Abstract Objective Receptor-activator of NF-κB ligand (TNFSF11, also known as RANKL) and its receptor RANK are essential regulators on bone remodeling, mammary gland development and ...hormone-associated breast cancer development. However, the expression pattern and role of RANKL/RANK axis in decidual stromal cells (DSCs) are unclear in human early pregnancy. Study design We analyzed RANKL/RANK expression in DSCs by real-time PCR, immunhistochemistry, enzyme-linked immunosorbent assay (ELISA) and flow cytometry, respectively. Then BrdU cell proliferation assay, flow cytometry assay and ELISA were performed to investigate the effect of recombinant human RANKL and DSCs-derived RANKL on the proliferation, apoptosis, chemokine (C-C motif) ligand 2 (CCL2) secretion, C-C chemokine receptor type 2 (CCR2) and other target proteins expression in DSCs in vitro , respectively. Results Here we show that DSCs co-express RANKL/RANK. Not only recombinant human (rh) RANKL but also the DSC-secreted RANKL stimulate proliferation and anti-apoptosis, and elevate CCL2 secretion and CCR2 expression of DSCs. Furthermore, the stimulatory effects on the proliferation, anti-apoptosis and the expression of Bcl-2 and Ki67 and inhibitory signaling on Fas ligand (FasL) in DSCs induced by RANKL can be partly reversed by the way of blocking CCL2 and or CCR2. Conclusions Our results have revealed that RANKL/RANK signal promotes Bcl-2 and Ki67 and decreases FasL expression, and further as a positive regulator for stimulating the proliferation and growth of DSCs through up-regulating CCL2/CCR2 signal, which finally contributes to the establishment and maintenance of physiological pregnancy.
Background and Purpose
Thioredoxin‐interacting protein (TXNIP), a regulator of cellular oxidative stress, has been associated with activation of NOD‐like receptor 3 (NLRP3) inflammasome, inflammation ...and lipid metabolism, suggesting it has a role in the pathogenesis of non‐alcoholic fatty liver disease (NAFLD) in diabetes. In this study we investigated whether TXNIP is involved in type 1 diabetes‐associated NAFLD and whether antioxidants, quercetin and allopurinol, alleviate NAFLD by targeting TXNIP.
Experimental Approach
Diabetes was induced in male Sprague‐Dawley rats by a single i.p. injection of 55 mg·kg−1 streptozotocin. Quercetin and allopurinol were given p.o. to diabetic rats for 7 weeks. Hepatic function, oxidative stress, inflammation and lipid levels were determined. Rat BRL‐3A and human HepG2 cells were exposed to high glucose (30 mM) in the presence and absence of antioxidants, TXNIP siRNA transfection or caspase‐1 inhibitor, Ac‐YVAD‐CMK.
Key Results
Quercetin and allopurinol significantly inhibited the TXNIP overexpression, activation of NLRP3 inflammasome, down‐regulation of PPARα and up‐regulation of sterol regulatory element binding protein‐1c (SREBP‐1c), SREBP‐2, fatty acid synthase and liver X receptor α, as well as elevation of ROS and IL‐1β in diabetic rat liver. These effects were confirmed in hepatocytes in vitro and it was further shown that TXNIP down‐regulation contributed to the suppression of NLRP3 inflammasome activation, inflammation and changes in PPARα and SREBPs.
Conclusions and Implications
Inhibition of hepatic TXNIP by quercetin and allopurinol contributes to the reduction in liver inflammation and lipid accumulation under hyperglycaemic conditions. The targeting of hepatic TXNIP by quercetin and allopurinol may have therapeutic implications for prevention of type 1 diabetes‐associated NAFLD.
The ionospheric scale height around the peak height of F2 layer （HmF2） is a very important parameter defining the profile of topside ionosphere. Based on observations of the EISCAT ESR radar, we ...statistically study the HmF2 at high latitudes. In order to derive the HmF2, a least square method is adopted to fit the electron density profile above the peak height of F2 layer （hmF2） from observations of the ESR radar. The result shows that it is in well agreement between the topside profiles deduced from the fitted HmF2 and the actual measuring topside profile with a height range from hmF2 to 300 km above the hmF2. Therefore, HmF2 can be considered as a constant in this range. With observations of the ESR between 1997 and 2008, we analyze the statistical characteristics of polar HmF2 with local time, season, and solar activity under quiet geomagnetic conditions （Kp≤2）, respectively. Variations of HmF2 in quiet days show a diurnal trend with a maximum in the morning and a minimum in the afternoon. The HmF2 always has the highest seasonal amplitude in summer under three kinds of solar activities. The seasonal magnitude of the HmF2 in winter remains between that in spring and that in autumn under low solar activity, while it is the lowest under moderate and high solar activities. We also compare measured HmF2 with those derived by IRI2007, which indicates that IRI2007 model can only approximately provide the average values of polar HmF2 in quiet days but is limited in presenting diurnal and solar activity variations of HmF2.
SiC@SiO
2
nanowires, as a functional nanocomposite, have attracted widespread attention due to their fascinating performance and broad application prospect. However, the low-cost, high yield ...preparation of large-scale SiC@SiO
2
nanowires is still a bottleneck, which hinders their industrial application. Herein, a carbothermal reduction strategy has been developed to synthesize SiC@SiO
2
nanowires, which breaks through the handicap of the traditional growth pattern that uses the aid of a substrate. Systematic characterization results illustrate that the yield of the as-obtained products greatly depends on the heating rate, and ten-gram scale SiC@SiO
2
nanowires (∼27.2 g) composed of a cubic β-SiC core and homogeneous amorphous SiO
2
coating are achieved under the optimum process parameters. The
in situ
mechanisms of expansion-insertion-growth and inhibition of expansion-package-obstruction are proposed to rationally interpret the growth process of SiC@SiO
2
nanowires and the effect of various heating rates, respectively. Furthermore, the SiC@SiO
2
nanowires display violet-blue photoluminescence and electromagnetic wave absorption properties. This study not only provides some beneficial suggestions for the commercial production of SiC@SiO
2
nanowires, but also reveals promising applications of SiC@SiO
2
nanowires in the optical and electromagnetic shielding fields. Moreover, the developed novel
in situ
growth mechanism enriches the growth theory of one-dimension nanomaterials and offers inspiration for their industrial-scale production.
SiC@SiO
2
nanowires, as a functional nanocomposite, have attracted widespread attention due to their fascinating performance and broad application prospect.
In this work, we report the in-orbit demonstration of X-ray pulsar navigation with Insight-Hard X-ray Modulation Telescope (Insight-HXMT) Satellite, which was launched on 2017 June 15. The new pulsar ...navigation method "Significance Enhancement of Pulse-profile with Orbit-dynamics" is adopted to determine the orbit with observations of only one pulsar. In this test, the Crab pulsar is chosen and observed by Insight-HXMT from 2017 August 31 to September 5. Using the five-day long observation data, the orbit of Insight-HXMT is determined successfully with the three telescopes onboard: High Energy X-ray Telescope, Medium Energy X-ray Telescope, and Low Energy X-ray Telescope, respectively. By combining all the data, the position and velocity of the Insight-HXMT are pinpointed to within 10 km (3 ) and 10 m s−1 (3 ), respectively.
Metaplastic breast cancer (MBC) is a rare disease, and there was rarely reported the treatment after recurrence and metastasis. Here, we report the treatment of an adult patient who suffered from MBC ...with lung, lymph nodes and left pleura metastasis after radical surgery. The next-generation sequencing result demonstrated that it had tumor mutational burden (TMB) of 12.0 Muts/Mb and microsatellite stability. The patient received sintilimab, an immune checkpoint inhibitor, plus chemotherapy and achieved partial response (PR). This is a report of a good outcome of metastatic MBC achieving 24 months of progression-free survival (PFS) and 39 months of overall survival (OS) with a combination therapy of immune checkpoint inhibitor and chemotherapy. Immunochemotherapy may have antitumor activity for relapse MBC. TMB may serve as a potential predictor associated with PD-1 inhibitors in MBC and help clinicians make an optimum treatment strategy. Keywords: metaplastic breast cancer, tumor mutational burden, immunotherapy, chemotherapy, progression-free survival, overall survival
Propionibacterium acnes plays a major role in acne vulgaris. In the pre‐experiment, the growth of P. acnes was inhibited effectively using surfactin; however, the antibacterial mechanism has not been ...described. Therefore, the aim of this study was to evaluate antibacterial activity and analyse the mechanism of surfactin against P. acnes. Minimum inhibitory concentration, time‐killing kinetics and scanning electron microscopy were used to evaluate the activity of surfactin against P. acnes, which showed that 128 μg ml−1 effectively inhibited growth. Cell wall permeability was evaluated by detecting the extracellular alkaline phosphatase activity, which increased to 1·83‐ and 2·32‐fold after incubating with 128 and 256 μg ml−1 of surfactin for 10 h, respectively. Propidium iodide fluorescence, leakage of nucleic acid, protein, K+, and Ca2+, membrane potential and the leakage of calcein from small unilamellar vesicles all increased after incubation with surfactin, indicating that its strong biological activities act mainly by altering membrane integrity. In a mouse model of acne, surfactin significantly reduced P. acnes–induced epidermal swelling and erythema. These results indicate that surfactin effectively inhibited the growth of P. acnes by destroying the cell wall and membrane, and is a potential candidate for acne treatment.
Significance and Impact of the Study: Surfactin has a wide range of targets, thus drug resistance development is difficult. This study clarified the antibacterial mechanism of surfactin against Propionibacterium acnes, which would benefit the development of acne cosmetics and cosmeceuticals, and provide a potential method for producing acne‐treating natural ingredients.
Clip domain serine proteases (CLIPs), characterized by one or more conserved clip domains, are essential components of extracellular signalling cascades in various biological processes, especially in ...innate immunity and the embryonic development of insects. Additionally, CLIPs may have additional non‐immune functions in insect development. In the present study, the clip domain serine protease gene Bombyx mori serine protease 95 (BmSP95), which encodes a 527‐residue protein, was cloned from the integument of B. mori. Bioinformatics analysis indicated that BmSP95 is a typical CLIP of the subfamily D and possesses a clip domain at the N terminus, a trypsin‐like serine protease (tryp_spc) domain at the C terminus and a conserved proline‐rich motif between these two domains. At the transcriptional level, BmSP95 is expressed in the integument during moulting and metamorphosis, and the expression pattern is consistent with the fluctuating 20‐hydroxyecdysone (20E) titre in B. mori. At the translational level, BmSP95 protein is synthesized in the epidermal cells, secreted as a zymogen and activated in the moulting fluid. Immunofluorescence revealed that BmSP95 is distributed into the old endocuticle in the moulting stage. The expression of BmSP95 was upregulated by 20E. Moreover, expression of BmSP95 was downregulated by pathogen infection. RNA interference‐mediated silencing of BmSP95 led to delayed moulting from pupa to moth. These results suggest that BmSP95 is involved in integument remodelling during moulting and metamorphosis.
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