Glucocorticoids (GCs) show powerful treatment effect on rheumatoid arthritis (RA). However, the clinical application is limited by their nonspecific distribution after systemic administration, ...serious adverse reactions during long-term administration. To achieve better treatment, reduce side effect, we here established a biomimetic exosome (Exo) encapsulating dexamethasone sodium phosphate (Dex) nanoparticle (Exo/Dex), whose surface was modified with folic acid (FA)-polyethylene glycol (PEG)-cholesterol (Chol) compound to attain FPC-Exo/Dex active targeting drug delivery system. The size of FPC-Exo/Dex was 128.43 + or - 16.27 nm, with a polydispersity index (PDI) of 0.36 + or - 0.05, and the Zeta potential was - 22.73 + or - 0.91 mV. The encapsulation efficiency (EE) of the preparation was 10.26 + or - 0.73%, with drug loading efficiency (DLE) of 18.81 + or - 2.05%. In vitro study showed this system displayed enhanced endocytosis and excellent anti-inflammation effect against RAW264.7 cells by suppressing pro-inflammatory cytokines and increasing anti-inflammatory cytokine. Further biodistribution study showed the fluorescence intensity of FPC-Exo/Dex was stronger than other Dex formulations in joints, suggesting its enhanced accumulation to inflammation sites. In vivo biodistribution experiment displayed FPC-Exo/Dex could preserve the bone and cartilage of CIA mice better and significantly reduce inflamed joints. Next in vivo safety evaluation demonstrated this biomimetic drug delivery system had no obvious hepatotoxicity and exhibited desirable biocompatibility. The present study provides a promising strategy for using exosome as nanocarrier to enhance the therapeutic effect of GCs against RA.
Cell search is the first step to establish downlink synchronization between user equipment (UE) and base station (BS) in the fifth generation (5G) new radio (NR) system. However, frequency offset and ...noise will cause a massive loss of synchronization performance. To solve this problem, a novel timing synchronization algorithm of primary synchronization signal (PSS) with anti-frequency offset and anti-noise is proposed, which includes the improved coarse synchronization algorithm based on Fourier transform and the fine synchronization algorithm based on the triple auto-correlation algorithm. The improved coarse synchronization algorithm not only has a strong frequency offset resistance, especially for large frequency offset, but also obtains the estimated frequency offset. The fine synchronization algorithm is more resistant to noise than the conventional algorithm. Finally, the algorithm analysis and simulation results show that the improved algorithm can work very well even when the normalized frequency offset increases to greater than 0.8, but the conventional algorithm fails to synchronize properly. Meanwhile, when the SNR is as low as −6dB, the detection accuracy of the timing synchronization based on the proposed fine synchronization algorithm is improved by about 31.7% compared with the conventional algorithm.
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•Autoimmune disease is a multifactorial disease with limited treatment option.•Thymoquinone is a natural product with potential against autoimmune disease.•Thymoquinone can regulate ...inflammatory process and signaling pathways.•Thymoquinone might be a possible therapeutic option for autoimmune disease.
Autoimmune diseases (AUDs) are a multifactorial disease, among which rheumatoid arthritis, systemic lupus erythematosus and multiple sclerosis are more prevalent. Several anti-inflammatory, biologics, and AUD-modifying drugs are found effective against them, but their repeated use are associated with various adverse effects. In this review article, we have focused on the regulation of inflammatory molecules, molecular signaling pathways, immune cells, and epigenetics by natural product thymoquinone on AUDs. Studies indicate that thymoquinone can regulate inflammatory molecules including interferons, interleukins, tumor necrosis factor-α (TNF-α), oxidative stress, regulatory T cells, and various signaling pathways such as nuclear factor kappa beta (NF-κβ), janus kinase/signal transduction and activator of transcription (JAK-STAT), mitogen-activated protein kinase (MAPK) at the molecular level and epigenetic alteration. As these molecules and signaling pathways with defective immune function play an important role in AUD development, controlling these molecules and deregulated molecular mechanism is a significant feature of AUD therapeutics. Interestingly thymoquinone is reported to possess all these potential. This article reviewed the deregulated mechanism of AUDs, and the action of thymoquinone on inflammatory molecules, immune cells, signaling pathways, and epigenetic machinery. Thymoquinone can be regarded as a potential drug candidate for AUD treatment.
TQFL12 is a novel derivative designed and synthesized on the basis of Thymoquinone (TQ) which is extracted from
seeds. We have demonstrated that TQFL12 was more effective in the treatment of TNBC ...than TQ. In order to directly reflect the acute toxicity of TQFL12 in vivo, in this study, we designed, synthesized, and compared it with TQ. The mice were administered drugs with different concentration gradients intraperitoneally, and death was observed within one week. The 24 h median lethal dose (LD
) of TQ was calculated to be 33.758 mg/kg, while that of TQFL12 on the 7th day was 81.405 mg/kg, and the toxicity was significantly lower than that of TQ. The liver and kidney tissues of the dead mice were observed by H&E staining. The kidneys of the TQ group had more severe renal damage, while the degree of the changes in the TQFL12 group was obviously less than that in the TQ group. Western blotting results showed that the expressions of phosphorylated levels of adenylate-activated protein kinase AMPKα were significantly up-regulated in the kidneys of the TQFL12 group. Therefore, it can be concluded that the acute toxicity of TQFL12 in vivo is significantly lower than that of TQ, and its anti-toxicity mechanism may be carried out through the AMPK signaling pathway, which has a good prospect for drug development.
Intelligent Reflecting Surface (IRS) can offer unprecedented channel capacity gains since it can reconfigure the signal propagation environment. We decide to maximize the channel capacity by jointly ...optimizing the transmit-power-constrained precoding matrix at the base station and the unit-modulus-constrained phase shift vector at the IRS in IRS-assisted multi-user downlink communication. We first convert the resulting non-convex problem into an equivalent problem, then use the alternate optimization algorithm. While fixing the phase shift vector, we can obtain the optimal precoding matrix directly by adopting standard optimization packages. While fixing the precoding matrix, we propose the Riemannian Trust-Region (RTR) algorithm to solve this optimization problem. And the key of the RTR algorithm is the solution of the trust-region sub-problem. We first adopt the accurate solution based on Newton's (ASNT) method to solve this sub-problem, which can obtain the global solution but cannot guarantee that the solution is optimal since the initial iteration point is difficult to choose. Then, we propose the Improved-Polyline (IPL) method, which can avoid the difficulty of the ASNT method and improve convergence speed and calculation efficiency. The numerical results show that the RTR algorithm has more significant performance gains and faster convergence speed compared with the existing approaches.
JMJD6 is a member of the Jumonji (JMJC) domain family of histone demethylases that contributes to catalyzing the demethylation of H3R2me2 and/or H4R3me2 and regulating the expression of specific ...genes. JMJD6-mediated demethylation modifications are involved in the regulation of transcription, chromatin structure, epigenetics, and genome integrity. The abnormal expression of JMJD6 is associated with the occurrence and development of a variety of tumors, including breast carcinoma, lung carcinoma, colon carcinoma, glioma, prostate carcinoma, melanoma, liver carcinoma, etc. Besides, JMJD6 regulates the innate immune response and affects many biological functions, as well as may play key roles in the regulation of immune response in tumors. Given the importance of epigenetic function in tumors, targeting JMJD6 gene by modulating the role of immune components in tumorigenesis and its development will contribute to the development of a promising strategy for cancer therapy. In this article, we introduce the structure and biological activities of JMJD6, followed by summarizing its roles in tumorigenesis and tumor development. Importantly, we highlight the potential functions of JMJD6 in the regulation of tumor immune response, as well as the development of JMJD6 targeted small-molecule inhibitors for cancer therapy.
Methotrexate (MTX) has been highlighted for Rheumatoid arthritis (RA) treatment, however, MTX does not accumulate well at inflamed sites, and long-term administration in high doses leads to severe ...side effects. In this study, a novel anti-RA nanoparticle complex was designed and constructed, which could improve the targeted accumulation in inflamed joints and reduce side effects.
Here, we prepared a pH-sensitive biomimetic drug delivery system based on macrophage-derived microvesicle (MV)-coated zeolitic imidazolate framework-8 nanoparticles that encapsulated the drug methotrexate (hereafter MV/MTX@ZIF-8). The MV/MTX@ZIF-8 nanoparticles were further modified with 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-folate (polyethylene glycol)-2000 (hereafter FPD/MV/MTX@ZIF-8) to exploit the high affinity of folate receptor β for folic acid on the surface of activated macrophages in RA. MTX@ZIF-8 nanoparticles showed high DLE (~ 70%) and EE (~ 82%). In vitro study showed that effective drug release in an acidic environment could be achieved. Further, we confirmed the activated macrophage could uptake much more FPD/MV/MTX@ZIF-8 than inactivated cells. In vivo biodistribution experiment displayed FPD/MV/MTX@ZIF-8 nanoparticles showed the longest circulation time and best joint targeting. Furthermore, pharmacodynamic experiments confirmed that FPD/MV/MTX@ZIF-8 showed sufficient therapeutic efficacy and safety to explore clinical applications.
This study provides a novel approach for the development of biocompatible drug-encapsulating nanomaterials based on MV-coated metal-organic frameworks for effective RA treatment.
COVID-19 is an acute respiratory disease caused by SARS-CoV-2 that has spawned a worldwide pandemic. ADAM17 is a sheddase associated with the modulation of the receptor ACE2 of SARS-CoV-2. Studies ...have revealed that malignant phenotypes of several cancer types are closely relevant to highly expressed ADAM17. However, ADAM17 regulation in SARS-CoV-2 invasion and its role on small molecules are unclear. Here, we evaluated the ADAM17 inhibitory effects of cordycepin (CD), thymoquinone (TQ), and N6, N6-dimethyladenosine (m
A), on cancer cells and predicted the anti-COVID-19 potential of the three compounds and their underlying signaling pathways by network pharmacology. It was found that CD, TQ, and m
A repressed the ADAM17 expression upon different cancer cells remarkably. Moreover, CD inhibited GFP-positive syncytia formation significantly, suggesting its potential against SARS-CoV-2. Pharmacological analysis by constructing CD-, TQ-, and m
A-based drug-target COVID-19 networks further indicated that ADAM17 is a potential target for anti-COVID-19 therapy with these compounds, and the mechanism might be relevant to viral infection and transmembrane receptors-mediated signal transduction. These findings imply that ADAM17 is of potentially medical significance for cancer patients infected with SARS-CoV-2, which provides potential new targets and insights for developing innovative drugs against COVID-19.
Infant drowning has occurred frequently in swimming pools recent years, which motivates the research on automatic real-time detection of the accident. Unlike youths or adults, swimming infants are ...small in terms of size and motion range, and unable to send out distress signals in emergencies, which exerts negative effects on the detection of drowning. Aiming at this problem, a new step is initialized towards detecting infant drowning automatically and efficiently based on video surveillance. Diverse live-scene videos of infant swimming and drowning are collected from a variety of natatoriums and labeled as datasets. A part of the datasets is downscaled or enlarged to enhance generalization ability of the model. On this basis, advantages of Faster R-CNN and a series of YOLOv5 models are specifically explored to enable fast and accurate detection of infant drowning in real-world. Supervised learning experiments are carried out, model test results show that mean Average Precision (mAP) of either Faster R-CNN or YOLOv5s of the series of YOLOv5 can be over 89%; the former can process merely 6 frames of videos per second with the precision of only 62.04%, while the latter can reach an average speed of 75 frames/s with the precision of about 86.6%. The YOLOv5s eventually stands out as an optimal model for detecting infant drowning in view of comprehensive performance, which is of great application value to reduce the accidents in swimming pools.
Background/Aims: Ubiquitin E3 ligase MARCH7 plays an important role in T cell proliferation and neuronal development. But its role in ovarian cancer remains unclear. This study aimed to investigate ...the role of Ubiquitin E3 ligase MARCH7 in ovarian cancer. Methods: Real-time PCR, immunohistochemistry and western blotting analysis were performed to determine the expression of MARCH7, MALAT1 and ATG7 in ovarian cancer cell lines and clinical specimens. The role of MARCH7 in maintaining ovarian cancer malignant phenotype was examined by Wound healing assay, Matrigel invasion assays and Mouse orthotopic xenograft model. Luciferase reporter assay, western blot analysis and ChIP assay were used to determine whether MARCH7 activates TGF-β-smad2/3 pathway by interacting with TGFβR2. Results: MARCH7 interacted with MALAT1 by miR-200a (microRNA-200a). MARCH7 may function as a competing endogenous RNA (ceRNA) to regulate the expression of ATG7 by competing with miR-200a. MARCH7 regulated TGF-β-smad2/3 pathway by interacting with TGFβR2. Inhibition of TGF-β-smad2/3 pathway downregulated MARCH7, MALAT1 and ATG7. MiR-200a regulated TGF-β induced autophagy, invasion and metastasis of SKOV3 cells by targeting MARCH7. MARCH7 silencing inhibited autophagy invasion and metastasis of SKOV3 cells both in vitro and in vivo. In contrast, MARCH7 overexpression promoted TGF-β induced autophagy, invasion and metastasis of A2780 cells in vitro by depending on MALAT1 and ATG7. We also found that TGF-β-smad2/3 pathway regulated MARCH7 and ATG7 through MALAT1. Conclusions: These findings suggested that TGFβR2-Smad2/3-MALAT1/MARCH7/ATG7 feedback loop mediated autophagy, migration and invasion in ovarian cancer.
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