Extravasated erythrocytes in cerebrospinal fluid (CSF) critically contribute to the pathogenesis of subarachnoid hemorrhage (SAH). Meningeal lymphatics have been reported to drain macromolecules and immune cells from CSF into cervical lymph nodes (CLNs). However, whether meningeal lymphatics are involved in clearing extravasated erythrocytes in CSF after SAH remains unclear. Here we show that a markedly higher number of erythrocytes are accumulated in the lymphatics of CLNs and meningeal lymphatics after SAH. When the meningeal lymphatics are depleted in a mouse model of SAH, the degree of erythrocyte aggregation in CLNs is significantly lower, while the associated neuroinflammation and the neurologic deficits are dramatically exacerbated. In addition, during SAH lymph flow is increased but without significant lymphangiogenesis and lymphangiectasia. Taken together, this work demonstrates that the meningeal lymphatics drain extravasated erythrocytes from CSF into CLNs after SAH, while suggesting that modulating this draining may offer therapeutic approaches to alleviate SAH severity.

To help doctors and patients evaluate lumbar intervertebral disc degeneration (IVDD) accurately and efficiently, we propose a segmentation network and a quantitation method for IVDD from T2MRI. A semantic segmentation network (BianqueNet) composed of three innovative modules achieves high-precision segmentation of IVDD-related regions. A quantitative method is used to calculate the signal intensity and geometric features of IVDD. Manual measurements have excellent agreement with automatic calculations, but the latter have better repeatability and efficiency. We investigate the relationship between IVDD parameters and demographic information (age, gender, position and IVDD grade) in a large population. Considering these parameters present strong correlation with IVDD grade, we establish a quantitative criterion for IVDD. This fully automated quantitation system for IVDD may provide more precise information for clinical practice, clinical trials, and mechanism investigation. It also would increase the number of patients that can be monitored.

Background: Rheumatoid arthritis (RA) is a chronic autoimmune disorder, characterized by an increased number of M1-like macrophages in the joints. Polyphyllin I (PPI), one of the main components in the Rhizoma of Paris polyphyllin, displays a selective inhibitory effect on various tumor cells. Here we sought to investigate the anti-rheumatoid arthritis effects and mechanisms of PPI on macrophages in vivo and in vitro. Materials and Methods: In vitro, primary bone marrow-derived macrophages (BMMs) and peritoneal elucidated macrophages (PEMs) were stimulated by lipopolysaccharide (LPS) and Interferon (IFN)-γ and then treated with PPI. We determined the degree of activation of IKKα/β and p65, two key mediators of the NF-κB-mediated inflammatory pathway, by measuring their phosphorylated forms by Western blot. The p65 nuclear localization was detected by immunofluorescent staining. Further, a NF-κB-linked luciferase reporter plasmid, as well as those expressing key mediators of the Toll-like receptor 4 pathway, such as myeloid differentiation primary response 88 (MYD88), interleukin-1 receptor (IL-1R) associated kinase (IRAK)-1, TNF receptor associated factors (TRAF)-6, Transforming growth factor-b–activated kinase 1 (TAK1) and p65, were used to identify the mechanism by which PPI achieves its inhibitory effects on macrophage-mediated inflammation. Moreover, a NF-κB inhibitor, p65-targeted siRNAs, and a p65 plasmid were further used to validate the anti-inflammatory mechanism of PPI. In vivo, PPI (1 mg/kg) was administered intragastrically one time a day for 7 weeks starting on the 42nd day after the first immunization with collagen in a collagen-induced arthritis (CIA) mouse model. Micro-computed Tomography scanning, histological examination, F4/80 and iNOS double immunofluorescent staining and CD4 immunohistochemical staining were performed to determine the effect of PPI treatment on joint structure and inflammation in this model. Results: PPI reduced the inflammatory cytokines production of PEMs stimulated by LPS/IFN-γ, inhibited the phosphorylation of IKKα/β and p65, and prevented p65 nuclear localization. The NF-κB luciferase assay showed that the target of PPI was closely related to the NF-κB pathway. Moreover, NF-κB inhibition, siRNA-mediated knockdown of p65, and p65 overexpression eliminated PPI's inhibitory effect. In addition, PPI attenuated the bone erosion and synovitis, as well as M1-like macrophage and T cell infiltration, in the ankle joint of the CIA model. Conclusion: PPI demonstrated effective amelioration of synovial inflammation in the ankle joint of CIA mice while suppressing NF-κB-mediated production of pro-inflammatory effectors in activated macrophages.

Osteoarthritis (OA) is a common chronic inflammatory disorder. Effective remodeling of inflammatory microenvironment in the joint is a promising strategy to prevent OA. However, current drugs remain unsatisfactory due to a lack of targeted and effective ways for relieving inflammatory conditions in OA joints. Bortezomib (BTZ), a proteasome inhibitor, could effectively inhibit proinflammatory cytokines but with poor accumulation in the inflammatory tissues. To overcome the shortcomings of BTZ delivery and to improve the efficacy of OA therapy, herein, we designed a novel nanomedicine (denoted as BTZ@PTK) by the co-assembly of BTZ and an amphiphilic copolymer (denoted as PTK) with ROS-cleaved thioketal (TK) linkages. The TK units in BTZ@PTK are first cleaved by the excessive ROS at OA sites, and then triggered the controlled release of BTZ, resulting in the accurate delivery and the inflammatory microenvironment remodeling. Accordingly, BTZ@PTK suppressed ROS generation and proinflammatory cytokines while promoting M1 macrophage apoptosis in lipopolysaccharide (LPS)-activated RAW264.7 macrophages or LPS/IFN-γ-treated primary macrophages, which leads to a better effect than BTZ. In OA mice, BTZ@PTK passively accumulates into inflamed joints to attenuate pain sensitivity and gait abnormality. Importantly, BTZ@PTK treatment successfully ameliorates synovitis with the reduction of synovial hyperplasia and synovitis scores by suppressing M1 macrophage polarization and promoting M1 macrophage apoptosis in the synovium, thereby delaying cartilage damage. Collectively, BTZ@PTK can effectively modulate inflammatory microenvironment for OA recession by activating M1 macrophage apoptosis and inhibiting M1macrophage-mediated inflammatory response.

Background: Osteoporosis has already been a growing health concern worldwide. The influence of living area, lifestyle, socioeconomic, and medical conditions on the occurrence of osteoporosis in the middle-aged and elderly people in China has not been fully addressed.Methods: The study was a multicenter cross-sectional study on the middle-aged and elderly permanent residents, which gathered information of 22,081 residents from June 2015 to August 2021 in seven representative regions of China. The bone mineral density of lumbar vertebrae and hip were determined using the dual-energy X-ray absorptiometry densitometer instruments. Serum levels of bone metabolism markers were also measured. Information about education, smoking, and chronic diseases were also collected through face-to-face interviews. Age-standardized prevalence and 95% confidence intervals (CIs) of osteopenia and osteoporosis by various criteria were estimated by subgroups and overall based on the data of China 2010 census. The relationships between the osteoporosis or osteopenia and sociodemographic variables or other factors were examined using univariate linear models and multivariable multinomial logit analyses.Results: After screening, 19,848 participants (90%) were enrolled for the final analysis. The age-standardized prevalence of osteoporosis was estimated to be 33.49%(95%CI, 32.80–34.18%) in the middle-aged and elderly Chinese permanent residents, for men and women was 20.73% (95% CI, 19.58–21.87%) and 38.05% (95% CI, 37.22–38.89%), respectively. The serum concentrations of bone metabolic markers, and calcium and phosphorus metabolism were influenced by age, body mass index (BMI), gender, education level, regions, and bone mass status. Women, aged 60 or above, BMI lower than 18.5 kg/m², low education level including middle school, primary school and no formal education as well as current regular smoking, a history of fracture were all significantly associated with a higher risk of osteoporosis and osteopenia in the middle-aged and elderly people.Conclusions: This study revealed dramatic regional differences in osteoporosis prevalence in China, and female, aged 60 or older, low BMI, low education level, current regular smoking, and a history of fracture were associated with a high risk of osteoporosis. More prevention and treatment resources should be invested into particular population exposed to these risk factors.