A concerning development during the coronavirus disease pandemic has been multisystem inflammatory syndrome in children. Reports of this condition in East Asia have been limited. In South Korea, 3 ...cases were reported to the national surveillance system for multisystem inflammatory syndrome in children. All case-patients were hospitalized and survived with no major disease sequelae.
Oncogenic targets acting in both tumor cells and tumor stromal cells may offer special therapeutic appeal. Interrogation of the Oncomine database revealed that 52 of 53 human breast carcinomas showed ...substantial upregulation of WNT family ligand WNT7B. Immunolabeling of human mammary carcinoma showed that WNT7B immunoreactivity was associated with both tumor cells and with tumor-associated macrophages. In the MMTV-PymT mouse model of mammary carcinoma, we found tumor progression relied upon WNT7B produced by myeloid cells in the microenvironment. Wnt7b deletion in myeloid cells reduced the mass and volume of tumors due to a failure in the angiogenic switch. In the tumor overall, there was no change in expression of Wnt/β-catenin pathway target genes, but in vascular endothelial cells (VEC), expression of these genes was reduced, suggesting that VECs respond to Wnt/β-catenin signaling. Mechanistic investigations revealed that failure of the angiogenic switch could be attributed to reduced Vegfa mRNA and protein expression in VECs, a source of VEGFA mRNA in the tumor that was limiting in the absence of myeloid WNT7B. We also noted a dramatic reduction in lung metastasis associated with decreased macrophage-mediated tumor cell invasion. Together, these results illustrated the critical role of myeloid WNT7B in tumor progression, acting at the levels of angiogenesis, invasion, and metastasis. We suggest that therapeutic suppression of WNT7B signaling might be advantageous due to targeting multiple aspects of tumor progression.
•SGK1 levels were reduced and α-synuclein levels were increased in the skeletal muscle of PD mice.•Knockdown of SGK1 in C2C12 cells led to increased α-synuclein expression.•The decrease in SGK1 could ...potentially contribute to PD by increasing α-synuclein expression in skeletal muscle.
Parkinson's disease (PD) is a neurodegenerative disease caused by loss of dopaminergic neurons in the substantia nigra and it is known to involve the accumulation of α-synuclein (α-syn), which is a neuroprotein that promotes degeneration of dopaminergic neurons. Serum/glucocorticoid-related kinase 1 (SGK1) is involved in the physiological and pathological processes in neurons. The aim of this study was to examine the relationship between SGK1 and α-syn expression in muscle tissue of a PD model and in C2C12 cells. Western blotting, immunohistochemistry, and immunofluorescence microscopy confirmed reduced SGK1 and increased α-syn expression in skeletal muscle of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice compared to the control group. To determine the relationship between SGK1 and α-syn, SGK1 small interfering RNA (siRNA) knockdown was performed in C2C12 cells, which showed that suppression of SGK1 levels resulted in increased α-syn expression. The main finding of our study is that reduction of SGK1 expression contributes to the pathogenesis of PD by increasing the expression of α-syn in skeletal muscle of MPTP-treated mice and C2C12 cells. This study confirms that decreased SGK1 induces increased α-syn expression in skeletal muscle, which suggests that maintaining SGK1 expression may improve PD symptoms.
Macrophages are required for tissue homeostasis through their role in regulation of the immune response and the resolution of injury. Here we show, using the kidney as a model, that the Wnt pathway ...ligand Wnt7b is produced by macrophages to stimulate repair and regeneration. When macrophages are inducibly ablated from the injured kidney, the canonical Wnt pathway response in kidney epithelial cells is reduced. Furthermore, when Wnt7b is somatically deleted in macrophages, repair of injury is greatly diminished. Finally, injection of the Wnt pathway regulator Dkk2 enhances the repair process and suggests a therapeutic option. Because Wnt7b is known to stimulate epithelial responses during kidney development, these findings suggest that macrophages are able to rapidly invade an injured tissue and reestablish a developmental program that is beneficial for repair and regeneration.
Although the link between inflammation and cancer initiation is well established, its role in metastatic diseases, the primary cause of cancer deaths, has been poorly explored. Our previous studies ...identified a population of metastasis-associated macrophages (MAMs) recruited to the lung that promote tumor cell seeding and growth. Here we show that FMS-like tyrosine kinase 1 (Flt1, also known as VEGFR1) labels a subset of macrophages in human breast cancers that are significantly enriched in metastatic sites. In mouse models of breast cancer pulmonary metastasis, MAMs uniquely express FLT1. Using several genetic models, we show that macrophage FLT1 signaling is critical for metastasis. FLT1 inhibition does not affect MAM recruitment to metastatic lesions but regulates a set of inflammatory response genes, including colony-stimulating factor 1 (CSF1), a central regulator of macrophage biology. Using a gain-of-function approach, we show that CSF1-mediated autocrine signaling in MAMs is downstream of FLT1 and can restore the tumor-promoting activity of FLT1-inhibited MAMs. Thus, CSF1 is epistatic to FLT1, establishing a link between FLT1 and inflammatory responses within breast tumor metastases. Importantly, FLT1 inhibition reduces tumor metastatic efficiency even after initial seeding, suggesting that these pathways represent therapeutic targets in metastatic disease.
Cartilage regeneration is a challenging issue due to poor regenerative properties of tissues. Electrospun nanofibers hold enormous potentials for treatments of cartilage defects. However, nanofibrous ...materials used for the treatment of cartilage defects often require physical and/or chemical modifications to promote the adhesion, proliferation, and differentiation of cells. Thus, it is highly desirable to improve their surface properties with functionality. We aim to design hydrophilic, adhesive, and compound K-loaded nanofibers for treatments of cartilage defects.
Hydrophilic and adhesive compound K-containing polycaprolactone nanofibers (CK/PCL NFs) were prepared by coatings of gallic acid-conjugated chitosan (CHI-GA). Therapeutic effects of CHI-GA/CK/PCL NFs were assessed by the expression level of genes involved in the cartilage matrix degradation, inflammatory response, and lipid accumulations in the chondrocytes. In addition, Cartilage damage was evaluated by safranin O staining and immunohistochemistry of interleukin-1β (IL-1β) using OA animal models. To explore the pathway associated with therapeutic effects of CHI-GA/CK/PCL NFs, cell adhesion, phalloidin staining, and the expression level of integrins and peroxisome proliferator-activated receptor (PPARs) were evaluated.
CHI-GA-coated side of the PCL NFs showed hydrophilic and adhesive properties, whereas the unmodified opposite side remained hydrophobic. The expression levels of genes involved in the degradation of the cartilage matrix, inflammation, and lipogenesis were decreased in CHI-GA/CK/PCL NFs owing to the release of CK. In vivo implantation of CHI-GA/CK/PCL NFs into the cartilage reduced cartilage degradation induced by destabilization of the medial meniscus (DMM) surgery. Furthermore, the accumulation of lipid deposition and expression levels of IL-1β was reduced through the upregulation of PPAR.
CHI-GA/CK/PCL NFs were effective in the treatments of cartilage defects by inhibiting the expression levels of genes involved in cartilage degradation, inflammation, and lipogenesis as well as reducing lipid accumulation and the expression level of IL-1β via increasing PPAR.
Normal development requires tight regulation of cell proliferation and cell death. Here, we have investigated these control mechanisms in the hyaloid vessels, a temporary vascular network in the ...mammalian eye that requires a Wnt/β-catenin response for scheduled regression. We investigated whether the hyaloid Wnt response was linked to the oncogene
, and the cyclin-dependent kinase inhibitor CDKN1A (P21), both established regulators of cell cycle progression and cell death. Our analysis showed that the Wnt pathway co-receptors LRP5 and LRP6 have overlapping activities that mediate the Wnt/β-catenin signaling in hyaloid vascular endothelial cells (VECs). We also showed that both
and
are downstream of the Wnt response and are required for hyaloid regression but for different reasons. Conditional deletion of
in VECs suppressed both proliferation and cell death. By contrast, conditional deletion of
resulted in VEC overproliferation that countered the effects of cell death on regression. When combined with analysis of MYC and CDKN1A protein levels, this analysis suggests that a Wnt/β-catenin and MYC-CDKN1A pathway regulates scheduled hyaloid vessel regression.
Schematic diagram of the 3D-printed poly(glycolic acid)/hydroxyapatite composite scaffold and characterization.
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•Porous PGA/HAp composite scaffolds with different mixture ratios were ...3D-printed with computer-aided modeling and printing parameters to investigate physicochemical properties and bone regeneration ability.•The PGA/HAp 12.5 wt% group exhibited the highest values for compressive modulus, with predominant proliferation of osteoblasts in comparison to the other groups.•Biodegradation rates of the PGA/HAp composite scaffolds were facilitated by increasing the HAp ratio. In in vivo animal experiments, the PGA/HAp group demonstrated 47% bone regeneration, with superior bone mineral density 8 weeks after surgery.•The promoted bone growth revealed thick osseous tissue formations that surrounded the PGA/HAp composite scaffolds.•The 3D-printed PGA/HAp scaffold can provide a feasible option to promote patient-specific bone regeneration.
Hydroxyapatite (HAp) is a major bone graft component for hard tissue regeneration. However, sintered HAp has poor formability and mechanical properties. Porous 3D scaffolds for bone tissue regeneration were printed with computer-aided modeling using poly(glycolic acid) (PGA) and HAp. PGA scaffolds containing HAp nanoparticles were fabricated with a 400μm pore size. PGA/HAp scaffolds containing 12.5wt% HAp showed considerable compressive strength, osteogenesis, mineralization, and biodegradation. In in vivo animal experiments, the PGA/HAp group exhibited 47% bone regeneration, with superior bone mineral density 8 weeks after surgery. 3D-printed PGA/HAp scaffolds could provide a feasible option to promote patient-specific bone regeneration.
Under some clinical conditions, the preparation of crowns of limited marginal thickness is inevitable. In such situations, it is questionable whether the same ideal preparation criteria can be ...applied equally. Since there are only a small number of studies focusing on the fracture resistance with respect to the marginal thickness, there is a need for a study evaluating whether zirconia crowns of limited marginal thickness are clinically acceptable. The purpose of this study is to evaluate the fracture resistance of monolithic zirconia crowns of limited marginal thickness in the posterior area. Methods: Abutments and CAD/CAM zirconia crowns with a marginal thickness of 1.0 mm were set as the control group, while experimental groups A, B, and C possessed reduced marginal thicknesses of 0.8 mm, 0.6 mm, and 0.4 mm, respectively (n = 10 per group). Resin-based abutment dies and monolithic zirconia crowns were fabricated using the CAD/CAM technique, and a universal testing machine was used to measure the fracture load value. Fractured specimens were examined with a scanning electron microscope. The data were analyzed using a one-way ANOVA and Bonferroni post hoc test (p < 0.05). Results: The means and standard deviations of the fracture load values of the control group and the three experimental groups were as follows: control group (1.0 mm): 3090.91 ± 527.77 N; group A (0.8 mm): 2645.39 ± 329.21 N; group B (0.6 mm): 2256.85 ± 454.15 N; group C (0.4 mm): 1957.8 ± 522.14 N. Conclusions: The crowns fabricated with a CAD/CAM zirconia block with limited marginal thicknesses of 0.6 mm and 0.4 mm showed significantly lower fracture resistance values compared to those with the recommended margin thickness of 1.0 mm.
Background: Hypoxia-inducible factor 1 alpha (HIF-1α), a component of HIF-1, is expressed in human tumors and renders cells able to survive and grow under hypoxic (low-oxygen) conditions. YC-1, ...3-(5′-hydroxymethyl-2′-furyl)-1-benzylindazole, an agent developed for circulatory disorders that inhibits platelet aggregation and vascular contraction, inhibits HIF-1 activity in vitro. We tested whether YC-1 inhibits HIF-1 and tumor growth in vivo. Methods: Hep3B hepatoma, NCI-H87 stomach carcinoma, Caki-1 renal carcinoma, SiHa cervical carcinoma, and SK-N-MC neuroblastoma cells were grown as xenografts in immunodeficient mice (69 mice total). After the tumors were 100–150 mm3, mice received daily intraperitoneal injections of vehicle or YC-1 (30 μg/g) for 2 weeks. HIF-1α protein levels and vascularity in tumors were assessed by immunohistochemistry, and the expression of HIF-1-inducible genes (vascular endothelial growth factor, aldolase, and enolase) was assessed by reverse transcription–polymerase chain reaction. All statistical tests were two-sided. Results: Compared with tumors from vehicle-treated mice, tumors from YC-1-treated mice were statistically significantly smaller (P<.01 for all comparisons), expressed lower levels of HIF-1α (P<.01 for all comparisons), were less vascularized (P<.01 for all comparisons), and expressed lower levels of HIF-1-inducible genes, regardless of tumor type. Conclusions: The inhibition of HIF-1α activity in tumors from YC-1-treated mice is associated with blocked angiogenesis and an inhibition of tumor growth. YC-1 has the potential to become the first antiangiogenic anticancer agent to target HIF-1α.
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