Bone morphogenetic proteins (BMPs) play important roles in skeletal development and repair. Previously, we found fibroblast growth factor 2 (FGF2) induced up-regulation of BMP2, 3, 4 in the process ...of rabbit articular cartilage repair, which resulted in satisfactory repair effects. As BMP2/4 show a clearly positive effect for cartilage repair, we investigated the functions of BMP3 in rabbit articular cartilage repair. In this paper, we find that BMP3 inhibits the repair of partial-thickness defect of articular cartilage in rabbit by inducing the degradation of extracellular matrix, interfering with the survival of chondrocytes surrounding the defect, and directly inhibiting the expression of BMP2 and BMP4. Meanwhile BMP3 suppress the repair of full-thickness cartilage defect by destroying the subchondral bone through modulating the proliferation and differentiation of bone marrow stem cells (BMSCs), and directly increasing the expression of BMP4. Although BMP3 has different functions in the repair of partial and full-thickness defects of articular cartilage in rabbit, the regulation of BMP expression is involved in both of them. Together with our previous findings, we suggest the regulation of the BMP signaling pathway by BMP3 is essential in articular cartilage repair.
Angiopoietin-2 (Ang-2) is a conditional antagonist and agonist for the endothelium-specific Tie-2 receptor. Although endogenous Ang-2 cooperates with vascular endothelial growth factor (VEGF) to ...protect tumor endothelial cells, the effect on tumor vasculature of high levels of exogenous Ang-2 with different levels of VEGF has not been studied in detail. Here, we report that systemic overexpression of Ang-2 leads to unexpected massive tumor vessel regression within 24 h, even without concomitant inhibition of VEGF. By impairing pericyte coverage of the tumor vasculature, Ang-2 destabilizes the tumor vascular bed while improving perfusion in surviving tumor vessels. Ang-2 overexpression transiently exacerbates tumor hypoxia without affecting ATP levels. Although sustained systemic Ang-2 overexpression does not affect tumor hypoxia and proliferation, it significantly inhibits tumor angiogenesis, promotes tumor apoptosis, and suppresses tumor growth. The similar antitumoral, antiangiogenic efficacy of systemic overexpression of Ang-2, soluble VEGF receptor-1, and the combination of both suggests that concomitant VEGF inhibition is not required for Ang-2-induced tumor vessel regression and growth delay. This study shows the important roles of Ang-2-induced pericyte dropout during tumor vessel regression. It also reveals that elevated Ang-2 levels have profound pleiotropic effects on tumor vessel structure, perfusion, oxygenation, and apoptosis.
The induction of tumor angiogenesis, a pathologic process critical for tumor progression, is mediated by multiple regulatory factors released by tumor and host cells. We investigated the role of the ...hematopoietic cytokine erythropoietin as an angiogenic factor that modulates tumor progression.
Fluorescently-labeled rodent mammary carcinoma cells were injected into dorsal skin-fold window chambers in mice, an angiogenesis model that allows direct, non-invasive, serial visualization and real-time assessment of tumor cells and neovascularization simultaneously using intravital microscopy and computerized image analysis during the initial stages of tumorigenesis. Erythropoietin or its antagonist proteins were co-injected with tumor cells into window chambers. In vivo growth of cells engineered to stably express a constitutively active erythropoietin receptor EPOR-R129C or the erythropoietin antagonist R103A-EPO were analyzed in window chambers and in the mammary fat pads of athymic nude mice. Co-injection of erythropoietin with tumor cells or expression of EPOR-R129C in tumor cells significantly stimulated tumor neovascularization and growth in window chambers. Co-injection of erythropoietin antagonist proteins (soluble EPOR or anti-EPO antibody) with tumor cells or stable expression of antagonist R103A-EPO protein secreted from tumor cells inhibited angiogenesis and impaired tumor growth. In orthotopic tumor xenograft studies, EPOR-R129C expression significantly promoted tumor growth associated with increased expression of Ki67 proliferation antigen, enhanced microvessel density, decreased tumor hypoxia, and increased phosphorylation of extracellular-regulated kinases ERK1/2. R103A-EPO antagonist expression in mammary carcinoma cells was associated with near-complete disruption of primary tumor formation in the mammary fat pad.
These data indicate that erythropoietin is an important angiogenic factor that regulates the induction of tumor cell-induced neovascularization and growth during the initial stages of tumorigenesis. The suppression of tumor angiogenesis and progression by erythropoietin blockade suggests that erythropoietin may constitute a potential target for the therapeutic modulation of angiogenesis in cancer.
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•The 2D ultrathin perforated Co3O4 nanosheets were fabricated by wet-chemical synthesis.•The Co3O4 nanosheets exhibited superior PMS activating ability for BPA degradation.•Large ...surface area, porous structure and strong adhesion with PMS led to the excellent catalytic activity.•PMS/Co3O4 system exhibits a highly selective oxidation on aromatics with electron donating groups.
Here a two-dimensional (2D) ultrathin perforated Co3O4 nanosheet is rationally designed by a wet-chemical synthesis to activate peroxymonosulfate (PMS) for efficient selective oxidation. And the physicochemical properties of catalyst were investigated by series of techniques. The Co3O4 nanosheets achieved a 98.0% degradation efficiency of bisphenol A (BPA) within 30 min, showing a 4 times higher kinetic constant (0.112 min−1) and 5 times lower Co2+ leakage (6.5 μg/L), than commercial Co3O4 microspheres. The great enhancement in catalytic performance was ascribed to the large surface area and pore diameter in porous 2D structure, as well as the strong electrostatic attraction with PMS. Moreover, the influence of several parameters such as initial pH, temperatures, humic acids and inorganic anions in the system on the remaval of BPA were systematically studied. Since sulfate radicals (SO4−) were proved to be the primary reactive oxygen species by EPR measurements and quenching experiments, the PMS/Co3O4 nanosheets exhibits a highly selective oxidation on aromatics with electron donating groups (i.e., –OH and –CH3), while a relatively low value for organics with electron-withdrawing groups (e.g., –NO2 and –COOH). A high ionization potential threshold was determined to be greater than 9.39 eV, corresponding to a high oxidation ability to react with the organics. Finally, possible degradation pathways were proposed based on twenty intermediate products determined from mass spectrometry.
Resistance of hypoxic solid tumor niches to chemotherapy and radiotherapy remains a major scientific challenge that calls for conceptually new approaches. Here we exploit a hitherto unrecognized ...ability of sickled erythrocytes (SSRBCs) but not normal RBCs (NLRBCs) to selectively target hypoxic tumor vascular microenviroment and induce diffuse vaso-occlusion. Within minutes after injection SSRBCs, but not NLRBCs, home and adhere to hypoxic 4T1 tumor vasculature with hemoglobin saturation levels at or below 10% that are distributed over 70% of the tumor space. The bound SSRBCs thereupon form microaggregates that obstruct/occlude up to 88% of tumor microvessels. Importantly, SSRBCs, but not normal RBCs, combined with exogenous prooxidant zinc protoporphyrin (ZnPP) induce a potent tumoricidal response via a mutual potentiating mechanism. In a clonogenic tumor cell survival assay, SSRBC surrogate hemin, along with H(2)O(2) and ZnPP demonstrate a similar mutual potentiation and tumoricidal effect. In contrast to existing treatments directed only to the hypoxic tumor cell, the present approach targets the hypoxic tumor vascular environment and induces injury to both tumor microvessels and tumor cells using intrinsic SSRBC-derived oxidants and locally generated ROS. Thus, the SSRBC appears to be a potent new tool for treatment of hypoxic solid tumors, which are notable for their resistance to existing cancer treatments.
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•Hydrogel and nanofiber-like aspartic acid-Cu(Ⅱ)-based nanozymes were synthesized.•The nanozymes exhibited outstanding peroxidase-like and antibacterial activity.•The nanozymes showed ...high stability over a broad range of temperatures and pH levels.
Nanozymes based on the coordination of amino acids and metal ions exhibit pronounced peroxidase (POD)-like activity, holding promising prospects in mitigating bacterial resistance caused by antibiotic misuse and harboring tremendous potential in the treatment of bacterial infections. In this study, L-/D-aspartic acid (L-/D-Asp) were individually coordinated with copper ions using a simple self-assembly approach, culminating in the creation of L-/D-hydrogel and nanofibers (L-/D-Gel and NFs) with POD-like actiity. These materials displayed excellent inhibitory effects against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). Particularly, compared to L-/D-Gel, L-/D-NFs demonstrated excellent catalytic activity at extremely low concentrations. Moreover, our prepared nanozymes exhibited higher catalytic activity over a broader range of temperature and pH levels compared to the natural enzyme horseradish peroxidase (HRP). In summary, the prepared L-/D-Gel and NFs, as a novel type of nanozyme, hold great promise for widespread applications in the treatment of bacterial infections in wounds.
It is well established that hypoxia potently stimulates tumor angiogenesis by activating hypoxia inducible factor-1 (HIF-1)-induced proangiogenic factors, such as vascular endothelial growth factor. ...However, very little is known about the role of hypoxia in incipient angiogenesis in avascular tumors during their early stages of growth. To noninvasively investigate the functional significance of hypoxia and HIF-1 activation in incipient tumor angiogenesis, we genetically engineered HCT116 human colon carcinoma cells and 4T1 mouse mammary carcinoma cells with constitutively expressed red fluorescence protein as a tumor marker and green fluorescence protein (GFP) as a reporter for hypoxia and HIF-1 activation. The accuracy of GFP fluorescence in reporting hypoxia was confirmed by flow cytometry analysis and by immunohistochemical comparison with pimonidazole, a well-established hypoxia marker drug. Mouse dorsal skin-fold window chambers showed that incipient angiogenesis preceded a detectable level of hypoxia. The detectable levels of hypoxia were spatially and temporally related with more intensive secondary angiogenesis following the initial onset of new vessel formation. Selective killing of hypoxic cells by tirapazamine efficiently eliminated or delayed the detection of hypoxic cells, but it did not significantly delay the onset of incipient angiogenesis. These findings provide the first in vivo evidence that incipient tumor angiogenesis may not depend on hypoxia or HIF-1 activation. This is in contrast to the clear role of hypoxia in driving angiogenesis once initial tumor microvessel formation has occurred.
In machine learning, the relatedness across multiple tasks is usually complex and entangled. Due to dataset bias, the relatedness among tasks might be distorted and mislead the training of the models ...with solid learning ability, such as the multi-task neural networks. In this paper, we propose the idea of Relatedness Refinement Multi-Task Learning (RRMTDL) by introducing adversarial learning in the multi-task deep neural network to tackle the problem. The RRMTDL deep learning model restrains the misleading relatedness task by adversarial training and extracts information sharing across tasks with valuable relatedness. With RRMTDL, multi-task deep learning can enhance the task-specific representation for the major tasks by excluding the misleading relatedness. We design tests with various combinations of task-relatedness to validate the proposed model. Experimental results show that the RRMTDL model can effectively refine the task relatedness and prominently outperform other multi-task deep learning models in datasets with entangled task labels.
S
-Adenosylmethionine (SAM) is a crucial small-molecule metabolite widely used in food and medicine. The development of high-throughput biosensors for SAM biosynthesis can significantly improve the ...titer of SAM. This paper constructed a synthetic transcription factor (TF)-based biosensor for SAM detecting in
Saccharomyces cerevisiae
. The synthetic TF, named MetJ-hER-VP16, consists of an
Escherichia coli
-derived DNA-binding domain MetJ, GS linker, the human estrogen receptor binding domain hER, and the viral activation domain VP16. The synthetic biosensor is capable of sensing SAM in a dose-dependent manner with fluorescence as the output. Additionally, it is tightly regulated by the inducer SAM and
β
-estradiol, which means that the fluorescence output is only available when both are present together. The synthetic SAM biosensor could potentially be applied for high-throughput metabolic engineering and is expected to improve SAM production.
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