γδ T cell antigen receptor polyspecificity enables T cell responses to a broad range of immune challenges.

γδ T cells are essential for immune defense and modulating physiological processes. While they have the potential to recognize large numbers of antigens through somatic gene rearrangement, the antigens which trigger most γδ T cell response remain unidentified, and the role of antigen recognition in γδ T cell function is contentious. Here, we show that some γδ T cell receptors (TCRs) exhibit polyspecificity, recognizing multiple ligands of diverse molecular nature. These ligands include haptens, metabolites, neurotransmitters, posttranslational modifications, as well as peptides and proteins of microbial and host origin. Polyspecific γδ T cells are enriched among activated cells in naive mice and the responding population in infection. They express diverse TCR sequences, have different functional potentials, and include the innate-like γδ T cells, such as the major IL-17 responders in various pathological/physiological conditions. We demonstrate that encountering their antigenic microbiome metabolite maintains their homeostasis and functional response, indicating that their ability to recognize multiple ligands is essential for their function. Human γδ T cells with similar polyspecificity also respond to various immune challenges. This study demonstrates that polyspecificity is a prevalent feature of γδ T cell antigen recognition, which enables rapid and robust T cell responses to a wide range of challenges, highlighting a unique function of γδ T cells.

Circadian Rhythm Regulated by Tumor Suppressor p53 and Time Delay in Unstressed Cells.

Circadian function and p53 network are interconnected on the molecular level, but the dynamics induced by the interaction between the circadian factor Per2 and the tumor suppressor p53 remains poorly understood. Here, we constructed an integrative model composed of a circadian clock module and a p53-Mdm2 feedback module to study the dynamics of p53-Per2 network in unstressed cells. As expected, the model can accurately predict the circadian rhythm, which is consistent with diverse experimental observations. In addition, using a combination of theoretical analysis and numerical simulation, the results demonstrated that p53 expression enhances the phase advance of circadian rhythm and reduces the robustness of circadian rhythm. Furthermore, the time delay required for the transcription and translation of Per2 protein induces oscillations by undergoing a supercritical Hopf bifurcation, and improves the robustness of circadian rhythm. In summary, this work shows that the p53-Per2 interaction and the time delay are two essential factors for circadian functions.

[Hierarchical first aid training scheme for elementary and middle school students: the practices from the construction of "Baoan Model" social emergency medicine training].

OBJECTIVE: To share the implementation experience of hierarchical first aid training scheme for elementary and middle school students in Baoan District of Shenzhen City and evaluate its effect of training. METHODS: During August 2018 and August 2019, elementary and middle schools students who participated in the first aid training held by emergency rescue training center of Baoan District were enrolled. Baseline information including the number of students, the number of attending tutors, the number of cardiopulmonary resuscitation (CPR) training models, automated external defibrillator (AED) models were recorded. According to hierarchical levels of three age, students received different courses with content from simple to hard: the course of elementary school students was consisting of dialing 120, smart animation on how to identify accidental damage, demonstration of AED and Hemlick techniques, CPR practise (40 minutes). The course of junior high school students was consisted of how to dial 120, how to identify accidental damage and simple disposal, application of CPR and AED, practice CPR and AED and Hemlick techniques (90 minutes). The course of high school students was consisted of how to dial 120, identify accidental damage and right disposal, identification of out-of-hospital cardiac arrest, the key-point of CPR and AED, practice CPR and AED, Hemlick techniques and hemostatic bandage (120 minutes). At the end of course, elementary school students were voluntary for skill assessment; junior high school students only were compulsory for skill assessment in small classes but not required in large classes, just for demonstration; additionally, the whole high school students were compulsory for skill assessment. The characteristics of first aid training students at different levels were collected in order to compare the differences on the usage of CPR training model and AED training model, the distribution of emergency resource, the ratio for passing examination. RESULTS: A total of 12 896 students and 2 086 training instructors took parted in 200 lists of first aid training courses, 8 557 CPR models and 8 493 AED models were used. On average, there are 65.27±5.61 students in each session, and 10.52±10.43 training instructors. There are 43.09±19.06 CPR training models and 42.77±18.61 AED training models. The mean ratio of student to tutor was 6.07±1.47, student to CPR model was 1.54±1.02, and student to AED model was 1.54±1.03. In the end of course, 10 494 students participated in the examination with the participation rate of 81.37%; 10 114 students passed the examination with the passing rate of 96.38%. Hierarchical analysis showed: compare to elementary school students, the average number of junior high school students in every training session significantly increased (cases: 69.94±8.77 vs. 58.69±6.12, P < 0.05), but the average number of high school students in every training session significantly decreased (cases: 57.35±5.79 vs. 58.69±6.12, P < 0.05). The proportion of instructors in junior high school students' training significantly reduced (5.94±1.39 vs. 6.48±2.02, P < 0.05). The examination ratio of junior high school students and high school students was increased significantly [81.07% (6 667/8 224), 100% (2 313/2 313) vs. 64.18% (1 514/2 359), both P < 0.05], but the ratio of passing the examination was significantly reduced [95.47% (6 365/6 667), 96.88% (2 241/2 313) vs. 99.60%(1 508/1 514), both P < 0.01]. This might be related to the low difficulty of elementary school students' assessment and the low proportion of compulsory examination. CONCLUSIONS: Hierarchical scheme is feasible for first aid training in elementary and middle school students, the content of course should be desighed from easy to hard. Synchronously, sufficient training instructors and training models should be equipped to ensure the quality.

Falls among older adults with sarcopenia dwelling in nursing home or community: A meta-analysis.

OBJECTIVES: To assess and quantify sarcopenia as a risk for falls among community-dwelling older people and nursing home older persons. METHODS: Prospective cohort studies that evaluated the association between sarcopenia and falls in older adults were identified via a systematic literature search of Medline (via Ovid), PubMed, EMBASE, and the Cochrane CENTRAL Library from database inception until October 15, 2018, in English and Chinese. RESULTS: 10 studies (10,073 participants) were included in the meta-analysis. Among older adults, having sarcopenia was significantly associated with a higher risk of falls, compared to older adults without sarcopenia (pooled OR-odds ratio = 1.52, 95% CI-confidence interval: 1.32-1.77, I2 = 39.1%). In addition, the results of subgroup analysis indicated that male participants with sarcopenia had a higher risk of falls than mixed gender participants with sarcopenia (pooled OR = 1.72, 95% CI: 1.36-2.18 versus pooled OR = 1.41, 95% CI: 1.16-1.70). Other subgroup analyses were conducted using different study follow-up periods (>1 year versus ≤ 1 year) (pooled OR 1.63, 95% CI: 1.38-1.92 versus 1.20, 95% CI: 0.87-1.65). In addition, community-dwelling older people with sarcopenia was significantly increase risk of fall, compared with non-sarcopenia (pooled OR = 1.69, 95% CI: 1.43-2.00), whereas it was not found among nursing home residents (pooled OR = 1.12, 95% CI: 0.84-1.51). Furthermore, sarcopenia definition subgroup analysis found that older adults with sarcopenia increase the risk of falls when using EWGSOP (pooled OR = 1.43, 95% CI: 1.19-1.72), FNIH (pooled OR = 1.82, 95% CI: 1.39-2.37), AWGS (pooled OR = 7.68, 95% CI: 1.41-41.80), respectively. CONCLUSION: The present study found that sarcopenia is a risk factor for falls among community-dwelling older people, but not among nursing home older persons. Future research is needed to provide evidence for specific interventions aimed at treating sarcopenia and preventing falls among older adults dwelling in the community.

Contribution of time delays to p53 oscillation in DNA damage response.

Although the oscillatory dynamics of the p53 network have been extensively studied, the understanding of the mechanism of delay-induced oscillations is still limited. In this paper, a comprehensive mathematical model of p53 network is studied, which contains two delayed negative feedback loops. By studying the model with and without explicit delays, the results indicate that the time delay of Mdm2 protein synthesis can well control the pulse shape but cannot induce p53 oscillation alone, while the time delay required for Wip1 protein synthesis induces a Hopf bifurcation to drive p53 oscillation. In addition, the synergy of the two delays will cause the p53 network to oscillate in advance, indicating that p53 begins the repair process earlier in the damaged cell. Furthermore, the stability and bifurcation of the model are addressed, which may highlight the role of time delay in p53 oscillations.

Oscillatory Dynamics of p53 Genetic Network Induced by Feedback Loops and Time Delays.

DNA damage caused by γ -irradiation initiates oscillatory expression of the p53 genetic network. Although many studies revealed the effects of the p53-Mdm2 circuit on p53 dynamics, a few studies explored the contribution of upstream kinases to p53 oscillation. In this paper, an integrated mathematical model of the p53 network in response to γ -irradiation is studied, which consists of five basic components, two ubiquitous time delays, and two negative feedback loops. It is found that recurrent p53 pulses are externally initiated by ataxia telangiectasia mutated (ATM), and the negative feedback loop formed between ATM and p53, via Wip1, plays a dominant role in generating p53 oscillation. In addition, p53 oscillation requires not only an appropriate Mdm2 negative strength but also a threshold level of Wip1 negative strength. Furthermore, the time delays required for transcription and translation of Mdm2 and Wip1 proteins are essential for p53 oscillation. In particular, the critical value of time delay for inducing oscillation and the properties of delay-driven Hopf bifurcation are theoretically analyzed. As expected, the results are clearly in consistence with biological experiments and observations.

Frailty as a Predictor of All-Cause Mortality Among Older Nursing Home Residents: A Systematic Review and Meta-analysis.

OBJECTIVES: We performed a meta-analysis based on prospective cohort studies to synthesize the pooled risk effect and to determine whether frailty is a predictor of all-cause mortality. DESIGN: Systematic review and meta-analysis. SETTING: PubMed, EMBASE, and the Cochrane Library were systematically searched in October 2018. A random effects model was applied to combine the results according to the heterogeneity of the included studies. PARTICIPANTS: Older nursing home residents. MEASUREMENTS: Mortality risk due to frailty. RESULTS: Fourteen studies (9076 participants) were included in this meta-analysis. Pooled results demonstrated that nursing home residents with frailty were at an increased risk of mortality [pooled hazards ratio (HR) = 1.88, 95% confidence interval (CI) = 1.57, 2.25, I2 = 47.8%, P < .001] compared to those without frailty. Results of subgroup analyses showed that frailty was significantly associated with the risk of mortality among older nursing home residents when using FRAIL-NH (pooled HR = 2.10, 95% CI = 1.60-2.77, P < .001) and Frailty Index (pooled HR = 1.74, 95% CI = 1.40-2.18, P < .001) to define frail people, whereas when using the diagnosis criteria of CSHA-CFS for frailty, the pooled HR was 2.82 (95% CI = 0.79-10.10, P = .111). In addition, the subgroup analysis for length of follow-up showed that studies with a follow-up period of 1 year or more (pooled HR = 1.83, 95% CI = 1.52, 2.21, P < .001) reported a significantly higher rate of mortality among individuals with frailty, compared to those without frailty. Similar results were also found in studies with a follow-up period of less than 1 year (pooled HR = 2.67, 95% CI = 1.43, 5.00, P = .002). CONCLUSIONS AND IMPLICATIONS: Frailty is a significant predictor of all-cause mortality in older nursing home residents. Therefore, there is an urgent need to screen for frailty in nursing home residents and carry out appropriate multidisciplinary intervention strategies to prevent poor outcomes and reduce the rate of mortality among older nursing home residents.

Chest-compression-only versus conventional cardiopulmonary resuscitation by bystanders for children with out-of-hospital cardiac arrest: A systematic review and meta-analysis.

BACKGROUND: For children with out-of-hospital cardiac arrest, previous observational studies regarding chest-compression-only CPR (CC-CPR) versus conventional CPR yielded inconsistent results. We aimed to summarize the current evidence and compare the outcomes after CC-CPR with those after conventional CPR by bystanders in children with out-of-hospital cardiac arrest. METHODS: Observational studies that compared CC-CPR to conventional CPR for children with out-of-hospital cardiac arrest were identified through systematic searches of three databases (PubMed, EMBASE, and the Cochrane Library). The primary outcome was 30-day survival after hospital discharge. STATA 11.0 was used for data analysis. RESULTS: Five studies with 14,427 participants were included. Pooled results indicated that children who received conventional CPR had a higher 30-day survival than those who received CC-CPR (odds ratio, 1.49; 95% confidence interval [CI], 1.27-1.74). Moreover, conventional CPR led to a higher 30-day neurologically intact survival compared to CC-CPR (odds ratio, 1.63; 95%CI, 1.30-2.04). Subgroup analyses showed that the higher survival associated with conventional CPR was only significant in children who had cardiac arrest with non-cardiac causes (odds ratio, 1.77; 95% CI, 1.30-2.40). CONCLUSIONS: Children who receive conventional CPR for out-of-hospital cardiac arrest may have better outcomes than those who receive CC-CPR. Due to the limited number of studies and lack of randomized trials included in this meta-analysis, more evidence is needed to confirm our findings.

Sarcopenia as a predictor of all-cause mortality among older nursing home residents: a systematic review and meta-analysis.

OBJECTIVES: This study aims to review the evidence of sarcopenia as a predictor of all-cause mortality among nursing home residents. DESIGN: Systematic review and meta-analysis of observational cohort studies. DATA SOURCES: PubMed, EMBASE and the Cochrane Library databases were searched for relevant articles. PARTICIPANTS: Nursing home residents. PRIMARY AND SECONDARY OUTCOME MEASURES: All-cause mortality. DATA ANALYSIS: Summary-adjusted HRs or risk ratios (RRs) were calculated by fixed-effects model. The risk of bias was assessed by Newcastle-Ottawa Scale. RESULTS: Of 2292 studies identified through the systematic review, six studies (1494 participants) were included in the meta-analysis. Sarcopenia was significantly associated with a higher risk for all-cause mortality among nursing home residents (pooled HR 1.86, 95% CI 1.42 to 2.45, p<0.001, I2=0). In addition, the subgroup analysis demonstrated that sarcopenia was associated with all-cause mortality (pooled HR 1.87,95% CI 1.38 to 2.52, p<0.001) when studies with a follow-up period of 1 year or more were analysed; however, this was not found for studies with the follow-up period less than 1 year. Furthermore, sarcopenia was significantly associated with the risk of mortality among older nursing home residents when using bioelectrical impedance analysis to diagnosis muscle mass (pooled HR 1.88, 95% CI 1.39 to 2.53, p<0.001); whereas, it was not found when anthropometric measures were used to diagnosis muscle mass. CONCLUSION: Sarcopenia is a significant predictor of all-cause mortality among older nursing home residents. Therefore, it is important to diagnose and treat sarcopenia to reduce mortality rates among nursing home residents. PROSPERO REGISTRATION NUMBER: CRD42018081668.

Sarcopenia as a predictor of hospitalization among older people: a systematic review and meta-analysis.

BACKGROUND: Previous cohort studies investigating the association between sarcopenia and the risk of hospitalization have been inconsistent. We performed a meta-analysis to determine if sarcopenia is a predictor of hospitalization. METHODS: Prospective cohort studies that evaluated the association between sarcopenia and hospitalization in older people were identified via a systematic search of four electronic databases (PubMed, EMBASE, Science Citation Index, and the Cochrane Library). A random-effect model was applied to combine the results according to the heterogeneity of the included studies. RESULTS: Five studies (2832 participants) were included in this meta-analysis. Pooled results demonstrated that older people with sarcopenia were at an increased risk of hospitalization (pooled hazards ratio [HR] = 1.57, 95% confidence interval [CI] = 1.26, 1.94, I2 = 4.5%, P = 0.000) compared to those without sarcopenia. Results of subgroup analyses showed that hospitalized patients with sarcopenia had a higher rate of hospitalization (HR = 2.01, 95% CI = 1.41, 2.88, p = 0.000) versus patients without sarcopenia. A similar result was also found in community-dwelling older people with sarcopenia versus those without sarcopenia (HR = 1.40, 95% CI = 1.05, 1.88, p = 0.023). In addition, the subgroup analysis for length of follow-up showed that studies with a follow-up period of 3 years or more (pooled HR = 1.52, 95% CI = 1.19, 1.94, P = 0.001) reported a significantly higher rate of hospitalization among individuals with sarcopenia compared to those without sarcopenia. However, this association was not found in the studies with a follow-up period of less than 3 years (pooled HR = 1.76, 95% CI = 0.90, 3.44, P = 0.099). CONCLUSIONS: Sarcopenia is a significant predictor of hospitalization among older individuals, and the association may not be significantly affected by the characteristics of the population or the definition of sarcopenia.

Oscillatory Dynamics of P53 Network With Time Delays.

AIMS AND OBJECTIVE: A large number of experimental evidences report that the oscillatory dynamics of p53 would regulate the cell fate decisions. Moreover, multiple time delays are ubiquitous in gene expression which have been demonstrated to lead to important consequences on dynamics of genetic networks. Although delay-driven sustained oscillation in p53-based networks is commonplace, the precise roles of such delays during the processes are not completely known. METHOD: Herein, an integrated model with five basic components and two time delays for the network is developed. Using such time delays as the bifurcation parameter, the existence of Hopf bifurcation is given by analyzing the relevant characteristic equations. Moreover, the effects of such time delays are studied and the expression levels of the main components of the system are compared when taking different parameters and time delays. RESULT AND CONCLUSION: The above theoretical results indicated that the transcriptional and translational delays can induce oscillation by undergoing a super-critical Hopf bifurcation. More interestingly, the length of these delays can control the amplitude and period of the oscillation. Furthermore, a certain range of model parameter values is essential for oscillation. Finally, we illustrated the main results in detail through numerical simulations.

Performance of ultrasound to monitor Achilles enthesitis in patients with ankylosing spondylitis during TNF-a antagonist therapy.

Enthesitis is considered as the primary anatomical lesion in ankylosing spondylitis (AS). We aimed to investigate the potential of ultrasound to detect early changes after TNF-a antagonist therapy of Achilles enthesitis of AS patients. One hundred AS patients with active disease, requiring TNF-a antagonist therapy, were included (etanercept n = 25, infliximab n = 25, adalimumab n = 25, non-biologic disease-modifying antirheumatic drugs (DMARDs) n = 25). Physical examination was performed to evaluate disease activity and detect Achilles enthesitis and/or retrocalcaneal bursitis. Ultrasound of the Achilles enthesitis was performed bilaterally. Follow-up examinations were performed 3 months after the initiation of therapy. Gray scale (GS) scores, Power Doppler (PD) scores, and total additive scores (TS) decreased significantly during TNF-a antagonist therapy but not in traditional non-biologic traditional DMARDs group. The bath ankylosing spondylitis disease activity index (BASDAI), bath ankylosing spondylitis metrology index (BASMI), bath ankylosing spondylitis functional index (BASFI), and Maastricht ankylosing spondylitis enthesitis score (MASES) all showed significant improvements. When three different TNF-a antagonists were analyzed separately, no significant difference was observed in GS, PD, and total scores. Subclinical Achilles enthesitis, detected only with GS ultrasound, is present in a subset of AS patients and a significant improvement can be demonstrated after 3 months of TNF-a antagonist therapy. Doppler ultrasound provides a reliable estimation to monitor the therapeutic response to TNF antagonists in AS patients with Achilles enthesitis. TNF-a antagonists have been shown to be effective in decreasing ultrasound signs of enthesitis after 3 months of therapy in AS patients.

Platelets induce a proinflammatory phenotype in monocytes via the CD147 pathway in rheumatoid arthritis.

INTRODUCTION: Activated platelets exert a proinflammatory action that can be largely ascribed to their ability to interact with monocytes. However, the mechanisms that promote dynamic changes in monocyte subsets in rheumatoid arthritis (RA) have not been clearly identified. The aim of this study was to determine whether platelet activation and the consequent formation of monocyte-platelet aggregates (MPA) might induce a proinflammatory phenotype in circulating monocytes in RA. METHODS: The surface phenotype of platelets and the frequencies of monocyte subpopulations in the peripheral blood of RA patients were determined using flow cytometry. Platelets were sorted and co-cultured with monocytes. In addition, monocyte activation was assessed by measuring the nuclear factor κB (NF-κB) pathway. The disease activity was evaluated using the 28-joint disease activity score. RESULTS: Platelet activation, circulating intermediate monocytes (Mon2) and MPA formation were significantly elevated in RA, especially in those with active disease status. Furthermore, Mon2 monocytes showed higher CD147 expression and responded to direct cell contact with activated platelets with higher cytokine production and matrix metallopeptidase 9 (MMP-9) secretion, which increased the expression of CD147. After the addition of specific antibodies for CD147, those effects were abolished. Furthermore, the NF-κB-driven inflammatory pathway may be involved in this process. CONCLUSION: These findings indicate an important role of platelet activation and the consequent formation of MPA in the generation of the proinflammatory cytokine milieu and for the promotion and maintenance of the pathogenically relevant Mon2 monocyte compartment in RA, which is likely to play an important role in the pathogenesis of autoimmunity.

CD147 up-regulates calcium-induced chemotaxis, adhesion ability and invasiveness of human neutrophils via a TRPM-7-mediated mechanism.

OBJECTIVES: We aimed to investigate whether CD147 can up-regulate the chemotactic, adhesive and invasive properties of human neutrophils and to determine the mechanism underlying this process. METHODS: Human promyelocytic leukaemia cells (HL-60) cells and peripheral blood or synovial fluid neutrophils were isolated from RA patients. Under cyclophilin A (CypA) stimulation, chemotaxis, adhesion potential and invasion ability were assessed using chemotaxis, adhesion and invasiveness assays. Lipid raft isolation and western blot were used to determine the mechanism underlying the effects of CypA stimulation. RESULTS: CD147 up-regulates the calcium-induced chemotaxis, adhesion ability and invasiveness of human neutrophils in RA patients. Transient receptor potential melastatin 7 may be responsible for this phenomenon. CONCLUSION: These findings suggest that in RA patients, abundant CypA up-regulates the calcium-induced chemotactic, adhesive and invasive properties of neutrophils via direct binding to CD147. Cyclophilin-CD147 interactions might contribute to the destruction of cartilage and bone in RA.

Inhibition of synovitis and joint destruction by a new single domain antibody specific for cyclophilin A in two different mouse models of rheumatoid arthritis.

INTRODUCTION: Cyclophilin A (CypA) is implicated in rheumatoid arthritis (RA) pathogenesis. We studied whether a novel anti-CypA single domain antibody (sdAb) treatment would modulate the severity of the disease in two different animal models of RA. METHODS: A novel sdAb, named sdAbA1, was screened from an immunized camel sdAb library and found to have a high binding affinity (KD = 6.9 × 10-9 M) for CypA. The SCID-HuRAg model and the collagen-induced arthritis (CIA) in mice were used to evaluate the effects of sdAbA1 treatment on inflammation and joint destruction. For in vitro analysis, monocytes/macrophages were purified from synovial fluid and peripheral blood of patients with RA and were tested for the effect of anti-CypA sdAb on metalloproteinase (MMP) production. Human monocyte cell line THP-1 cells were selected and western blot analyses were performed to examine the potential signaling pathways. RESULTS: In the CIA model of RA, the sdAbA1 treatment resulted in a significant decrease in clinical symptoms as well as of joint damage (P <0.05). In the SCID-HuRAg model, treatment with anti-CypA antibody sdAbA1 significantly reduced cartilage erosion, inflammatory cell numbers and MMP-9 production in the implanted tissues (P <0.05). It also significantly reduced the levels of human inflammatory cytokines IL-6 and IL-8 in mouse serum (P <0.05). No toxic effects were observed in the two animal models. In vitro results showed that sdAbA1 could counteract CypA-dependent MMP-9 secretion and IL-8 production by interfering with the ERK-NF-κB pathway. CONCLUSIONS: Blockade of CypA significantly inhibited synovitis and cartilage/bone erosion in the two tested animal models of RA. Our findings provide evidence that sdAbA1 may be a potential therapeutic agent for RA.

CD147 induces angiogenesis through a vascular endothelial growth factor and hypoxia-inducible transcription factor 1α-mediated pathway in rheumatoid arthritis.

OBJECTIVE: Rheumatoid arthritis (RA) is an inflammatory and angiogenic disease. However, the molecular mechanisms that promote angiogenesis in RA have not been clearly identified. Our objective was to study the role of CD147 in angiogenesis and determine whether the strategy in which CD147 is suppressed might be useful in reducing angiogenesis in RA. METHODS: Correlations among expression levels of CD147, vascular endothelial growth factor (VEGF), and hypoxia-inducible factor 1α (HIF-1α) were determined by immunohistochemistry staining. RA fibroblast-like synoviocytes (FLS) cells were cultured under various conditions, and the production of VEGF and HIF-1α was examined by real-time polymerase chain reaction and enzyme-linked immunosorbent assay. The SCID mouse coimplantation model of RA (SCID-HuRAg) was established, mice were treated with CD147 monoclonal antibody, infliximab, or both CD147 and infliximab, and the volume of the grafts and the average vascular density were measured and analyzed. Western blot analyses were performed to examine the potential signaling pathways. RESULTS: The expression levels of CD147 showed significantly positive correlations with VEGF and HIF-1α levels, as well as with vascular density, in RA synovium. After small interfering RNA transfection or after addition of specific antibodies for CD147, the production of VEGF and HIF-1α were significantly reduced. The expression of VEGF and HIF-1α decreased more after CD147 inhibition than after infliximab treatment in the engrafted tissues in SCID-HuRAg mice. The phosphatidylinositol 3-kinase/Akt pathway may be involved in this process. CONCLUSION: CD147 induces up-regulation of VEGF and HIF-1α in RA FLS, further promotes angiogenesis, and leads to the persistence of synovitis. Inhibition of CD147 may be a promising target for novel therapeutic strategies.

[Effect of cyclophilin A on monocyte-derived foam cells].

AIM: To observe whether cyclophilin A (CypA)has an effect on macrophage-derived foam cells, and to investigate the involvement of CypA in the development of atherosclerosis. METHODS: The foam cell model was established through incubating the human monocyte line (THP-1 cells) with oxidized low density lipoproteins (ox-LDL). The cells were stained with fresh oil red O to study the morphology of the macrophage-derived foam cells. The cell adhesion, invasion and the production of matrix metalloproteinase (MMPs) of the macrophage-derived foam cells were detected by adhesion assay, invasion assay and gelatin zymography respectively both in the absence or presence of different concentrations of purified CypA (50, 100, 200 µg/L). Then the foam cells were respectively pre-treated with CsA, c7b8f10, HAb18 mAb, and dual treatment of c7b8f10 and HAb18 mAb respectively, to investigate the inhibitory effect on macrophage-derived foam cells. RESULTS: The adhesion, invasion and the production of MMP-9 and MMP-2 were enhanced during the differentiation of monocytes into macrophages (P<0.05). CypA, especially in the concentration of 100 ng/mL, significantly promoted the function of macrophage-derived foam cells (P<0.05). CsA, c7b8f10, HAb18 mAb, and c7b8f10- HAb18 mAb combination dramatically inhibited the function of macrophage-derived foam cells both in the absence or presence of CypA (P<0.05). The c7b8f10- HAb18 mAb combination pretreatment had the most obviously suppressive effect on macrophage-derived foam cells (P<0.05). CONCLUSION: These findings suggest that CypA up regulates the adhesion, the invasion and the expressions of MMP-2 and MMP-9 in macrophage-derived foam cells. The CypA effect is blocked by the pretreatment of the different antagonists. This research might suggest the correlation between atherosclerosis pathogenesis and the vulnerability of atherosclerotic plaques, and thus give us some good ideas for atherosclerosis therapy in future.