained release of TCZ from needle tips and a rapid release of Apt1-67 from needle bodies by using methacrylate groups grafted hyaluronic acid as the fillings of needle tips and polyvinyl alcohol/polyvinyl pyrrolidone as the fillings of needle bodies. Our results demonstrated that TCZ and Apt1-67 were distributed in MN as expected, and they could be released to the surroundings in the skin. In vivo studies revealed that combined medication via MN (TCZ/[email protected]) was superior to MN loaded with a single drug. Compared with subcutaneous injection, TCZ/[email protected]was of great advantage in inhibiting bone erosion and alleviating symptoms of CIA mice. This study not only provides a novel approach for combined medication with different release properties but also supplies a strategy for improving drug efficacy.Keywords:separable microneedles;tocilizumab;aptamer Apt1-67;rheumatoid arthritis
研究领域:
药学
·
生物医学工程
·
风湿病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2024
·
IF 4.8
Xiaoxue Cao,Zhaoran Wang,Yi Jiao,Wenya Diao,Qishun Geng,Lu Zhao,Zihan Wang,Xing Wang,Mengxiao Zhang,Jiahe Xu,Bailiang Wang,Tingting Deng,Cheng Xiao
Treg cell-based therapy has exhibited promising efficacy in combatting rheumatoid arthritis (RA). Dihydroartemisinin (DHA) exerts broad immunomodulatory effects across various diseases, with its recent spotlight on T-cell regulation in autoimmune conditions. The modulation of DHA on Treg cells and its therapeutic role in RA has yet to be fully elucidated. This study seeks to unveil the influence of DHA on Treg cells in RA and furnish innovative substantiation for the potential of DHA to ameliorate RA. To this end, we initially scrutinized the impact of DHA-modulated Treg cells on osteoclast (OC) formation in vitro using Treg cell-bone marrow-derived monocyte (BMM) coculture systems. Subsequently, employing the collagen-induced arthritis (CIA) rat model, we validated the efficacy of DHA and probed its influence on Treg cells in the spleen and popliteal lymph nodes (PLN). Finally, leveraging deep proteomic analysis with data-independent acquisition (DIA) and parallel accumulation-serial fragmentation (PASEF) technology, we found the alterations in the Treg cell proteome in PLN by proteomic analysis. Our findings indicate that DHA augmented suppressive Treg cells, thereby impeding OC formation in vitro. Consistently, DHA mitigated erosive joint destruction and osteoclastogenesis by replenishing splenic and joint-draining lymph node Treg cells in CIA rats. Notably, DHA induced alterations in the Treg cell proteome in PLN, manifesting distinct upregulation of alloantigen Col2a1 (Type II collagen alfa 1 chain) and CD8a (T-cell surface glycoprotein CD8 alpha chain) in Treg cells, signifying DHA's targeted modulation of Treg cells, rendering them more adept at sustaining immune tolerance and impeding bone erosion. These results unveil a novel facet of DHA in the treatment of RA.
研究领域:
免疫学
·
风湿病学
·
药理学
·
蛋白质组学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2016
·
IF 5.091
Shan Liu,Lingxin Zhu,Jie Zhang,Jingjing Yu,Xue Cheng,Bin Peng
Previous studies, including those from our laboratory, have demonstrated that the natural flavonoid isoliquiritigenin (ISL) is a promising agent for bone destructive diseases. However, the mechanisms underlying its anti-osteoclastogenic effects are still far from clear. Here, we evaluated the potential alterations of autophagy and nuclear factor-κB (NF-κB) during anti-osteoclastogenic effects by ISL in vitro and in vivo . We observed that ISL inhibited the receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis and suppressed autophagic microtubule-associated protein light chain 3 (LC3)-II and Beclin 1 accumulation. ISL treatment resulted in the interruption of several specific features for autophagy in osteoclast precursors, including acidic vesicular organelle formation, LC3-II accumulation, and appearance of autophagic vacuoles. The RANKL-stimulated expression levels of autophagy-related genes and proteins also diminished in ISL-treated osteoclast precursors. The reactivation of autophagy by rapamycin almost reversed the ISL-elicited anti-osteoclastogenic effects. Interestingly, ISL inhibited the RANKL-stimulated NF-κB expression and nuclear translocation, whereas the NF-κB inhibitor Bay 11-7082 markedly suppressed the RANKL-induced autophagic activation. Consistent with the in vitro results, the administration of ISL could attenuate osteoclastogenic cathepsin K , autophagic LC3, and NF-κB expression to protect against inflammatory calvarial bone erosion in vivo . Our findings highlight the inhibition of NF-κB-dependent autophagy as an important mechanism of ISL-mediated anti-osteoclastogenic activity.
研究领域:
药理学
·
免疫学
·
骨骼生物学
✓ 已验证
DOI
PubMed
高影响因子
International Journal of Nanomedicine
·
2023
·
IF 8
Shenting Zhu,Lingxin Zhu,Jingjing Yu,Yanqing Wang,Bin Peng
Background: Epigallocatechin gallate (EGCG), the major anti-inflammatory compound in green tea, has been shown to suppress osteoclast (OC) differentiation. However, the low aqueous solubility of EGCG always leads to poor bioavailability, adverse effects, and several drawbacks for clinical applications.Purpose: In this study, we synthesized EGCG-capped gold nanoparticles (EGCG-GNPs) to solve the drawbacks for clinical uses of EGCG in bone destruction disorders by direct reduction of HAuCl4 in EGCG aqueous solution.Methods and Results: The obtained EGCG-GNPs were negatively charged and spherical. Theoretical calculation results suggested that EGCG was released from GNPs in an acidic environment. Cellular uptake study showed an obviously large amount of intracellular EGCG-GNPs without cytotoxicity. EGCG-GNPs exhibited better effects in reducing intracellular reactive oxygen species levels than free EGCG. A more dramatic anti-osteoclastogenic effect induced by EGCG-GNPs than free EGCG was observed in lipopolysaccharide (LPS)-stimulated bone marrow macrophages, including decreased formation of TRAP-positive multinuclear cells and actin rings. Meanwhile, EGCG-GNPs not only suppressed the mRNA expression of genetic markers of OC differentiation but also inhibited MAPK signaling pathways. Furthermore, we confirmed that EGCG-GNPs greatly reversed bone resorption in the LPS-induced calvarial bone erosion model in vivo, which was more effective than applying free EGCG, specifically in inhibiting the number of OCs, improving bone density, and preventing bone loss.Conclusion: EGCG-GNPs showed better anti-osteoclastogenic effect than free EGCG in vitro and in vivo, indicating their potential in anti-bone resorption treatment strategy.
研究领域:
纳米技术
·
药理学
·
骨科
·
炎症研究
✓ 已验证
DOI
PubMed
高影响因子
FASEB JOURNAL
·
2018
·Vol. 32
·期 6
·3398-3410
·
IF 5.595
Yugai Jia,Yumeng Miao,Mengfan Yue,Mei Shu,Zhifeng Wei,Yue Dai
Tetrandrine, a bisbenzylisoquinoline alkaloid, was previously demonstrated to attenuate inflammation and cartilage destruction in the ankles of mice with collagen-induced arthritis (CIA). Here, we explored the underlying mechanism by which tetrandrine prevented arthritis-induced bone erosion by focusing on the differentiation and function of osteoclasts. We found that daily administration of tetrandrine (30 mg/kg) markedly reduced the bone damage and decreased the number of osteoclasts in CIA rats. In vitro , tetrandrine inhibited receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis at the early stage and reduced the expressions of osteoclast-related marker genes. In bone marrow-derived macrophages and RAW264.7 cells, tetrandrine inhibited RANKL-induced translocation of NF-κB-p65 and nuclear factor of activated T cell 1 (NFATc1) through suppressing spleen tyrosine kinase (Syk)-Bruton's tyrosine kinase-PLCγ2-Ca 2+ signaling. Of interest, tetrandrine did not affect the phosphorylation of immunoreceptor tyrosine-based activation motifs, the conventional upstream of Syk, but it inhibited the activity of Syk by enhancing its ubiquitination and degradation. The anti–osteoclastogenesis effect of tetrandrine nearly disappeared when it was used in combination with the Syk inhibitor piceatannol or in constitutively activated Syk-overexpressing cells. Taken together, tetrandrine attenuated CIA-induced bone destruction by inhibiting osteoclastogenesis through hindering the translocation of NF-κB-p65 and NFATc1 via reducing the activation of Syk.—Jia Y., Miao, Y., Yue, M., Shu, M., Wei, Z., Dai Y. Tetrandrine attenuates the bone erosion in collagen-induced arthritis rats by inhibiting osteoclastogenesis via spleen tyrosine kinase. FASEB J. 32, 3398–3410 (2018). www.fasebj.org
研究领域:
药理学
·
免疫学
·
风湿病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Nature Communications
·
2023
·Vol. 14
·期 1
·1-20
·
IF 16.6
Han Haobo,Xing Jiakai,Chen Wenqi,Jia Jiaxin,Li Quanshun
In rheumatoid arthritis (RA), insufficient apoptosis of macrophages and excessive generation of pro-inflammatory cytokines are intimately connected, accelerating the development of disease. Here, a fluorinated polyamidoamine dendrimer (FP) is used to deliver miR-23b to reduce inflammation by triggering the apoptosis of as well as inhibiting the inflammatory response in macrophages. Following the intravenous injection of FP/miR-23b nanoparticles in experimental RA models, the nanoparticles show therapeutic efficacy with inhibition of inflammatory response, reduced bone and cartilage erosion, suppression of synoviocyte infiltration and the recovery of mobility. Moreover, the nanoparticles accumulate in the inflamed joint and are non-specifically captured by synoviocytes, leading to the restoration of miR-23b expression in the synovium. The miR-23b nanoparticles target Tab2 , Tab3 and Ikka to regulate the activation of NF-κB pathway in the hyperplastic synovium, thereby promoting anti-inflammatory and anti-proliferative responses. Additionally, the intravenous administration of FP/miR-23b nanoparticles do not induce obvious systemic toxicity. Overall, our work demonstrates that the combination of apoptosis induction and inflammatory inhibition could be a promising approach in the treatment of RA and possibly other autoimmune diseases.
研究领域:
药理学
·
免疫学
·
风湿病学
·
纳米技术
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2023
·
IF 15.1
Meng-Wen Ma,Kai-Lin He,Chao-Qing Li,Xiao-Ting Xie,Sui Zhou,Bin Zhang,Xiao-Lin Hou,Cheng Li,Yuan-Di Zhao,Ling-Li Dong,Bo Liu
Rheumatoid arthritis (RA) is an autoimmune disease, in which inflammatory macrophages play a crucial role by secreting a large number of proinflammatory factors to aggravate inflammatory response. In addition, reactive oxygen species (ROS) are abundant in hypoxic joints, inducing chondrocyte apoptosis and causing irreversible bone destruction. In this work, we synthesized hyaluronic acid-modified platinum-tellurium nanorods (HPT) as a photothermal agent to target RA joints, ablating inflammatory macrophages and scavenging ROS in the microenvironment. Hyaluronic acid can specifically bind to the CD44 receptors, which are over-expressed on the surface of inflammatory macrophages, achieving active targeting and improving therapy effectiveness. Under the irradiation of an 808 nm laser, thermal energy produced by HPT, which has high photothermal conversion efficiency is sufficient to induce apoptosis of inflammatory macrophages. Simultaneously, platinum particles on the surface of tellurium nanorods can effectively remove a variety of ROS, reducing oxidative stress and alleviating inflammatory response in RA joints. Collagen-induced arthritis (CIA) mice had been used to study the therapeutic potential of HPT. The results revealed that the clinical scores in CIA mice injected with HPT and irradiated with a near-infrared laser were significantly reduced. The inflammatory response was also obviously relieved, when compared with CIA mice injected with PBS. Micro-CT imaging revealed that bone erosion was visibly reduced in the HPT + Laser group. These results demonstrate that multifunctional HPT is promising to serve as a therapeutic platform for the treatment of RA.
研究领域:
纳米技术
·
生物医学工程
·
药学
·
免疫学
·
风湿病学
✓ 已验证
产品关联
DOI
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2016
·
IF 7.441
Qin Wang,Jiayu Jiang,Wenfei Chen,Hao Jiang,Zhirong Zhang,Xun Sun
Glucocorticoid (GC) is the cornerstone therapy of rheumatoid arthritis , but high doses are associated with serious adverse effects. In an effort to improve the efficacy of low-dose GC therapy, we developed a micelle system for targeted delivery to inflamed joints and validated the approach in a rat model of arthritis. Micelles loaded with dexamethasone (Dex) self-assembled from the amphipathic poly (ethylene glycol)-block–poly (εcaprolactone) (PCL–PEG) polymer via film dispersion, and they were injected intravenously at a dose of only 0.8 mg/kg into rats with adjuvant-induced arthritis. The micelles persisted for a relatively long time in the circulation, and they accumulated preferentially in inflamed joints. Micelle-delivered Dex potently reduced joint swelling, bone erosion, and inflammatory cytokine expression in both joint tissue and serum. PCL–PEG micelles caused only moderate adverse effects on body weight, lymphocyte count and blood glucose concentration, and they weakly activated the host complement system. These results suggest that encapsulating Dex in PCL–PEG micelles may allow for safe and effective low-dose GC therapy targeting inflammatory disorders.
研究领域:
药理学
·
风湿病学
·
纳米技术
·
炎症
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MOLECULAR PHARMACEUTICS
·
2023
·
IF 4.9
Yisi Liu,Jun Yao,Guotao Deng,Gang Zhong,Jianping Zhao,Qiumei Lan,Jinzhi Meng,Yin Yu,Fei Chen
Osteoarthritis (OA) affects numerous patients worldwide, and there are no approved disease-modifying drugs. Repurposing FDA-approved small molecular drugs could be a promising alternative strategy to treat OA. Disulfiram (DSF), a clinically approved drug for treatment of alcoholism, inhibits inflammasome activation and exhibits a protective role in interleukin-1β-induced cardiac injury. However, its efficacy in treating OA remains to be explored due to its poor water solubility and stability, which limit its use in OA treatment. Here, the anti-inflammatory effect of DSF is evaluated in vitro, and a double-layer encapsulation approach is developed for intra-articular delivery of DSF for OA treatment in vivo. DSF is loaded into poly(lactic-co-glycolic acid)-based nanoparticles and encapsulated in gelatin methacrylate microgels through a microfluidic device. Results show that DSF effectively inhibits the expression of key inflammatory cytokines in OA chondrocytes, and the double-layer encapsulation approach reduces the burst release of DSF and prolongs its retention time in the in vitro study. Sustained release of DSF from microgels mitigates cartilage inflammation and subchondral bone erosion in a monoiodoacetate-induced rat OA model. This work demonstrates the potential of repurposing FDA-approved drugs for OA treatment and provides a promising platform for intra-articular delivery of small molecules for superior therapeutic effect.
研究领域:
药学
·
生物医学工程
·
骨科
·
药物递送系统
·
炎症研究
✓ 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）