Brain capillaries are crucial for cognitive functions by supplying oxygen and other nutrients to and removing metabolic wastes from the brain. Recent studies have demonstrated that constriction of ...brain capillaries is triggered by beta-amyloid (Aβ) oligomers via endothelin-1 (ET1)-mediated action on the ET1 receptor A (ETRA), potentially exacerbating Aβ plaque deposition, the primary pathophysiology of Alzheimer’s disease (AD). However, direct evidence is still lacking whether changes in brain capillaries are causally involved in the pathophysiology of AD. Using APP/PS1 mouse model of AD (AD mice) relative to age-matched negative littermates, we identified that reductions of density and diameter of hippocampal capillaries occurred from 4 to 7 months old while Aβ plaque deposition and spatial memory deficit developed at 7 months old. Notably, the injection of ET1 into the hippocampus induced early Aβ plaque deposition at 5 months old in AD mice. Conversely, treatment of ferulic acid against the ETRA to counteract the ET1-mediated vasoconstriction for 30 days prevented reductions of density and diameter of hippocampal capillaries as well as ameliorated Aβ plaque deposition and spatial memory deficit at 7 months old in AD mice. Thus, these data suggest that reductions of density and diameter of hippocampal capillaries are crucial for initiating Aβ plaque deposition and spatial memory deficit at the early stages, implicating the development of new therapies for halting or curing memory decline in AD.
Aim
Hepatocellular carcinoma (HCC) is common and causes many deaths worldwide. The aim of this study is to explore the mechanism by which long non‐coding RNA FGD5‐AS1 regulates HCC cell proliferation ...and stemness.
Methods
Tumor and normal adjacent tissues were harvested from HCC patients. Real‐time quantitative reverse transcription‐PCR was applied to examine the expression of FGD5‐AS1, miR‐223, Epithelial cell transforming sequence 2 (ECT2) and FAT1. The protein levels of ECT2, FAT1, proliferating cell nuclear antigen (PCNA), OCT4, CD133 and CD90 were analyzed by western blot. The localization of FGD5‐AS1 was examined by Fluorescence in situ hybridization. Cell proliferation was analyzed with CCK‐8 and colony formation assays. Spheroid formation was used for analyzing cell stemness. Gene interaction was examined by RNA immunoprecipitation and luciferase activity assays. A subcutaneous xenograft mouse model was established to analyze HCC growth and stemness in vivo. Immunohistochemistry staining was used to analyze the expression PCNA and OCT4 in subcutaneous tumors.
Results
FGD5‐AS1 was upregulated in HCC and its high expression indicated poor prognosis of patients. High expression of FGD5‐AS1 enhanced HCC cell proliferation and stemness. Knockdown of FGD5‐AS1 restrained tumor growth and stemness in mice. FGD5‐AS1 directly sponged miR‐223 and promoted the expression of ECT2 and FAT1 in HCC. Both knockdown of miR‐223 and overexpression of ECT2 and FAT1 reversed FGD5‐AS1 silencing‐mediated suppression of HCC cell proliferation and stemness.
Conclusion
FGD5‐AS1 directly sponged miR‐223 and promoted the expression of ECT2 and FAT1 in HCC, thus enhancing HCC cell proliferation and stemness. Our study identifies potential prognostic biomarkers and therapeutic targets for HCC.
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BFBNIB, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
•Luteolin and chloroquine bind to the main protease of SARS-CoV-2•The binding sites of luteolin are highly consistent with the main protease inhibitors•Luteolin can be used as a potent compound ...against SARS-CoV-2•Binding of luteolin is conducive to the study of antiviral mechanism of traditional Chinese medicine
In the current spread of novel coronavirus (SARS-CoV-2), antiviral drug discovery is of great importance. AutoDock Vina was used to screen potential drugs by molecular docking with the structural protein and non-structural protein sites of new coronavirus. Ribavirin, a common antiviral drug, remdesivir, chloroquine and luteolin were studied. Honeysuckle is generally believed to have antiviral effects in traditional Chinese medicine. In this study, luteolin (the main flavonoid in honeysuckle) was found to bind with a high affinity to the same sites of the main protease of SARS-CoV-2 as the control molecule. Chloroquine has been proved clinically effective and can bind to the main protease; this may be the antiviral mechanism of this drug. The study was restricted to molecular docking without validation by molecular dynamics simulations. Interactions with the main protease may play a key role in fighting against viruses. Luteolin is a potential antiviral molecule worthy of attention.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
The recent advanced LIGO/Virgo detections of gravitational waves (GWs) from stellar binary black hole (BBH) mergers, in particular GW190521, which is potentially associated with a quasar, ...have stimulated renewed interest in active galactic nuclei as factories of merging BBHs. Compact objects evolving from massive stars are unavoidably enshrouded by a massive envelope to form accretion-modified stars (AMSs) in the dense gaseous environment of a supermassive black hole (SMBH) accretion disk. We show that most AMSs form binaries due to gravitational interaction with each other during radial migration in the SMBH disk, forming BBHs inside the AMS. When a BBH is born, its orbit is initially governed by the tidal torque of the SMBH. Bondi accretion onto a BBH at a hyper-Eddington rate naturally develops and then controls the evolution of its orbits. We find that Bondi accretion leads to efficient removal of the orbital angular momentum of the binary, whose final merger produces a GW burst. Meanwhile, the Blandford–Znajek mechanism pumps the spin energy of the merged BH to produce an electromagnetic counterpart (EMC). Moreover, hyper-Eddington accretion onto the BBH develops powerful outflows and triggers a Bondi explosion, which manifests itself as an EMC of the GW burst, depending on the viscosity of the accretion flow. Thermal emission from the Bondi sphere appears as one of the EMCs. The BBHs radiate GWs with frequencies of ∼10
2
Hz, which are accessible to LIGO.
Mitochondria and cell membrane play important roles in maintaining cellular activity and stability. Here, a single-agent self-delivery chimeric peptide based nanoparticle (designated as M-ChiP) was ...developed for mitochondria and plasma membrane dual-targeted photodynamic tumor therapy. Without additional carrier, M-ChiP possessed high drug loading efficacy as well as the excellent ability of producing reactive oxygen species (ROS). Moreover, the dual-targeting property facilitated the effective subcellular localization of photosensitizer protoporphyrin IX (PpIX) to generate ROS in situ for enhanced photodynamic therapy (PDT). Notably, plasma membrane-targeted PDT would enhance the membrane permeability to improve the cellular delivery of M-ChiP, and even directly disrupt the cell membrane to induce cell necrosis. Additionally, mitochondria-targeted PDT would decrease mitochondrial membrane potential and significantly promote the cell apoptosis. Both in vitro and in vivo investigations indicated that this combinatorial PDT in mitochondria and plasma membrane could achieve the therapeutic effect maximization with reduced side effects. The single-agent self-delivery system with dual-targeting strategy was demonstrated to be a promising nanoplatform for synergistic tumor therapy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The self-cleaning property is usually connected to superhydrophobic surfaces (SHSs) where the dust particles can be easily removed by the rolling motion of droplets. It seems that superhydrophobicity ...(its durability is questionable nowadays) is a necessity. However here, it is disclosed that self-cleaning can also be realized on an ordinary surface by droplet impinging. The effects of surface wettability and the types of dust particles are considered. The self-cleaning is realized by two steps: (1) the pickup of particles by the water-air interface of an impinging droplet, (2) the release of the impinging droplets from the surface. It can be observed that only the trailing edges of the droplets can pick up particles when the droplets recoil from the inclined surfaces. The hydrophilic surface can also achieve self-cleaning under some conditions. This interesting finding may be helpful for the successful implementation of self-cleaning with common surfaces.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Caffeine is a major component of xanthine alkaloids and commonly consumed in many popular beverages. Due to its occasional side effects, reduction of caffeine in a natural way is of great importance ...and economic significance. Recent studies reveal that caffeine can be converted into non-stimulatory theacrine in the rare tea plant Camellia assamica var. kucha (Kucha), which involves oxidation at the C8 and methylation at the N9 positions of caffeine. However, the underlying molecular mechanism remains unclear. Here, we identify the theacrine synthase CkTcS from Kucha, which possesses novel N9-methyltransferase activity using 1,3,7-trimethyluric acid but not caffeine as a substrate, confirming that C8 oxidation takes place prior to N9-methylation. The crystal structure of the CkTcS complex reveals the key residues that are required for the N9-methylation, providing insights into how caffeine N-methyltransferases in tea plants have evolved to catalyze regioselective N-methylation through fine tuning of their active sites. These results may guide the future development of decaffeinated drinks.
The current operational multi-band atmospheric correction algorithms implemented by NASA and NOAA for global remote sensing of ocean color from VIIRS (Visible Infrared Imaging Radiometer Suite) data ...are mostly based on the 2-band version of the SeaWiFS (Sea-Viewing Wide Field-of-View Sensor) algorithm. These algorithms generally use two NIR bands, one centered near 0.75 μm and the other near 0.865 μm, and a band ratio method for deriving aerosol information. The algorithms work quite well over open ocean waters. However, water leaving reflectances over turbid coastal waters are frequently not derived. We describe here a spectrum-matching algorithm using shortwave IR (SWIR) bands above 1 μm for retrieving water leaving reflectances in the visible from VIIRS data. The SWIR bands centered near 1.24, 1.61, and 2.25 μm are used in a spectrum-matching process to obtain spectral aerosol information, which is subsequently extrapolated to the visible region for the derivation of water leaving reflectances of visible bands. We present retrieval results for four VIIRS scenes acquired over turbid waters. We demonstrate that the spatial coverages of our retrieving results can be improved significantly in comparison with those retrieved with the current NOAA operational algorithm. If our SWIR algorithm is implemented for operational data processing, the algorithm can potentially be complimentary to current NASA and NOAA VIIRS algorithms over turbid waters to increase spatial coverages.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Abnormal tumor metabolism causes the hypoxic microenvironment, which greatly limits the efficacy of photodynamic therapy (PDT). In this work, a strategy of metabolic reprogramming is proposed to ...economize O2 for enhanced PDT against hypoxic tumors. The carrier‐free O2‐economizer (designated as LonCe) is prepared based on the metabolic antitumor drug of Lonidamine (Lon) and the photosensitizer of chlorin e6 (Ce6). By virtue of intermolecular interactions, Lon and Ce6 self‐assemble into nanosized LonCe with favorable stability and high drug contents. Compared with Ce6, LonCe exhibits an improved cellular uptake and photodynamic property for tumor treatment. Moreover, LonCe is capable of inhibiting cell metabolism and mitochondrial respiration to remit the tumor hypoxia, which would promote reactive oxygen species (ROS) production and elevate the PDT efficacy on tumor suppression. In vivo experiments indicate that intravenously injected LonCe prefers to accumulate at the tumor site for highly efficient PDT regardless of the hypoxic environment. Besides, the self‐delivery LonCe is fabricated without any carriers, which avoids the excipients induced system toxicity and immunogenicity in vivo. This carrier‐free nanomedicine with cell respiratory inhibition mechanism would expedite the development and clinical translation of photodynamic nanoplatforms in tumor treatment.
A carrier‐free O2‐economizer (designated as LonCe) is developed based on the metabolic drug Lonidamine (Lon) and photosensitizer chlorin e6 (Ce6), which can interrupt cell metabolism and depress mitochondrial respiration to remit the tumor hypoxia. Experiments show that LonCe will greatly improve the antitumor effect by O2‐economized photodynamic therapy regardless of the hypoxic microenvironment.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Arterial calcification is a key pathologic component of vascular diseases such as atherosclerosis, coronary artery disease, and peripheral vascular disease. A hallmark of this pathological process is ...the phenotypic transition of vascular smooth muscle cells (VSMCs) to osteoblast-like cells. Several studies have demonstrated that microRNAs (miRNAs) regulate osteoblast differentiation, but it is unclear whether miRNAs also regulate VSMC-mediated arterial calcification. In the present study, we sought to characterize the role of miR-133a in regulating VSMC-mediated arterial calcification. Northern blotting analysis of VSMCs treated with β-glycerophosphate demonstrated that miR-133a was significantly decreased during osteogenic differentiation. Overexpression of miR-133a inhibited VSMC transdifferentiation into osteoblast-like cells as evidenced by a decrease in alkaline phosphatase activity, osteocalcin secretion, Runx2 expression, and mineralized nodule formation. Conversely, the knockdown of miR-133a using an miR-133a inhibitor promoted osteogenic differentiation of VSMCs by increasing alkaline phosphatase activity, osteocalcin secretion, and Runx2 expression. Runx2 was identified as a direct target of miR-133a by a cotransfection experiment in VSMCs with luciferase reporter plasmids containing wild-type or mutant 3′-untranslated region sequences of Runx2. Furthermore, the pro-osteogenic effects of miR-133a inhibitor were abrogated in Runx2-knockdown cells, and the inhibition of osteogenic differentiation by pre–miR-133a was reversed by overexpression of Runx2, providing functional evidence that the effects of miR-133a in osteogenic differentiation were mediated by targeting Runx2. These results demonstrate that miR-133a is a key negative regulator of the osteogenic differentiation of VSMCs.
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