The blood-brain barrier (BBB) establishes a protective interface between the central neuronal system and peripheral blood circulation and is crucial for homeostasis of the CNS. BBB formation starts when the endothelial cells (ECs) invade the CNS and pericytes are recruited to the nascent vessels during embryogenesis. Despite the essential function of pericyte-EC interaction during BBB development, the molecular mechanisms coordinating the pericyte-EC behavior and communication remain incompletely understood. Here, we report a single cell receptor, CD146, that presents dynamic expression patterns in the cerebrovasculature at the stages of BBB induction and maturation, coordinates the interplay of ECs and pericytes, and orchestrates BBB development spatiotemporally. In mouse brain, CD146 is first expressed in the cerebrovascular ECs of immature capillaries without pericyte coverage; with increased coverage of pericytes, CD146 could only be detected in pericytes, but not in cerebrovascular ECs. Specific deletion of Cd146 in mice ECs resulted in reduced brain endothelial claudin-5 expression and BBB breakdown. By analyzing mice with specific deletion of Cd146 in pericytes, which have defects in pericyte coverage and BBB integrity, we demonstrate that CD146 functions as a coreceptor of PDGF receptor-β to mediate pericyte recruitment to cerebrovascular ECs. Moreover, we found that the attached pericytes in turn downregulate endothelial CD146 by secreting TGF-β1 to promote further BBB maturation. These results reveal that the dynamic expression of CD146 controls the behavior of ECs and pericytes, thereby coordinating the formation of a mature and stable BBB.lood-brain barrier (BBB) development is a sequential and well-orchestrated process that commences when brain endothelial cells (ECs; BECs) invade the embryonic neuroectoderm from the surrounding vascular plexus and induce BBB properties by establishing paracellular tight junctions (TJs) (1). Endothelial TJs are formed by a complex of transmembrane proteins, including claudins and occludin, as well as cytoplasmic adaptors such as zonula occludens protein 1 (ZO-1), thus creating a highresistance paracellular barrier to molecules and ions (2). Compelling evidence shows that claudin-5 plays a key role in the induction of BBB properties, and specific loss of claudin-5 in mice results in a more leaky BBB (3-5). Following the establishment of the TJs, the BECs of nascent vessels recruit pericytes to the endothelial walls, which improve the barrier function of BECs by stabilizing TJs and decreasing transcytosis, and are crucial for maturation of the BBB (6). Importantly, pericytes suppress the expression of leukocyte adhesion molecules (LAMs) in BECs to reduce the invasion of immune cells into the CNS, therefore regulating CNS immune surveillance, a critical feature of the mature BBB (6, 7). Thus, as a dynamic interface with a range of interrelated functions, the BBB results from extremely effective TJs, pericyte recruitment, and regulation of leukocyte extravasation, there...

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The use of immunotherapy has achieved great advances in the treatment of cancer. Macrophages play a pivotal role in the immune defense system, serving both as phagocytes (removal of pathogens and cancer cells) and as antigen‐presenting cells (activation of T cells). However, research regarding tumor immunotherapy is mainly focused on the adaptive immune system. The usefulness of innate immune cells (eg, macrophages) in the treatment of cancer has not been extensively investigated. Recent advances in synthetic biology and the increasing understanding of the cluster of differentiation 47/signal regulatory protein alpha (CD47/SIRPɑ) axis may provide new opportunities for the clinical application of engineered macrophages. The CD47/SIRPɑ axis is a major known pathway, repressing phagocytosis and activation of macrophages. In this article, we summarize the currently available evidence regarding the CD47/SIRPɑ axis, and immunotherapies based on blockage. In addition, we propose cell therapy strategies based on macrophage engineering.

SummaryBackground/ObjectiveTanshinol is the main active component of Salvia miltiorrhiza Bunge, a significant Traditional Chinese Medicine used to treat cardiovascular disease. We have shown that tanshinol exerts an antiosteoporostic effect via the enhancement of bone formation in vivo and in vitro. However, the mechanism remains unclear. Based on the polyphenol group in the structure of tanshinol, we speculate the protective action on skeletal tissue is related to antioxidative capacity. Our in vitro evidence indicated that tanshinol stimulated osteoblastic differentiation by its antioxidaive capacity. In this study, we aim to further confirm the effect of tanshinol on bone formation and the underlying mechanism in zebrafish in vivo.MethodsWe used a Danio rerio (zebrafish) model, which has a bone formation process similar to humans, and evaluated the relationship between the dose and the effect of tanshinol on bone formation determined using alizarin red S staining or fluorescence intensity analysis in normal and glucocorticoid (GC)-induced inhibition of an osteogenesis model using wild-type zebrafish and cortical bone transgenic zebrafish tg(sp7:egfp). The expression of osteoblast-specific genes and reactive oxygen species (ROS) were tested.ResultsOur data showed that dexamethasone exerts a series of consequences, including the inhibition of bone formation, decrease of bone mass, downregulation of expression of osteoblast-specific genes (runx2a, ALP, osteocalcin, and sp7), as well as the accumulation of ROS generation and decreased capacity of antioxidants. Tanshinol showed a protective effect on promoting bone formation and bone mass both in wild-type larval zebrafish and transgenic zebrafish. Furthermore, tanshinol attenuated the inhibition of osteogenesis elicited by oxidative stress in the zebrafish exposed to dexamethasone.ConclusionThe present findings suggest that tanshinol prevented decreased osteogenesis in GC-treated larval zebrafish via scavenging ROS and stimulated the expression of osteoblast-specific genes. Tanshinol treatment may be developed as a novel therapeutic approach under recent recognised conditions of GC-induced osteoporosis.

Amentoflavone is a bioflavonoid found in a variety of traditional Chinese medicines such as Gingko and Selaginella tamariscina. It has been reported that amentoflavone has anti-inflammatory, antioxidant, antiviral and anticancer effects. However, the effect of amentoflavone on osteogenic differentiation of human mesenchymal stem cells (hMSCs) has not been studied. In this study, we aim to explore the effect of amentoflavone on the proliferation and osteogenic differentiation of hMSCs. The results showed that amentoflavone significantly enhanced the proliferation, alkaline phosphatase (ALP) activity and mineralization in hMSCs. Western blot analysis revealed that the expression of runt-related transcription factor 2 and osterix proteins was upregulated in amentoflavone-treated hMSCs. Furthermore, we investigated the possible signaling pathways responsible for osteogenic differentiation of hMSCs by amentoflavone. We found that amentoflavone significantly increased the levels of phosphorylated JNK and p-p38. The amentoflavone-induced increases of ALP and mineralization were significantly diminished when the JNK and p38 MAPK pathways were blocked by selected inhibitors (SP600125, SB203580) in hMSCs. Furthermore, in vivo evidence indicated that amentoflavone protected against the dexamethasone-induced inhibition of osteoblast differentiation in tg(sp7:egfp) zebrafish larvae. Thus, we showed for the first time that amentoflavone improves the osteogenesis of hMSCs through the JNK and p38 MAPK pathway. Amentoflavone may be beneficial in treating bone-related disorders.

Background The zebrafish ( Danio rerio ) has recently been shown to be an ideal model to study bone disease including osteoporosis. The zebrafish osteoporosis model could be induced by glucocorticoid treatment with chemical staining for reflecting the level of bone mineralization. However, this methodology was unstable. Here, we developed a novel methodology to directly evaluate the bone mass and density. Methods We generated and used the bone of transgenic zebrafish Tg ( ola.sp7:nls GFP ) to evaluate the bone mass and density by measuring the areal extent and the integrated optical density ( IOD ) of enhanced green fluorescent protein ( eGFP ). This methodology was further compared with the traditional chemically stained method showing the bone mineralization. Furthermore, genes related to zebrafish osteoporosis were analyzed by quantitative reverse transcription‐polymerase chain reaction ( qRT ‐ PCR ). Results Our results of new methods were consistent with those from chemically stained fish, following glucocorticoid‐induction or epimedium flavonoid ( FE )‐rescue treatments. qRT ‐ PCR analyses on mRNA levels revealed that glucocorticoid induces osteoporosis by downregulating the expression of osteoblast‐related factors osterix , osteocalcin , and osteopontin , and upregulating the expression of osteoclast‐related factor tartrate‐resistant acid phosphatase. In FE ‐rescued fish, the expression of osteogenic factors osterix, osteocalcin , and osteopontin were increased. Conclusion Compared to the traditional chemical staining methods, the new osteoporosis model using Tg( ola.sp7:nls GFP ) is more convenient and efficient for studying osteoporosis in vivo, and especially for high‐throughput anti‐osteoporosis drug screening.

BackgroundThe risk of fatal adverse events (FAEs) due to bevacizumab-based chemotherapy has not been well described; we carried out an updated meta-analysis regarding this issue.MethodsAn electronic search of Medline, Embase and The Cochrane Central Register of Controlled Trials was conducted to investigate the effects of randomized controlled trials on bevacizumab treatment on cancer patients. Random or fixed-effect meta-analytical models were used to evaluate the risk ratio (RR) of FAEs due to the use of bevacizumab.ResultsThirty-four trials were included. Allocation to bevacizumab therapy significantly increased the risk of FAEs; the RR was 1.29 (95% CI:1.05–1.57). This association varied significantly with tumor types (P = 0.002) and chemotherapeutic agents (P = 0.005) but not with bevacizumab dose (P = 0.90). Increased risk was seen in patients with non–small cell lung cancer, pancreatic cancer, prostate cancer, and ovarian cancer. However, FAEs were lower in breast cancer patients treated with bevacizumab. In addition, bevacizumab was associated with an increased risk of FAEs in patients who received concomitant agents of taxanes and/or platinum.ConclusionCompared with chemotherapy alone, the addition of bevacizumab was associated with an increased risk of FAEs among patients with special tumor types, particularly when combined with chemotherapeutic agents such as platinum.