infections are often complicated by the fact that it can easily form a biofilm that increases its resistance to antibiotics. Consequently, the development of novel antibacterial agents against ...biofilm-associated drug-resistant
is urgently needed. Herein, we report a series of 3-hydroxy-pyridin-4(1
)-ones-ciprofloxacin conjugates that were designed and synthesized as dual antibacterial and antibiofilm agents against
. A potential 2-substituted 3-hydroxy-1,6-dimethylpyridin-4(1
)-one-ciprofloxacin conjugate (
) was identified and had the best minimum inhibitory concentrations of 0.86 and 0.43 μM against
27853 and PAO1 and reduced 78.3% of biofilm formation. In addition,
eradicates mature biofilms and kills living bacterial cells that are incorporated into the biofilm. Studies on the antibiofilm mechanism of conjugates showed that
interferes with iron uptake by bacteria, inhibits their motility, and reduces the production of virulence. These results demonstrate that 3-hydroxy-pyridin-4(1
)-ones-ciprofloxacin conjugates are potent in the treatment of biofilm-associated drug-resistant
infections.
Non-small cell lung cancer (NSCLC) is characterized by a high incidence of metastasis and poor survival. As epithelial-mesenchymal transition (EMT) is well recognized as a major factor initiating ...tumor metastasis, developing EMT inhibitor could be a feasible treatment for metastatic NSCLC. Recent studies show that triptolide isolated from Tripterygium wilfordii Hook F attenuated the migration and invasion of breast cancer, colon carcinoma, and ovarian cancer cells, and EMT played important roles in this process. In the present study we investigated the effect of triptolide on the migration and invasion of NSCLC cell lines. We showed that triptolide (0.5, 1.0, 2.0 nM) concentration-dependently inhibited the migration and invasion of NCI-H1299 cells. Triptolide treatment concentration-dependently suppressed EMT in NCI-H1299 cells, evidenced by significantly elevated E-cadherin expression and reduced expression of ZEB1, vimentin, and slug. Furthermore, triptolide treatment suppressed β-catenin expression in NCI-H1299 and NCI-H460 cells, overexpression of β-catenin antagonized triptolide-caused inhibition on EMT, whereas knockout of β-catenin enhanced the inhibitory effect of triptolide on EMT. Administration of triptolide (0.75, 1.5 mg/kg per day, ip, every 2 days) for 18 days in NCI-H1299 xenograft mice dose-dependently suppressed the tumor growth, restrained EMT, and decreased lung metastasis, as evidence by significantly decreased expression of mesenchymal markers, increased expression of epithelial markers as well as reduced number of pulmonary lung metastatic foci. These results demonstrate that triptolide suppresses NSCLC metastasis by targeting EMT via reducing β-catenin expression. Our study implies that triptolide may be developed as a potential agent for the therapy of NSCLC metastasis.
Programmed cell death 1 receptor (PD-1) and its ligands constitute an inhibitory pathway to mediate the mechanism of immune tolerance and provide immune homeostasis. Significantly, the binding ...partners of PD-1 and its associated ligands are diverse, which facilitates immunosuppression in cooperation with other immune checkpoint proteins. Accumulating evidence has demonstrated the important immunosuppressive role of the PD-1 axis in the tumor microenvironment and in autoimmune diseases. In addition, PD-1 blockades have been approved to treat various cancers, including solid tumors and hematological malignancies. Here, we provide a comprehensive review of the PD-1 pathway, focusing on the structure and expression of PD-1, programmed cell death 1 ligand 1 (PD-L1), and programmed cell death 1 ligand 2 (PD-L2); the diverse biological functions of PD-1 signaling in health and immune-related diseases (including tumor immunity, autoimmunity, infectious immunity, transplantation immunity, allergy and immune privilege); and immune-related adverse events related to PD-1 and PD-L1 inhibitors.
The assembly of two functional molecules via a sulfur linking atom allows an access to a diverse array of thioether‐containing compounds. Herein, we disclose a metal‐free thiolation of ...imidazopyridines with a variety of functionalized haloalkanes using elemental sulfur.
Excessive consumption of Fe (II) and massive generation of sludge containing Fe (III) from classic Fenton process remains a major obstacle for its poor recycling of Fe (III) to Fe (II). Therefore, ...the MHACF‐MIL‐101(Cr) system, by introducing H2, Pd0 and MIL‐101(Cr) into Fenton reaction system, was developed at normal temperature and pressure. In this system, the reduction of FeIII back to FeII by solid catalyst Pd/MIL‐101(Cr) for the storage and activation of H2, was accelerated significantly by above 10‐fold and 5‐fold controlled with the H2‐MIL‐101(Cr) system and H2‐Pd0 system, respectively. However, the concentration of Fe (II) generated by the reduction of Fe (III) could not be detected with the only input of H2 and without the addition of MOFs material. In addition, the apparent consumption of Fe (II) in MHACF‐MIL‐101(Cr) system was half of that in classical Fenton system, while more Fe (II) might be reused infinitely in fact. Accordingly, only trace amount of Fe (II) vs H2O2 concentration was needed and hydroxyl radicals through the detection of para‐hydroxybenzoic acid (p‐HBA) as the oxidative product of benzoic acid (BA) by·OH could be continuously generated for the effective degradation of 4‐chlorophenol(4‐CP). The effects of initial pH, concentration of 4‐CP, dosage of Fe2+, H2O2 and Pd/MIL‐101(Cr) catalyst, Pd content and H2 flow were investigated, combined with systematic controlled experiments. Moreover, the robustness and morphology change of Pd/MIL‐101(Cr) were thoroughly analyzed. This study enables better understanding of the H2‐mediated Fenton reaction enhanced by Pd/MIL‐101(Cr) and thus, will shed new light on how to accelerate Fe (III)/Fe (II) redox cycle and develop more efficient Fenton system.
This work investigated the degradation of 4‐chlorophenol in the novel MHACF‐MIL‐101(Cr) reaction system at normal temperature and pressure. The introduction of H2 and Pd/MIL‐101(Cr) accelerated the FeII/FeIII redox cycle and led to higher contaminant degradation using only trace level FeII in several reaction cycles. In other words, it could reduce the final disposal amount of iron sludge derived from the Fenton reaction. Therefore, it offers potential for the development of significantly improved the application of Fenton reaction.
To estimate the incidence of thromboembolism in children with primary nephrotic syndrome with Meta-analysis.
Relevant studies published from January 1, 1980 to December 31, 2021 were retrieved from ...Pubmed, Web of science, Cochrane library, China National Knowledge Infrastructure (CNKI), China Science and Technology Journal Database(VIP) and Wangfang Database. Quality evaluation of the literatures included was conducted according to Agency for Healthcare Research and Quality(AHRQ) assessment tool, followed by data extraction and Meta-analysis with software RevMan 5.3.
A total of seven studies involving 3675 subjects were included. The overall prevalence was 4.9% with 95% CI of 2.83 to 7.05.However, a significant heterogeneity (P < 0.001) was observed with I
= 89%. The prevalence of venous thromboembolism was 3.3% with 95% CI of 1.7 to 4.9. The prevalence of arterial thromboembolism was 0.5% with 95% CI of 0.2 to 1.4.
Children with nephrotic syndrome are prone to thromboembolism, and it may lead to disability or death, therefore prevention measures is critical to decreasing the prevalence of thromboembolism.
Chronic myeloid leukemia (CML) is a hematological tumor derived from hematopoietic stem cells. The aim of this study is to analyze the biological characteristics and identify the diagnostic markers ...of CML. We obtained the expression profiles from the Gene Expression Omnibus (GEO) database and identified 210 differentially expressed genes (DEGs) between CML and normal samples. These DEGs are mainly enriched in immune-related pathways such as Th1 and Th2 cell differentiation, primary immunodeficiency, T cell receptor signaling pathway, antigen processing and presentation pathways. Based on these DEGs, we identified two molecular subtypes using a consensus clustering algorithm. Cluster A was an immunosuppressive phenotype with reduced immune cell infiltration and significant activation of metabolism-related pathways such as reactive oxygen species, glycolysis and mTORC1; Cluster B was an immune activating phenotype with increased infiltration of CD4 + and CD8 + T cells and NK cells, and increased activation of signaling pathways such as interferon gamma (IFN-γ) response, IL6-JAK-STAT3 and inflammatory response. Drug prediction results showed that patients in Cluster B had a higher therapeutic response to anti-PD-1 and anti-CTLA4 and were more sensitive to imatinib, nilotinib and dasatinib. Support Vector Machine Recursive Feature Elimination (SVM-RFE), Least Absolute Shrinkage Selection Operator (LASSO) and Random Forest (RF) algorithms identified 4 CML diagnostic genes (HDC, SMPDL3A, IRF4 and AQP3), and the risk score model constructed by these genes improved the diagnostic accuracy. We further validated the diagnostic value of the 4 genes and the risk score model in a clinical cohort, and the risk score can be used in the differential diagnosis of CML and other hematological malignancies. The risk score can also be used to identify molecular subtypes and predict response to imatinib treatment. These results reveal the characteristics of immunosuppression and metabolic reprogramming in CML patients, and the identification of molecular subtypes and biomarkers provides new ideas and insights for the clinical diagnosis and treatment.
Dysregulation of microRNAs (miRNAs) is associated with the pathogenesis of rheumatoid arthritis (RA). Our previous studies confirmed that Duanteng Yimu decoction (DTYMT) effectively inhibits RA ...fibroblast-like synoviocyte (FLS) proliferation. In this study, we investigated the influence of DTYMT on miR-221 in RA individuals. Hematoxylin–eosin (HE) staining was performed to assess histopathological alterations in collagen-induced arthritis (CIA) mice. The expression of miR-221-3p and TLR4 in PBMC, FLS, and cartilage was measured by RT-qPCR. In the in vitro experiments, DTYMT-containing serum was incubated with FLS-transfected miR-221 mimic or inhibitor. CCK-8 was performed to determine FLS proliferation, and the secretion of IL-1β, IL-6, IL-18, and TNF-α was quantified by ELISA assay. In addition, the regulation of miR-221 expression on FLS apoptosis was assessed using flow cytometry. Finally, western blot was employed to reflect TLR4/MyD88 protein levels. HE results showed that DTYMT effectively reduced synovial hyperplasia in the joints of CIA mice. RT-qPCR assay of FLS and cartilage of the model group showed that miR-221-3p and TLR4 significantly increased compared with those in the normal group. All outcomes were improved by DTYMT. The miR-221 mimic reversed the inhibitory effect of DTYMT-containing serum on FLS proliferation, the release of IL-1β, IL-18, IL-6, and TNF-α, and FLS apoptosis, as well as TLR4/MyD88 protein levels. The results showed that miR-221 promotes the activity of RA-FLS by activating TLR4/MyD88 signaling, and DTYMT treats RA by reducing miR-221 in CIA mice.
High bone mass (HBM) is usually caused by gene mutations, and its mechanism remains unclear. In the present study, we identified a novel mutation in the long noncoding RNA
that is associated with ...HBM. Subsequent analysis in 1,465 Chinese subjects revealed that heterozygous
individuals had higher bone density compared with subjects with WT
Mutant
increased the formation of the CD31
Emcn
endothelium in the bone marrow, which stimulated angiogenesis during osteogenesis. Mechanistically, mutant
directly binds to Krüppel-like factor 3 (KLF3) to inhibit its activity. Mice depleted of
in endothelial cells showed a high abundance of CD31
Emcn
vessels and increased bone mass. Notably, we identified a natural compound, Ophiopogonin D, which functions as a KLF3 inhibitor. Administration of Ophiopogonin D increased the abundance of CD31
Emcn
vessels and bone formation. Our findings revealed a specific mutation in lncRNA
that is involved in the pathogenesis of HBM and provides a new target to treat osteoporosis.
Heavy concrete shielding properties for carbon therapy Wang, Jin-Long; Lu, Jiade J; Ding, Da-Jun ...
Nuclear engineering and technology,
June 2023, 2023-06-00, 2023-06-01, 2023-06, Letnik:
55, Številka:
6
Journal Article
Recenzirano
Odprti dostop
As medical facilities are usually built at urban areas, special concrete aggregates and evaluation methods are needed to optimize the design of concrete walls by balancing density, thickness, ...material composition, cost, and other factors. Carbon treatment rooms require a high radiation shielding requirement, as the neutron yield from carbon therapy is much higher than the neutron yield of protons. In this case study, the maximum carbon energy is 430 MeV/u and the maximum current is 0.27 nA from a hybrid particle therapy system. Hospital or facility construction should consider this requirement to design a special heavy concrete. In this work, magnetite is adopted as the major aggregate. Density is determined mainly by the major aggregate content of magnetite, and a heavy concrete test block was constructed for structural tests. The compressive strength is 35.7 MPa. The density ranges from 3.65 g/cm3 to 4.14 g/cm3, and the iron mass content ranges from 53.78% to 60.38% from the 12 cored sample measurements. It was found that there is a linear relationship between density and iron content, and mixing impurities should be the major reason leading to the nonuniform element and density distribution. The effect of this nonuniformity on radiation shielding properties for a carbon treatment room is investigated by three groups of Monte Carlo simulations. Higher density dominates to reduce shielding thickness. However, a higher content of high-Z elements will weaken the shielding strength, especially at a lower dose rate threshold and vice versa. The weakened side effect of a high iron content on the shielding property is obvious at 2.5 μSv/h. Therefore, we should not blindly pursue high Z content in engineering. If the thickness is constrained to 2 m, then the density can be reduced to 3.3 g/cm3, which will save cost by reducing the magnetite composition with 50.44% iron content. If a higher density of 3.9 g/cm3 with 57.65% iron content is selected for construction, then the thickness of the wall can be reduced to 174.2 cm, which will save space for equipment installation.
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