Accumulation of evidence indicates that miRNAs have crucial roles in the regulation of EMT-associated properties, such as proliferation, migration and invasion. However, the underlying molecular ...mechanisms are not entirely illustrated. Here, we investigated the role of miR-296-5p in hepatocellular carcinoma (HCC) progression.
In vitro cell morphology, proliferation, migration and invasion were compared between HCC cell lines with up- or down-regulation of miR-296-5p. Immunofluorescence and Western blot immunofluorescence assays were used to detect the expression of EMT markers. Bioinformatics programs, luciferase reporter assay and rescue experiments were used to validate the downstream targets of miR-296-5p. Xenograft nude mouse models were established to observe tumor growth and metastasis. Immunohistochemical assays were conducted to study the relationships between miR-296-5p expression and Neuregulin-1 (NRG1)/EMT markers in human HCC samples and mice.
miR-296-5p was prominently downregulated in HCC tissues relative to adjacent normal liver tissues and associated with favorable prognosis. Overexpression of miR-296-5p inhibited EMT along with migration and invasion of HCC cells via suppressing NRG1/ERBB2/ERBB3/RAS/MAPK/Fra-2 signaling in vitro. More importantly, miR-296-5p disrupted intrahepatic and pulmonary metastasis in vivo. NRG1, as a direct target of miR-296-5p, mediates downstream biological responses. In HCC tissues from patients and mice, the levels of miR-296-5p and NRG1 also showed an inverse relationship.
miR-296-5p inhibited EMT-related metastasis of HCC through NRG1/ERBB2/ERBB3/RAS/MAPK/Fra-2 signaling.
Recent progress on salient object detection (SOD) mostly benefits from the explosive development of Convolutional Neural Networks (CNNs). However, much of the improvement comes with the larger ...network size and heavier computation overhead, which, in our view, is not mobile-friendly and thus difficult to deploy in practice. To promote more practical SOD systems, we introduce a novel Stereoscopically Attentive Multi-scale (SAM) module, which adopts a stereoscopic attention mechanism to adaptively fuse the features of various scales. Embarking on this module, we propose an extremely lightweight network, namely SAMNet, for SOD. Extensive experiments on popular benchmarks demonstrate that the proposed SAMNet yields comparable accuracy with state-of-the-art methods while running at a GPU speed of 343fps and a CPU speed of 5fps for <inline-formula> <tex-math notation="LaTeX">336 \times 336 </tex-math></inline-formula> inputs with only 1.33M parameters. Therefore, SAMNet paves a new path towards SOD. The source code is available on the project page https://mmcheng.net/SAMNet/ .
We developed a spectroscopic monitoring project to investigate the kinematics of the broad-line region (BLR) in active galactic nuclei (AGNs) with ultrafast outflows (UFOs). Mrk 79 is a radio-quiet ...AGN with UFOs and warm absorbers and has been monitored by three reverberation mapping (RM) campaigns, but its BLR kinematics are not yet understood. In this paper, we report the results from a new RM campaign of Mrk 79, which was undertaken with the Lijiang 2.4 m telescope. Mrk 79 appears to come out the faint state, with the mean flux approximately a magnitude fainter than the historical record. We successfully measured the lags of the broad emission lines including Hβ λ4861, Hγ λ4340, He ii λ4686, and He i λ5876 with respect to the varying AGN continuum. Based on the broad Hβ λ4861 line, we measured a black hole mass of M = 5.13 − 1.55 + 1.57 × 10 7 M , and an estimated accretion rate of M ̇ = ( 0.05 0.02 ) L Edd c − 2 , indicating that Mrk 79 is a sub-Eddington accretor. We found that Mrk 79 deviates from the canonical Radius−Luminosity relationship. The marginal blueshift of the broad He ii λ4686 line detected from the rms spectrum indicates outflow of high-ionization gas. The velocity-resolved lag profiles of the broad Hγ λ4340, Hβ λ4861, and He i λ5876 lines show similar signatures such that the largest lag occurs in the red wing of the lines and then the lag decreases to both sides. These signatures may suggest that the BLR of Keplerian motion probably exists as outflow gas motion. All findings including UFOs, warm absorbers, and the kinematics of high- and low-ionization BLR, may provide indirect evidence that the BLR of Mrk 79 probably originates from a disk wind.
Hypoxia is a major contributor to global kidney diseases. Targeting hypoxia is a promising therapeutic option against both acute kidney injury and chronic kidney disease; however, an effective ...strategy that can achieve simultaneous targeted kidney hypoxia imaging and therapy has yet to be established. Herein, we fabricated a unique nano-sized hypoxia-sensitive coassembly (Pc/C5A@EVs) via molecular recognition and self-assembly, which is composed of the macrocyclic amphiphile C5A, the commercial dye sulfonated aluminum phthalocyanine (Pc) and mesenchymal stem cell-excreted extracellular vesicles (MSC-EVs).
In murine models of unilateral or bilateral ischemia/reperfusion injury, MSC-EVs protected the Pc/C5A complex from immune metabolism, prolonged the circulation time of the complex, and specifically led Pc/C5A to hypoxic kidneys via surface integrin receptor α
β
and α
β
, where Pc/C5A released the near-infrared fluorescence of Pc and achieved enhanced hypoxia-sensitive imaging. Meanwhile, the coassembly significantly recovered kidney function by attenuating cell apoptosis, inhibiting the progression of renal fibrosis and reducing tubulointerstitial inflammation. Mechanistically, the Pc/C5A coassembly induced M1-to-M2 macrophage transition by inhibiting the HIF-1α expression in hypoxic renal tubular epithelial cells (TECs) and downstream NF-κB signaling pathway to exert their regenerative effects.
This synergetic nanoscale coassembly with great translational potential provides a novel strategy for precise kidney hypoxia diagnosis and efficient kidney injury treatment. Furthermore, our strategy of coassembling exogenous macrocyclic receptors with endogenous cell-derived membranous structures may offer a functional platform to address multiple clinical needs.
This paper demonstrated a simple and validated fluorescence enhancing method to selectively recognize and discriminate the amino acid phenylalanine (Phe). 1H NMR spectroscopy reveal that the ...palmatine (PAL) can be encapsulated into the cucurbit 8uril (Q 8) in aqueous solution to form stable 1:2 host−guest inclusion complex PAL2@Q 8, which exhibits moderate intensity fluorescence property. Interestingly, the addition of the Phe into the inclusion complex PAL2@Q 8 leads to dramatically enhancing of the fluorescence intensity. In contrast, the addition of any other natural amino acids into the inclusion complex PAL2@Q 8 gives no fluorescence variation. Furthermore, it is easy to detect the concentration of Phe in target aqueous solution according to the linear relationship between fluorescence intensity and concentration of the Phe.
This study presents a simple and validated fluorescence enhancing method to selectively recognize and determinate the amino acid phenylalanine (Phe). Display omitted
•A fluorescence enhancing method for the selective recognition of the amino acid phenylalanine (Phe) has been reported.•Palmatine (PAL) can be encapsulated into the cucurbit 8uril (Q 8) in aqueous solution to form stable 1:2 host−guest inclusion complex.•Interestingly, the addition of the Phe dramatically enhanced the fluorescence intensity of the inclusion complex.•In contrast, the addition of any other 19 natural amino acids gives no fluorescence variation.
MicroRNA-612 (miR-612) has been proven to suppress EMT, stemness, and tumor metastasis of hepatocellular carcinoma (HCC) via PI3K/AKT2 and Sp1/Nanog signaling. However, its biological roles on HCC ...progression are far from elucidated.
We found direct downstream target of miR-612, hadha by RNA immunoprecipitation and sequencing. To explore its biological characteristic, potential molecular mechanism, and clinical relevance in HCC patients, we performed several in-vitro and in-vivo models, as well as human tissue chip.
Ectopic expression of miR-612 could partially reverse the level of HADHA, then suppress function of pseudopods, and diminish metastatic and invasive potential of HCC by lipid reprogramming. In detail, miR-612 might reduce invadopodia formation via HADHA-mediated cell membrane cholesterol alteration and accompanied with the inhibition of Wnt/β-catenin regulated EMT occurrence. Our results showed that the maximum oxygen consumption rates (OCR) of HCCLM3
and HCCLM3
cells were decreased nearly by 40% and 60% of their counterparts (p < 0.05). The levels of acetyl CoA were significantly decreased, about 1/3 (p > 0.05) or 1/2 (p < 0.05) of their controls, in exogenous miR-612 or hadha-shRNA transfected HCCLM3 cell lines. Besides, overexpression of hadha cell lines had a high expression level of total cholesterol, especially 27-hydroxycholesterol (p < 0.005). SREBP2 protein expression level as well as its downstream targets, HMGCS1, HMGCR, MVD, SQLE were all deregulated by HADHA. Meanwhile, the ATP levels were reduced to 1/2 and 1/4 in HCCLM3
(p < 0.05) and HCCLM3
(p < 0.01) respectively. Moreover, patients with low miR-612 levels and high HADHA levels had a poor prognosis with shorter overall survival.
miR-612 can suppress the formation of invadopodia, EMT, and HCC metastasis and by HADHA-mediated lipid programming, which may provide a new insight of miR-612 on tumor metastasis and progression.
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Over the last several decades, hydrogen sulfide (H2S) has been found to exert multiple physiological functions in mammal systems. The endogenous production of H2S is primarily ...mediated by cystathione β-synthase (CBS), cystathione γ-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (3-MST). These enzymes are widely expressed in the liver tissues and regulate hepatic functions by acting on various molecular targets.
In the present review, we will highlight the recent advancements in the cellular events triggered by H2S under liver diseases. The therapeutic effects of H2S donors on hepatic diseases will also be discussed.
As a critical regulator of liver functions, H2S is critically involved in the etiology of various liver disorders, such as nonalcoholic steatohepatitis (NASH), hepatic fibrosis, hepatic ischemia/reperfusion (IR) injury, and liver cancer. Targeting H2S-producing enzymes may be a promising strategy for managing hepatic disorders.
Rheumatoid arthritis (RA) joint inflammation severely affects joint function and quality of life in patients and leads to joint deformities and limb disability. The non-steroidal anti-inflammatory ...drugs used in the treatment of RA do not fully control the progression of joint inflammation and bone destruction and have notable adverse reactions. Traditional Chinese medicine formula JuanBiQiangGu Granules (JBQG) are commonly used for the treatment of RA inflammation and delay of bone destruction, but has not been evaluated through high-quality clinical studies. There is a pressing need for well-designed, randomized, parallel, controlled clinical studies to evaluate the exact effect of JBQG on RA joint inflammation and improvement of patient quality of life.
This is a randomized, parallel, controlled clinical study in which 144 patients with rheumatoid arthritis who met the inclusion criteria were randomly assigned to 2 groups in a 1:1 ratio. The JBQG group received methotrexate 7.5 mg qw and JBQG granules 8 mg tid, while the MTX group received methotrexate 7.5 mg qw. The endpoint was 12 weeks after treatment. Relevant indices at baseline, 4 weeks, 8 weeks, and 12 weeks after treatment were observed and recorded, and DAS28-ESR, HAQ-DI, and Sharp scores were recorded for each patient. Blood samples were collected to test for CRP, ESR, TNF-α, IL-1β, IL-6, IL-17, and INF-γ, and adverse reactions and liver and kidney function (AST, ALT, Cr, BUN) were recorded for safety assessment. After 12 weeks of treatment, the effect of JBQG granules on disease activity, improvement in bone damage, and patient quality of life scores and safety in RA patients were evaluated.
A total of 144 subjects completed treatment (71 in the JBQG group and 73 in the MTX group) and were included in the analysis. At baseline, there were no significant differences between the groups in terms of the observed indicators (
> 0.05). After treatment, 76.06% of patients in the JBQG group had DAS28-ESR levels below or equal to Low, including 45.07% in Remission and 5.63% in High, compared to 53.1% in the MTX group below or equal to Low, 12.33% in Remission, and 17.81% in High. CRP was significantly reduced (8.54 ± 5.87 vs. 11.86 ± 7.92,
< 0.05,
= 0.005), ESR was significantly reduced (15.1 ± 6.11 vs. 21.96 ± 9.19,
< 0.0001), TNF-α was significantly reduced (1.44 ± 0.83 vs. 1.85 ± 1.07,
< 0.05,
= 0.011), IL-17 was significantly reduced (0.53 ± 0.33 vs. 0.71 ± 0.38,
< 0.05,
= 0.004), and INF-γ was significantly reduced (3.2 ± 1.51 vs. 3.89 ± 1.77,
< 0.05,
= 0.014). The median (IQR) OPG in the JBQG group was 2.54 (2.21-3.01), significantly higher than in the MTX group 2.06 (1.81-2.32),
< 0.0001), and the median (IQR)
-CTX in the JBQG group was 0.4 (0.32-0.43), significantly lower than in the MTX group 0.55 (0.47-0.67),
< 0.0001). The median (IQR) VSA scores were 2 (1-3), a decrease from 3 (2-4) in the MTX group (
< 0.0001). The median (IQR) Sharp scores were 1 (1-2), a decrease from 2 (1-2) in the MTX group, but the difference was not statistically significant (
> 0.05,
= 0.28). The median (IQR) HAQ-DI scores were 11 (8-16), significantly lower than in the MTX group 26 (16-30) (
< 0.0001). The median (IQR) AST in the JBQG group was 16 (12-20), with a significant difference compared to the MTX group 19 (13-25) (
< 0.01,
= 0.004); the median (IQR) ALT in the JBQG group was 14 (10-18), with a significant difference compared to the MTX group 16 (11-22.5) (
< 0.05,
= 0.015). There were no statistically significant differences in Cr or BUN (
> 0.05).
JuanBiQiangGu Granules can be used to treat patients with rheumatoid arthritis, alleviate joint inflammation, reduce the incidence of adverse reactions to methotrexate, and has good safety.
http://www.chinadrugtrials.org.cn/index.html; identifier: ChiCTR2100046373.
A compact third-order filtering antenna array with high gain and two controllable radiation nulls is proposed. The antenna consists of one narrow patch in the center fed by the coaxial port and four ...wide patches placed around it. Four shortend stub-loaded resonators are capacitively coupled between the center patch and the outer patches, which makes the radiated Efields of the center patch and the outer patches in-phase at the center frequency of the passband to realize the high gain and outof-phase at the low and high stopbands to introduce a pair of radiation nulls. The working principle of the filtering antenna array can be explained by the coupled-resonator network. Finally, a filtering antenna array centered at 3.5 GHz with a fractional bandwidth of 4.26%, a high maximum gain of 12.2 dBi, high out-of-band selectivity, and wide stopband is designed, fabricated, and measured.
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