Mesenchymal Stem Cell Transplantation Reverses Multi-Organ Dysfunction in Systemic Lupus Erythematosus Mice and Humans

Systemic Lupus Erythematosus (SLE) is a multisystem autoimmune disease that, despite the advances in immunosuppressive medical therapies, remains potentially fatal in some patients, especially in treatment-refractory patients. Here we reported that impairment of bone marrow mesenchymal stem cells (BMMSCs) and their associated osteoblastic niche deficiency contribute in part to the pathogenesis of SLE-like disease in MRL/lpr mice. Interestingly, allogenic BMMSC transplantation (MSCT) is capable of reconstructing the bone marrow osteoblastic niche and more effectively reverses multi-organ dysfunction as compared to medical immunosuppression with cyclophosphamide (CTX). At the cellular level, MSCT, not CTX treatment, was capable to induce osteoblastic niche reconstruction, possibly contributing to the recovery of regulatory T cells and re-establishment of the immune homeostasis. Based on the promising clinical outcomes in SLE mice, we treated 4 CTX/glucocorticoid treatment-refractory SLE patients using allogenic MSCT and showed a stable 12-18 months disease remission in all treated patients. The patients benefited an amelioration of disease activity, improvement in serologic markers and renal function. These early evidences suggest that allogenic MSCT may be a feasible and safe salvage therapy in refractory SLE patients

GSKJ4 Protects Mice Against Early Sepsis via Reducing Proinflammatory Factors and Up-Regulating MiR-146a

Sepsis, defined as life-threatening organ dysfunction, is one of the most common causes of mortality in intensive care units with limited therapeutic options. However, the mechanism underlying the regulation of epigenetics on sepsis remains largely undefined. Here we showed that JMJD3, the histone lysine demethylase, played a critical role in the epigenetic regulation of innate immunity during early sepsis. Pharmacological inhibition of JMJD3 by GSKJ4 protected mice against early septic death and reduced pro-inflammatory cytokine interleukin-1β (IL-1β) production as well as IL-6, tumor necrosis factor-α (TNF-α), and monocyte chemotactic protein-1 (MCP-1) expression. Interestingly, GSKJ4 up-regulated the transcription of anti-inflammatory microRNA-146a (miR-146a) in peritoneal macrophages from septic mice. Mechanistically, JMJD3 negatively regulated the transcription of miR-146a via its demethylation of H3K27me3 on the promoter of miR-146a. Moreover, the transcription of miR-146a was positively regulated by nuclear factor-κB (NF-κB) p65. Inhibition of NF-κB p65 promoted JMJD3 binding to miR-146a promoter and decreased the tri-methylation level of H3K27, while the inhibition of JMJD3 did not affect the recruitment of NF-κB p65 to miR-146a promoter. These results highlight an epigenetic mechanism by which JMJD3 was inhibited by NF-κB p65 from binding to miR-146a promoter to promote the anti-inflammatory response. Taken together, our findings uncover a key role for JMJD3 in modulating the miR-146a transcription and shed light on the JMJD3 inhibitors could be potential therapeutic agents for early sepsis therapy

MicroRNA-29b contributes to pre-eclampsia through its effects on apoptosis, invasion and angiogenesis of trophoblast cells,”

Abstract PE (pre-eclampsia), a pregnancy-specific disorder, is characterized by increased trophoblast cell death and deficient trophoblast invasion and reduced trophoblast-mediated remodelling of spiral arteries. The present study was performed to determine the function of miR-29b (microRNA-29b) in trophoblast cells and its underlying role in the pathogenesis of PE. The prediction of miR-29b target genes was performed using computer-based programs, including Targetscan, Pictar and miRBase. The function of these target genes was analysed further by gene ontology (GO). The effects of miR-29b on apoptosis, and invasion and angiogenesis of trophoblast cell lines (HTR-8/SVneo, BeWo and JAR) were examined by flow cytometry and Matrigel assay respectively. We found that miR-29b induced apoptosis and inhibited invasion and angiogenesis of trophoblast cells. Further studies confirmed that miR-29b regulated the expression of MCL1 (myeloid cell leukaemia sequence 1), MMP2 (encoding matrix metallproteinase 2), VEGFA (vascular endothelial growth factor A) and ITGB1 (integrin β1) genes by directly binding to their 3 -UTRs (untranslated regions). Moreover, we identified that there was an inverse correlation between miR-29b and its target genes in subjects with PE. Taken together, these findings support a novel role for miR-29b in invasion, apoptosis and angiogenesis of trophoblast cells, and miR-29b may become a new potential therapeutic target for PE

Mesenchymal stem cell transplantation for diffuse alveolar hemorrhage in SLE

Background. A 19-year-old girl was diagnosed with systemic lupus erythematosus, based on findings of arthritis, malar rash, positive antinuclear antibody test and high levels of antibodies to double-stranded DNA. Two months after diagnosis, the patient presented with a sudden drop in blood hemoglobin level. Several days later, she developed bloody sputum, rapidly progressive dyspnea and hypoxemia. High-resolution CT showed diffuse alveolar infiltrates in both lung fields.Investigations. Physical examination, complete blood count, erythrocyte sedimentation rate, urinalysis, 24-h urine protein excretion, fecal occult blood test, d-dimer test, acid hemolysis test, activated partial thromboplastin time and prothrombin time, direct and indirect Coombs tests, bone marrow smear, arterial blood gas, sputum smear and culture, and high-resolution CT scan of the chest.Diagnosis. Diffuse alveolar hemorrhage associated with systemic lupus erythematosus.Management. The patient did not respond to pulsed intravenous methylprednisolone (two courses of 500 mg per day for 3 days) and intravenous immunoglobulin (20 g per day for 5 days). The patient was referred to a specialist treatment center for allogenic transplantation using umbilical-cord-derived mesenchymal stem cells. She underwent transplantation with an infusion of 8 - 10 7 mesenchymal stem cells. After showing dramatic improvements in her clinical condition, oxygenation level, radiographic and hematological status, the patient was discharged from hospital approximately 5 weeks after undergoing transplantation. © 2010 Macmillan Publishers Limited.postprin

Research capacity of global health institutions in China: a gap analysis focusing on their collaboration with other low-income and middle-income countries.

INTRODUCTION: This paper presented qualitative and quantitative data collected on the research capacity of global health institutions in China and aimed to provide a landscaping review of the development of global health as a new discipline in the largest emerging economy of the world. METHODS: Mixed methods were used and they included a bibliometric analysis, a standardised survey and indepth interviews with top officials of 11 selected global health research and educational institutions in mainland China. RESULTS: The bibliometric analysis revealed that each institution had its own focus areas, some with a balanced focus among chronic illness, infectious disease and health systems, while others only focused on one of these areas. Interviews of key staff from each institution showed common themes: recognition that the current research capacity in global health is relatively weak, optimism towards the future, as well as an emphasis on mutual beneficial networking with other countries. Specific obstacles raised and the solutions applied by each institution were listed and discussed. CONCLUSION: Global health institutions in China are going through a transition from learning and following established protocols to taking a more leading role in setting up China's own footprint in this area. Gaps still remain, both in comparison with international institutions, as well as between the leading Chinese institutions and those that have just started. More investment needs to be made, from both public and private domains, to improve the overall capacity as well as the mutual learning and communication within the academic community in China

A conjugate of an anti-midkine single-chain variable fragment to doxorubicin inhibits tumor growth

Doxorubicin (DOX) was conjugated to a single-chain variable fragment (scFv) against human midkine (MK), and the conjugate (scFv-DOX) was used to target the chemotherapeutic agent to a mouse solid tumor model in which the tumor cells expressed high levels of human MK. The His-tagged recombinant scFv was expressed in bacteria, purified by metal affinity chromatography, and then conjugated to DOX using oxidative dextran (Dex) as a linker. The molecular formula of this immunoconjugate was scFv(Dex)1.3(DOX)20. In vitro apoptosis assays showed that the scFv-DOX conjugate was more cytotoxic against MK-transfected human adenocarcinoma cells (BGC823-MK) than untransfected cells (55.3 ± 2.4 vs 22.4 ± 3.8%) for three independent experiments. Nude mice bearing BGC823-MK solid tumors received scFv-DOX or equivalent doses of scFv + DOX for 2 weeks and tumor growth was more effectively inhibited by the scFv-DOX conjugate than by scFv + DOX (51.83% inhibition vs 40.81%). Histological analysis of the tumor tissues revealed that the highest levels of DOX accumulated in tumors from mice treated with scFv-DOX and this resulted in more extensive tumor cell death than in animals treated with the equivalent dose of scFv + DOX. These results show that the scFv-DOX conjugate effectively inhibited tumor growth in vivo and suggest that antigen-specific scFv may be competent drug-carriers

Feasibility of a Culturally Specific DEmentia Competence Education for Nursing Home Taskforce (DECENT) Programme: A Mixed-Method Approach

Although educational resources have been developed to build staff‘s dementia care competence in Western culture, their applicability and cultural relevance to the Chinese population are questionable. To address this gap, the DEmentia Competence Education for Nursing home Taskforce (DECENT) programme was developed and tailored to Chinese staff. This study aimed to evaluate the feasibility and preliminary effects of the DECENT programme. A one-group pretest–posttest study, embedded with a qualitative component, was conducted among 12 healthcare professionals. The DECENT programme comprised eight topics covering essential competencies in dementia care. It was delivered face-to-face by a qualified educator once per week for 60–90 min over 8 weeks. Outcomes were measured at baseline and immediately post-intervention. A satisfaction survey and individual interviews were conducted post-intervention to understand participants’ perceptions and experience with the intervention. Nine participants finished the post-intervention assessment. Except for staff’s attitudes towards people with dementia, quantitative findings generally demonstrated positive changes following the intervention. Three categories were identified from the qualitative data: well-developed programme, perceived benefits, and barriers. The findings showed that the DECENT programme is feasible and is perceived by nursing home staff as relevant and useful to daily practice. A larger-scale study is needed to evaluate its effectiveness

Characterization and Significance of Monocytes in Acute Stanford Type B Aortic Dissection

Acute aortic dissection (AAD) is one of the most common fatal diseases noted in vascular surgery. Human monocytes circulate in dynamic equilibrium and display a considerable heterogeneity. However, the role of monocytes in AAD remains elusive. In our recent study, we firstly obtained blood samples from 22 patients with Stanford type B AAD and 44 age-, sex-, and comorbidity-matched control subjects. And the monocyte proportions were evaluated by flow cytometry. Results showed that the percentage of total CD14+ monocytes in the blood samples of Stanford AAD patients was increased significantly compared with that of normal volunteers (P<0.0005), and the absolute numbers of CD14brightCD16+ and CD14brightCD16- monocytes both increased significantly regardless of the percentage of PBMC or CD14+ cells, while CD14dimCD16+ monocytes displayed the opposite tendency. However, the percentage of CD14+ cells and its three subsets demonstrated no correlation with D-dimer (DD) and C-reactive protein (CRP). Then, blood mononuclear cell (PBMC) samples were collected by Ficoll density gradient centrifugation, followed with CD14+ magnetic bead sorting. After the purity of CD14+ cells was validated over 90%, AAD-related genes were concentrated in CD14+ monocytes. There were no significant differences observed with regard to the mRNA expression levels of MMP1 (P=0.0946), MMP2 (P=0.3941), MMP9 (P=0.2919), IL-6 (P=0.4223), and IL-10 (P=0.3375) of the CD14+ monocytes in Stanford type B AAD patients compared with those of normal volunteers. The expression levels of IL-17 (P<0.05) was higher in Stanford type B AAD patients, while the expression levels of TIMP1(P<0.05), TIMP2(P<0.01), TGF-β1 (P<0.01), SMAD3 (P<0.01), ACTA2 (P<0.001), and ADAMTS-1 (P<0.001) decreased. The data suggested that monocytes might play an important role in the development of Stanford type B AAD. Understanding of the production, differentiation, and function of monocyte subsets might dictate future therapeutic avenues for Stanford type B AAD treatment and can aid the identification of novel biomarkers or potential therapeutic targets for decreasing inflammation in AAD