BMP9-regulated angiogenic signaling plays an important role in the osteogenic differentiation of mesenchymal progenitor cells.

Mesenchymal stromal progenitor cells (MSCs) are multipotent progenitors that can be isolated from numerous tissues. MSCs can undergo osteogenic differentiation under proper stimuli. We have recently demonstrated that bone morphogenetic protein 9 (BMP9) is one of the most osteogenic BMPs. As one of the least studied BMPs, BMP9 has been shown to regulate angiogenesis in endothelial cells. However, it is unclear whether BMP9-regulated angiogenic signaling plays any important role in the BMP9-initiated osteogenic pathway in MSCs. Here, we investigate the functional role of hypoxia-inducible factor 1α (HIF1α)-mediated angiogenic signaling in BMP9-regulated osteogenic differentiation of MSCs. We find that BMP9 induces HIF1α expression in MSCs through Smad1/5/8 signaling. Exogenous expression of HIF1α potentiates BMP9-induced osteogenic differentiation of MSCs both in vitro and in vivo. siRNA-mediated silencing of HIF1α or HIF1α inhibitor CAY10585 profoundly blunts BMP9-induced osteogenic signaling in MSCs. HIF1α expression regulated by cobalt-induced hypoxia also recapitulates the synergistic effect between HIF1α and BMP9 in osteogenic differentiation. Mechanistically, HIF1α is shown to exert its synergistic effect with BMP9 by inducing both angiogenic signaling and osteogenic signaling in MSCs. Thus, our findings should not only expand our understanding of the molecular basis behind BMP9-regulated osteoblastic lineage-specific differentiation, but also provide an opportunity to harness the BMP9-induced synergy between osteogenic and angiogenic signaling pathways in regenerative medicine.

Effect of Manual Lymphatic Drainage on Breast Cancer-Related Postmastectomy Lymphedema: A Meta-analysis of Randomized Controlled Trials.

BACKGROUND: Manual lymphatic drainage (MLD) is widely used in the treatment of breast cancer-related postmastectomy lymphedema (BCRL). However, the therapeutic benefit of MLD on BCRL remains controversial. OBJECTIVE: The aim of this study was to analyze the efficacy of MLD for BCRL. METHOD: Four electronic databases were systematically searched for trials comparing MLD and no MLD treatment as options for BCRL. Comparative treatment results included reduction of upper extremity limb volume with subgroup analysis by the number and duration of treatments. RESULTS: A total of 457 patients were included in the analysis. There was no significant difference in the amount of upper extremity edema between the MLD treatment and control or no MLD groups ( P = .11). However, when the treatment course was ≥20 sessions, there was a significant reduction in the upper extremity volume ( P = .03). There was also a significant reduction in the upper extremity volume when treatment duration was >2 weeks ( P = .03). CONCLUSION: Manual lymphatic drainage treatment statistically did not reduce the upper extremity limb volume of BCRL, but upper extremity volume was reduced at statistically significant levels when treatment number were ≥20 sessions or the duration of treatment was >2 weeks. IMPLICATION FOR PRACTICE: Reduction in upper limb volume is dependent on the number and duration of treatments. When treatment number were ≥20 sessions, or the duration of treatment was >2 weeks, reduction of upper limb volume was statistically achieved. Manual lymphatic drainage treatment can be clinically recommended to treat BCRL according to these parameters.

Anticoagulant management by low-dose of low molecular weight heparin in patients with nonvalvular atrial fibrillation following hemorrhagic transformation and complicated with venous thrombosis: Five case reports and literature review.

ABSTRACT: For patients with nonvalvular atrial fibrillation (NVAF) following hemorrhagic infarction (HI)/hemorrhage transformation (HT) and complicated with venous thrombosis, the management of anticoagulation is controversial. Our study intends to explore the safety and effectiveness of using low-dose of low molecular weight heparin (LMWH) to treat NVAF patients with HI (or HT) and complicated with venous thrombosis.Between January 2018 and January 2019, NVAF related acute ischemic stroke patients with HT/HI, hospitalized in the department of neurology or rehabilitation in our hospital, are enrolled retrospectively. Among them, those who were found to have venous thrombosis and undergo anticoagulation (LMWH) during the treatment were extracted. We investigate the efficacy and safety in those patients who have been treated with anticoagulant of LMWH.Five cases accepted LMWH within 3 weeks attributed to the appearance of venous thrombosis, and all of them did not display new symptomatic bleeding or recurrent stroke. However, based on the results of a head computed tomography scan, there were 2 cases of slightly increased intracranial hemorrhage, and then we reduced the dose of anticoagulant. In addition, color ultrasound showed that venous thrombosis disappeared or became stable.Patients with NVAF following HI/HT have a higher risk of thromboembolism. Early acceptance of low-dose LMWH as an anticoagulant is relatively safe and may gain benefit. However, in the process of anticoagulant therapy, we should follow-up head computed tomography/magnetic resonance imaging frequently, as well as D-dimer values, limb vascular ultrasound. Besides, the changes of symptoms and signs should be focused to judge the symptomatic bleeding or recurrent stroke. Furthermore, it is better to adjust anticoagulant drug dosage according to specific conditions.

Enhancement of the Effect of Methyl Pyropheophorbide-a-Mediated Photodynamic Therapy was Achieved by Increasing ROS through Inhibition of Nrf2-HO-1 or Nrf2-ABCG2 Signaling.

BACKGROUND: Emerging evidence indicates that the transcription factor nuclear factor-E2-related factor 2 (Nrf2) plays an essential role in cellular defense against oxidative stress; its activation has been related to cytoprotection. OBJECTIVE: Here, we investigated the role of Nrf2 in improving the efficacy of methyl pyropheophorbide-amediated photodynamic therapy (Mppa-PDT) via the downregulation of Nrf2. METHOD: Human ovarian cancer A2780 cells and SKOV3 cells were treated with Mppa-PDT and siRNA transfection was performed to inhibit Nrf2. After treated with siRNA and Mppa-PDT, the cell viability was examined with CCK-8 assay; cell apoptosis was detected tested by flow cytometry with Annexin V-FITC/PI; the celluar reactive oxygen species (ROS) and mitochondrial membrane potential were measured with DCFHDA and JC-1 staining; expression of protein was assessed by western blot analysis. RESULTS: We found that Nrf2 translocated from the cytoplasm to the nucleus in vitro and in vivo, and the expression of Nrf2 and P-Nrf2 increased through a possible mechanism regulated by mitogen-activated protein kinase (MAPK) after Mppa-PDT treatment. Furthermore, cytotoxicity and apoptosis induced by Mppa-PDT increased after Nrf2down-regulation. Nrf2 down -regulation increased reactive oxygen species (ROS) levels by attenuating antioxidants or pumping Mppa out of cells,which resulted from the inhibition of Nrf2-HO-1 or Nrf2- ABCG2 signaling. In addition, SKOV3 cells exhibited increased resistance to Mppa-PDT, and the expression levels of P-Nrf2 and ABCG2 were higher in SKOV3 cells than in A2780 cells, suggesting that Nrf2-ABCG2 signaling might be involved in the intrinsic resistanceto Mppa-PDT. CONCLUSION: These results provided evidence that Nrf2 down-regulation can enhance the effect of Mppa-PDT.

Growth hormone synergizes with BMP9 in osteogenic differentiation by activating the JAK/STAT/IGF1 pathway in murine multilineage cells.

Growth hormone (GH) is usually released by somatotrophs in the anterior pituitary in response to the GH-releasing hormone and plays an important role in skeleton development and postnatal growth. However, it is unclear if extrapituitary GH exerts any effect on murine multilineage cells (MMCs). MMCs are multipotent progenitors that give rise to several lineages, including bone, cartilage, and fat. We have identified bone morphogenic protein 9 (BMP9) as one of the most osteogenic BMPs in MMCs by regulating a distinct set of downstream mediators. In this study, we find that GH is one of the most significantly upregulated genes by BMP9 in mouse MMCs through expression-profiling analysis. We confirm that GH is a direct early target of and upregulated by BMP9 signaling. Exogenous GH synergizes with BMP9 on inducing early and late osteogenic markers in MMCs. Furthermore, BMP9 and GH costimulation leads to a significant expansion of growth plate in cultured limb explants. Although GH alone does not induce de novo bone formation in an ectopic bone formation model, BMP9 and GH costimulated MMCs form more mature bone, which can be inhibited by silencing GH expression. The synergistic osteogenic activity between BMP9 and GH can be significantly blunted by JAK/STAT inhibitors, leading to a decrease in GH-regulated insulin-like growth factor 1 (IGF1) expression in MMCs. Our results strongly suggest that BMP9 may effectively regulate extrapituitary GH expression in MMCs. Thus, it is conceivable that the BMP9-GH-IGF axis may be exploited as an innovative strategy to enhance osteogenesis in regenerative medicine.