摘要：
A novel reactive oxygen species‐responsive biodegradable nanoparticle (NP@PolyRHAPM) is designed, in which astaxanthin can reduce intracellular ROS levels and rapamycin‐enhanced autophagy levels, and restore mitochondrial function, hence successfully repolarizing M1 macrophages into M2 phenotypes. This repolarization enhances the proliferation and viability of chondrocytes while inhibiting apoptosis. Overall, this ROS‐responsive nanocarrier system provides a new avenue for progressive OA therapy. Abstract Osteoarthritis (OA) is a chronic joint disease characterized by synovitis and joint cartilage destruction. The severity of OA is highly associated with the imbalance between M1 and M2 synovial macrophages. In this study, a novel strategy is designed to modulate macrophage polarization by reducing intracellular reactive oxygen species (ROS) levels and regulating mitochondrial function. A ROS‐responsive polymer is synthesized to self‐assemble with astaxanthin and autophagy activator rapamycin to form nanoparticles (NP@PolyRHAPM). In vitro experiments show that NP@PolyRHAPM significantly reduced intracellular ROS levels. Furthermore, NP@PolyRHAPM restored mitochondrial membrane potential, increased glutathione (GSH) levels, and promoted intracellular autophagy, hence successfully repolarizing M1 macrophages into the M2 phenotype. This repolarization enhanced chondrocyte proliferation and vitality while inhibiting apoptosis. In vivo experiments utilizing an anterior cruciate ligament transection (ACLT)‐induced OA mouse model revealed the anti‐inflammatory and cartilage‐protective effects of NP@PolyRHAPM, effectively mitigating OA progression. Consequently, the findings suggest that intra‐articular delivery of ROS‐responsive nanocarrier systems holds significant promise as a potential and effective therapeutic strategy for OA treatment.
摘要：
Inflammation is a common feature of many inflammatory diseases and tumors, and plays a decisive role in their development. Exosomes are extracellular vesicles unleashed by assorted types of cells, and it is widely known that exosomes of different immune cell sources play different functions. Exosome production has recently been reported for immune cells comprising macrophages, T cells, B cells, and dendritic cells (DCs). Immune cell-derived exosomes are involved in a variety of inflammatory responses.Herein, we summarize and review the role of macrophages, T cells, B cells, and dendritic cells (DC) in inflammatory diseases, with a focus on the role of immune cell-derived exosomes in osteoarthritis, rheumatoid arthritis, and the inflammatory tumor microenvironment (TME).These findings are expected to be important for developing new treatments for inflammatory diseases and ameliorating tumor-related inflammation.
摘要：
BACKGROUND: Senile osteoporosis (SOP) is an age-related metabolic bone disease that currently lacks specific therapeutic interventions. Thus, this study aimed to investigate the effect of Astragaloside IV (AS-IV) on macrophage senescence, bone marrow mesenchymal stem cell (BMSC) osteogenesis, and SOP progression. METHODS: A senescent macrophage model was established and treated with varying concentrations of AS-IV. Cell activity was measured using the CCK8 assay. The senescence levels of macrophages were evaluated through β-galactosidase staining, PCR, and immunofluorescence. Macrophage mitochondrial function was assessed using ROS and JC-1 staining. Macrophage polarization was evaluated through PCR, Western blot, and immunofluorescence. The inhibitory effects of AS-IV on macrophage senescence were investigated using Western blot analysis. Furthermore, the effects of macrophage conditioned medium (CM) on BMSCs osteogenic were detected using ALP, alizarin red, and PCR. RESULTS: AS-IV inhibited macrophage senescence and M1 polarization, alleviated mitochondrial dysfunction, and promoted M2 polarization. Mechanistically, it suppressed the STING/NF-κB pathway in H2O2-activated macrophages. Conversely, the STING agonist c-di-GMP reversed the effects of AS-IV on macrophage senescence. Additionally, AS-IV-induced macrophage CM promoted BMSC osteogenic differentiation. In vivo, AS-IV treatment ameliorated aberrant bone microstructure and bone mass loss in the SOP mouse model, inhibited macrophage senescence, and promoted M2 polarization. CONCLUSIONS: By modulating the STING/NF-κB signaling pathway, AS-IV potentially inhibited macrophage senescence and stimulated osteogenic differentiation of BMSCs, thus exerting an anti-osteoporotic effect. Consequently, AS-IV may serve as an effective therapeutic candidate for the treatment of osteoporosis.
作者机构：
[Li, Muzhe; Yin, Han; Liu, Shuyun; Tian, Guangzhao; Guo, Quanyi; Deng, Haotian] Chinese Peoples Liberat Army Gen Hosp, Inst Orthoped, Key Lab Musculoskeletal Trauma & War Injuries PLA, Med Ctr 1,Beijing Key Lab Regenerat Med Orthoped, 28 Fuxing Rd, Beijing 100853, Peoples R China.;[Chen, Zhiwei; Li, Muzhe; Yi, Guoliang] Univ South China, Affiliated Hosp 1, Hengyang Med Sch, Dept Orthoped, 69 Chuanshan Rd, Hengyang 421000, Hunan, Peoples R China.;[Chen, Mingxue] Peking Univ, Beijing Jishuitan Hosp, Dept Orthoped Surg, Clin Coll 4, Beijing 100035, Peoples R China.;[Guo, Weimin] Sun Yat Sen Univ, Affiliated Hosp 1, Dept Orthopaed Surg, Guangdong Prov Key Lab Orthoped & Traumatol, 58 Zhongshan Second Rd, Guangzhou 510080, Guangdong, Peoples R China.
通讯机构：
[Quanyi Guo; Shuyun Liu] I;[Zhiwei Chen] D;Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma and War Injuries PLA, No. 28 Fuxing Road, Haidian District, Beijing 100853, China<&wdkj&>Department of Orthopedics, The First Affiliated Hospital, Hengyang Medical School, University of South China, No. 69, Chuanshan Road, Hengyang 421000, Hunan Province, China
摘要：
Zinc is an essential trace element for bone growth and bone homeostasis in the human body. Bone mesenchymal stem cells (BMSCs) are multipotent progenitors existing in the bone marrow stroma with the capability of differentiating along multiple lineage pathways. Zinc plays a paramount role in BMSCs, which can be spurred differentiating into osteoblasts, chondrocytes, or adipocytes, and modulates the formation and activity of osteoclasts. The expression of related genes also changed during the differentiation of various cell phenotypes. Based on the important role of zinc in BMSC differentiation, using zinc as a therapeutic approach for bone remodeling will be a promising method. This review explores the role of zinc ion in the differentiation of BMSCs into various cell phenotypes and outlines the existing research on their molecular mechanism.
摘要：
The use of interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitor as a treatment for the inflammatory joint disease is a promising method. However, its underlying mechanism in osteoarthritis (OA) remains unclear. The purpose of this study is to look into the effects of adenovirus-mediated knockdown of IRAK4 on synovitis in the OA rabbit model. Ad-shIRAK4 was injected two weeks after anterior cruciate ligament resection. Six weeks later, the rabbits were killed. The expression of IRAK4, TNFR-associated factor 6(TRAF6), TGF-activated kinase 1(TAK1), p-IKB kinase (p-IKK), p-nuclear factor kappa-B (p-NFκB), p38, and p-p38 in the synovial membrane was detected by western blot, qRT-PCR, and immunohistochemistry analysis. Immunohistochemistry was to detect the expression of IRAK4 proteins in articular cartilage. H&E staining was to assess the pathological changes of synovium and cartilage. The levels of interleukin (IL)-1β, tumor necrosis factor-α(TNF-α), and MMP-13 in the synovial fluid were measured by ELISA. X-ray and micro-computerized tomography (μCT) scans were used to assess knee joint conditions and microstructure of subchondral bone. IRAK4 expression levels in synovial tissues of the OA model group exhibited a significant upward trend. Ad-shIRAK4 significantly reduced IRAK4 mRNA expression in synovium tissues. Notably, Ad-shIRAK4 suppressed the Toll-like receptor/interleukin-1 receptor (TLR/IL-1R) signaling. In addition, in the Ad-shIRAK4 treatment group, we can see less inflammatory cell infiltration and reduced hyperplasia and angiogenesis. The levels of IL-1β, TNF-α, and MMP-13 in the synovial fluid in the OA model group were significantly higher than that in the control group, which were reduced by Ad-shIRAK4 treatment. Finally, Results of HE stains, immunohistochemistry, and μCT showed that Ad-shIRAK4 treatment has a protective effect on cartilage damage. IRAK4 is significantly upregulated in the synovium from the osteoarthritis rabbit model. In addition, Ad-shIRAK4 reduced the expression of IRAK4 and suppressed TLR/IL-1R signaling in the synovium from the osteoarthritis rabbit model. Ad-shIRAK4 could alleviate synovitis and cartilage degradation in the osteoarthritis rabbit model, and thus alleviate the symptoms of OA and prevent the progression of OA.
通讯机构：
[Chen, Zhiwei] U;Univ South China, Affiliated Hosp 1, Dept Orthopaed, 69 Chuanshan Rd, Hengyang 421001, Hunan, Peoples R China.
关键词：
COVID-19;meta-analysis;nonsevere;severe
摘要：
BACKGROUND: This meta-analysis aimed to compare the clinical symptoms of COVID-19 pneumonia in children. METHODS AND ANALYSIS: Electronic databases including PubMed, EMBASE, Web of Science, China National Knowledge Infrastructure (CNKI) database, Wanfang Database, and Chinese Biomedical Literature Database (CBM) were searched from its inception to June 21, 2020. We only included studies that reported clinical symptoms of COVID pneumonia in children. Quality of the included studies was assessed by 2 authors. Pooled results were summarized by STATA 12.0 software.The heterogeneity was measured by I2 tests (I2 < 50 indicates little heterogeneity, I2≥50 indicates high heterogeneity). Publication bias was performed by funnel plot and statistically assessed by Begg test (P > .05 as no publication bias). RESULTS: Results will be shown as figures or tables. CONCLUSION: Our study aims to systematically present the clinical symptoms of COVID-19 pneumonia patients in children, so as to further provide guidance for clinical management.
摘要：
Synoviocytes are located in the synovium lining layer, which is composed of macrophage-like synoviocytes (MLS) and fibroblast-like synoviocytes (FLS) with different characteristics. Mitochondria, which exist in most cells, are two membrane-covered organelles. In addition to providing the necessary ATP for synoviocytes, mitochondria are involved in the regulation of redox homeostasis and the integration of synoviocytes death signals. In recent years, mitochondrial dysfunction has been found in rheumatoid arthritis (RA) and osteoarthritis (OA). Interestingly, recent studies have started uncovering that mitochondria that were previously reported to play a role in chondrocytes or immune cells, but not known to have pronounced roles in synoviocytes, can actually play crucial roles in the regulation of the pathological properties of the synoviocytes. The purpose of this review is to summarize our current understanding of the key role of mitochondria in synoviocytes, including mitochondrial dysfunction in synoviocytes can induce and aggravate inflammatory responses and changes in mitochondrial structure and function with the involvement of multiple cytokines, signal pathway, and hypoxic state of synovial tissue alter the response of synoviocytes to apoptotic stimulation. Also, mitochondrial abnormalities in synoviocytes promote the synoviocytes invasion and proliferation.
期刊：
JOURNAL OF CLINICAL INVESTIGATION,2021年131(10) ISSN：0021-9738
通讯作者：
Liang, W.;He, J.;Fan, J.-B.
作者机构：
[Chen, Hanzhang; Wang, Jiaxuan; Yin, Weiqiang; Mo, Lili; Liu, Jun; Li, Caichen; He, Jianxing; Liang, Wenhua] Guangzhou Med Univ, Affiliated Hosp 1, China Natl Ctr Resp Med, China State Key Lab Resp Dis,Dept Thorac Surg & O, Guangzhou, Peoples R China.;[Chen, Hanzhang; Wang, Jiaxuan; Yin, Weiqiang; Mo, Lili; Liu, Jun; Li, Caichen; He, Jianxing; Liang, Wenhua] Natl Clin Res Ctr Resp Dis, Guangzhou, Peoples R China.;[Chen, Zhiwei; Tu, Xixiang; Zhao, Dezhi; Li, Hui; Fan, Jian-Bing; Tao, Jinsheng; Jiang, Zeyu] AnchorDx Med Co, Guangzhou, Peoples R China.;[Chen, Zhiwei; Liu, Xin] AnchorDx Inc, Fremont, CA USA.;[Cheng, Chao] Sun Yat Sen Univ, Affiliated Hosp 1, Dept Thorac Surg, Guangzhou, Peoples R China.
通讯机构：
[Fan, J.-B.; Liang, W.; He, J.] D;Department of Pathology, 1838 ShaTai Road, China;Department of Thoracic Surgery and Oncology, 151 Yanjiang Road, China
