Structure determines properties, and properties determine applications, which is an important ideology of natural sciences. For optical materials, it is vital to lucubrate the corresponding ...relationship between the local crystal structure and luminescence properties for their design, synthesis, and application. This work reports a newly designed Y2Mg2Al2Si2O12(YMAS):Eu3+ red phosphor, in which difunctional Eu3+ ion is used as a red-light activator and spectroscopic probe. The qualitative and quantitative studies on the relationship between the local crystal structure and the luminescence properties of YMAS:Eu3+ are performed experimentally and computationally, using the Y3Al5O12 (YAG):Eu3+ as contrast. Moreover, compared with YAG:Eu3+, the newly designed YMAS:Eu3+ has stronger luminescence, superior Commission Internationale de L’Eclairage chromaticity coordinates, a lower optimal doping concentration, and equally excellent thermal stability. The satisfactory color-rendering index of packaged white-light-emitting diodes demonstrates its potential performance as a red phosphor. Briefly, this work provides not only a new case for the study of the local crystal structure and luminescence properties but also a new possibility for the application of a red phosphor in solid-state lighting.
Chemoresistance is the main obstacle in the clinical treatment of osteosarcoma (OS). In this study, we investigated the role of EF-hand domain-containing protein 1 (EFHD1) in OS chemotherapy ...resistance. We found that the expression of EFHD1 was highly correlated with the clinical outcome after chemotherapy. We overexpressed EFHD1 in 143B cells and found that it increased their resistance to cell death after drug treatment. Conversely, knockdown of EFHD1 in 143BR cells (a cisplatin-less-sensitive OS cell line derived from 143B cells) increased their sensitivity to treatment. Mechanistically, EFHD1 bound to adenine nucleotide translocase-3 (ANT3) and inhibited its conformational change, thereby inhibiting the opening of the mitochondrial membrane permeability transition pore (mPTP). This effect could maintain mitochondrial function, thereby favoring OS cell survival. The ANT3 conformational inhibitor carboxyatractyloside (CATR), which can promote mPTP opening, enhanced the chemosensitivity of EFHD1-overexpressing cells when combined with cisplatin. The ANT3 conformational inhibitor bongkrekic acid (BKA), which can inhibit mPTP opening, restored the resistance of EFHD1 knockdown cells. In conclusion, our results suggest that EFHD1-ANT3-mPTP might be a promising target for OS therapy in the future.
Pancreatic ductal adenocarcinoma (PDAC) features an immunosuppressive tumor microenvironment (TME) that resists immunotherapy. Tumor-associated macrophages, abundant in the TME, modulate T cell ...responses. Bone marrow stromal antigen 2-positive (BST2+) macrophages increase in KrasG12D/+; Trp53R172H/+; Pdx1-Cre mouse models during PDAC progression. However, their role in PDAC remains elusive. Our findings reveal a negative correlation between BST2+ macrophage levels and PDAC patient prognosis. Moreover, an increased ratio of exhausted CD8+ T cells is observed in tumors with up-regulated BST2+ macrophages. Mechanistically, BST2+ macrophages secrete CXCL7 through the ERK pathway and bind with CXCR2 to activate the AKT/mTOR pathway, promoting CD8+ T cell exhaustion. The combined blockade of CXCL7 and programmed death-ligand 1 successfully decelerates tumor growth. Additionally, cGAS-STING pathway activation in macrophages induces interferon (IFN)α synthesis leading to BST2 overexpression in the PDAC TME. This study provides insights into IFNα-induced BST2+ macrophages driving an immune-suppressive TME through ERK-CXCL7 signaling to regulate CD8+ T cell exhaustion in PDAC.
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•IFNα-induced BST2+ macrophages were highly expressed in PDAC and had a poor prognosis•BST2+ macrophages drive CD8+ T cell exhaustion through the ERK-CXCL7 pathway•PD-L1-CXCL7 antibody combination enhances anti-tumor efficacy in BST2+ macrophage tumors•PDAC mtDNA damage activates cGAS-STING-IFNα within macrophages, inducing BST2 expression
Zheng et al. uncover that mtDNA damage in PDAC triggers the cGAS-STING-IFNα pathway. Therefore, IFNα-induced BST2+ macrophages drive CD8+ T cell exhaustion and pancreatic tumor growth via the ERK-CXCL7-CXCR2/AKT/mTOR pathway.
The function of signal regulatory protein alpha (SIRPA) has been well studied in macrophages and dendritic cells, but relatively less in tumors. Notably, SIRPA is upregulated in osteosarcoma tissues, ...particularly in metastatic tissues, and is associated with unfavorable clinical outcomes. Knockdown of SIRPA impaired OS cell migration by decreasing specificity protein 1 (SP1) stability and arginine uptake. Importantly, SIRPA phosphorylated SP1 at threonine 278 (Thr278) through extracellular signal-regulated kinase (ERK) activation to protect SP1 from proteasomal degradation. In addition, SP1 increased solute carrier family 7 member 3 (SLC7A3) expression by binding to the SLC7A3 promoter and increased the capability of arginine uptake, thereby facilitating OS cell migration. More interestingly, arginine promoted the stability of SP1 in an ERK-independent manner and thus formed the “SP1 stabilization circle”. Combined treatment with the anti-SIRPA antibody and arginase, which blocked the circle, impaired tumor metastasis in mice bearing xenografts formed from SIRPA-overexpressing cells. In summary, our study demonstrates that the upregulation of SIRPA promotes OS metastasis via the “SP1 stabilization circle” and SLC7A3-mediated arginine uptake, which might serve as a target for OS treatment.
•SIRPA is overexpressed in high active osteosarcoma and promotes metastasis.•SIRPA enhances the expression of SLC7A3 and facilitate arginine utilization.•SIRPA increases SP1 stability via phosphorylation of SP1 at Thr273.•SP1 stabilization cycle plays a key role in the metastasis in OS.•Combination therapy targeting both SIRPA and arginine inhibits tumor metastasis.
Many studies have explored new methods to cure acute lung injury (ALI); however, none of those methods could significantly change the high mortality rate of ALI. Shenfu is a Chinese traditional ...medicine that might be effective against ALI.
Our study explores the therapeutic potential of Shenfu in ALI.
Male C57BL/6 mice were assigned to control, lipopolysaccharide (LPS) (500 µg/100 μL per mouse), and LPS + Shenfu (30 mL/kg) groups. Shenfu (10 µL/mL) was added to LPS (10 µg/mL) treated MLE-12 cells for 48 h in vitro. Male C57BL/6 mice were divided into four groups: LPS, LPS + 3% dextran sulphate sodium (DSS), 3% DSS + Shenfu, and LPS + 3% DSS + Shenfu.
Compared with the ALI group, Shenfu reduced wet/dry weight ratio (19.8%, 36.2%), and reduced the IL-2 (40.9%, 61.6%), IFN-γ (43.5%, 53.3%) TNF-α (54.1%, 42.1%), IL-6 (54.8%,70%), and IL-1β (39.9%, 65.1%), reduced serum uric acid (18.8%, 48.7%) and creatinine (17.4%, 41.1%). Moreover, Shenfu enhanced cell viability (17.2%, 59.9%) and inhibited cell apoptosis (63.0%) and p38/ERK phosphorylation in in vitro cultured epithelial cells with LPS stimulation. Mechanistically, Shenfu mediated the protective effect by upregulating claudin-4 expression. In addition, Shenfu could protect against both lung and intestinal epithelial damage in acute gastrointestinal injury-exacerbated ALI.
Taken together, the results revealed the therapeutic effect and the underlying mechanism of Shenfu injection in an ALI in mouse model, indicating its clinical potential to treat patients with ALI.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
This article describes the fabrication of hollow manganese/cobalt oxide nanoparticles (MCO NPs) with a tunable size through a redox reaction and the Kirkendall effect for cancer imaging and drug ...delivery. MCO-70 NPs (with an average size of 70 nm) can act as glutathione (GSH)-responsive contrast agents for dual
T
1
/
T
2
-weighted magnetic resonance imaging (MRI). The degradation of MCO NPs by GSH led to the enhancement of their
T
1
and
T
2
signals by 2.24- and 3.43-fold compared with those of MCO NPs before degradation, respectively. Antitumor agents such as doxorubicin (Dox) could be encapsulated inside the cavity of the hollow MCO NPs (MCO-70-Dox) and be released in the presence of GSH. The MCO-70-Dox NPs showed good tumor growth inhibition effects
in vitro
and
in vivo
, and can be promising drug delivery vehicles and MRI contrast agents for tumor diagnosis and reporting drug release.
A simple strategy to synthesize manganese/cobalt oxide nanoparticles and their application as a GSH-responsive nanoscale drug delivery system were reported.
Expansion in vitro prior to mesenchymal stem cells (MSCs) application is a necessary process. Functional and genomic stability has a crucial role in stem-cell-based therapies. However, the exact ...expression and co-expressed profiles of coding and non-coding RNAs in human bone marrow (BM)-MSCs in vitro aging are still lacking. In the present studies, the change of morphology, immunophenotype, and capacity of proliferation, differentiation, and immunoregulation of MSCs at passage (P) 4, P6, P8, P10, and P12 were investigated. RNA sequencing identified that 439 mRNAs, 65 long noncoding RNAs (lncRNAs), 59 microRNAs (miRNAs), and 229 circular RNAs (circRNAs) were differentially expressed (DE) in P12 compared with P4, with a similar trend in P6. Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA) identified several significant biological processes and pathways, including binding, ossification, and Wnt and PPAR signaling pathways. Interaction and co-expression/localization analyses were performed for DE mRNAs and lncRNAs, and several key lncRNAs, circRNAs, and important pathways like autophagy and mitophagy were identified in the competing endogenous RNA (ceRNA) network. Some key RNAs found in the bioinformatics analysis were validated. Our studies indicate that replicative senescence of MSCs is a continuous process, including widespread alterations in biological characteristics and global gene expression patterns that need to be considered before therapeutic applications of MSCs.
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Probes into effects of long-term culture on the biological characteristics and ceRNA network-associated RNA profiles of human bone-marrow-derived mesenchymal stem cells (MSCs) demonstrated key molecules and networks, which might be applied potentially to MSC product manufacturing and quality assessment.
Purpose:
To investigate the associations of MRI radiological features and prognosis of glioma with the status of isocitrate dehydrogenase 1 (IDH1).
Material and Methods:
A total of 116 patients with ...gliomas were retrospectively recruited from January 2013 to December 2015. All patients were undergone routine MRI (T1WI, T2WI, T2-FLAIR) scanning and contrast-enhanced MRI T1WI before surgery. The following imaging features were included: tumor location, diameter, the pattern of growth, boundary, the degree of enhancement, mass effect, edema, cross the middle line, under the ependyma. χ
2
and Fisher's exact probability tests were used to determine the significance of associations between MRI features and IDH1 mutation of glioma. The survival distributions were estimated using Kaplan-Meier compared by Log-rank test. Univariate and multivariate analyses were performed using Cox regression.
Results:
Gliomas with IDH1 mutant were significantly more likely to exhibit homogeneous signal intensity (
p
= 0.009) on non-contrast MRI protocols and less contrast enhancement (
p
= 0.000) on contrast enhanced T1WI. IDH1 mutant type glioma was more inclined to cross the midline to invade contralateral hemisphere (
p
= 0.001). The overall survival between IDH1 mutated and wild type glioma were significantly different (
p
= 0.000), age ≤ 40 (
p
= 0.003), KPS scores > 80 before operation (
p
= 0.000) and low grade glioma (
p
= 0.000).
Conclusions:
Our results suggest IDH1 mutant in gliomas is more likely to exhibit homogeneous signal intensity, less contrast enhancement and more inclined to cross the midline. Patients with IDH1 mutated, age ≤ 40, KPS scores > 80 before operation and low-grade glioma may have a longer life and better prognosis.
Although angiogenesis-osteogenesis coupling is important in ankylosing spondylitis (AS), therapeutic agents targeting the vasculature remain elusive. Here, we identified activating transcription ...factor 6 (ATF6) as an important regulator of angiogenesis in the pathogenesis of AS. First, we found that ATF6 and fibroblast growth factor 2 (FGF2) levels were higher in SKG mice and in cartilage of pateints with AS1. The proangiogenic activity of human chondrocytes was enhanced by the activation of the ATF6-FGF2 axis following 7 days of stimulation with inflammatory factors, e.g., tumor necrosis factor alpha (TNF-α), interferon-γ (IFN-γ) or interleukin-17 (IL-17). Mechanistically, ATF6 interacted with the FGF2 promotor and promoted its transcription. Treatment with the ATF6 inhibitor Ceapin-A7 inhibited angiogenesis in vitro and angiogenesis-osteogenesis coupling in vivo. ATF6 may aggravate angiogenesis-osteogenesis coupling during AS by mediating FGF2 transcription in chondrocytes, implying that ATF6 represents a promising therapeutic target for AS.
Display omitted FGF2 is an effective factor that promotes angiogenesis-osteogenesis coupling and plays an important role in AS. Chondrocytes stimulated for 7 days with proinflammatory cytokines undergo chronic ERS with ATF6 pathway activation. By directly binding to the FGF2 promoter, ATF6 increases FGF2 expression. Treatment of chondrocytes with the ATF6 inhibitor Ceapin-A7 effectively inhibits FGF2 expression.
•Prolonged inflammatory stimulation triggers ERS in human chondrocytes•ERS upregulated FGF2 through ATF6 pathway, thereby promoting angiogenesis•Ceapin-A7 decreases the number of vessels and osteophytes in the AS mouse model•ATF6 may be a promising therapeutic target for AS
Biological sciences; Physiology; Molecular biology
Mesenchymal stem cells (MSCs) are pluripotent stem cells capable of differentiating into osteocytes, adipocytes and chondrocytes. However, in osteoporosis, the balance of differentiation is tipped ...toward adipogenesis and the key mechanism is controversial. Researches have shown that, as upstream regulatory elements of gene expression, enhancers ar involved in the expression of identity genes. In this study, we identified enhancers-mediated gene FOXO3 promoting MSC adipogenic differentiation by activating autophagy.
We integrated data of RNA sequencing (RNA-seq), chromatin immunoprecipitation sequencing (ChIP-seq) and ATAC-sequencing (ATAC-seq) to find the identity gene FOXO3. The expression of FOXO3 protein, adipogenic transcription factors and the substrate of autophagy were measured by western blotting. The Oil Red O (ORO) staining was used to visualize the adipogenesis of MSCs. Immunohistochemistry was used to visualize the FOXO3 expression in adipocytes in bone marrow. Immunofluorescence was used to detect the expression of PPARγ and LC3B.
During adipogenesis, enhancers redistribute to genes associated with adipogenic differentiation, among which we identified the pivotal identity gene FOXO3. FOXO3 could promote the expression of the adipogenic transcription factors PPARγ, CEBPα, and CEBPβ during adipogenic differentiation, while PPARγ, CEBPα, and CEBPβ could in turn bind to FOXO3 and continue to promote FOXO3 expression to form a positive feedback loop. Consistently elevated FOXO3 expression promotes autophagy by activating the PI3K-AKT pathway which mediates adipogenic differentiation.
Pivotal identity gene FOXO3 promotes autophagy by activating PI3K-AKT pathway, which provokes adipogenic differentiation of MSCs. Enhancer-regulated adipogenic identity gene FOXO3 could be an attractive treatment for osteoporosis.
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