P73 antisense RNA 1 T (non-protein coding), also known as TP73-AS1, is a long non-coding RNA (lncRNA) which is involved in cell proliferation and the development of tumors. However, the exact effects ...and molecular mechanisms of TP73-AS1 in hepatocellular carcinoma (HCC) progression are still unknown. The present study is aimed to investigate the detailed functions and the mechanism of TP73-AS1 in regulation of HCC cell proliferation.
TP73-AS1 expression in HCC tissues and cell lines was determined using real-time PCR assays; the correlation of TP73-AS1 expression with clinicopathological features of HCC was analyzed. The functions of TP73-AS1 in regulation of HCC cell proliferation was evaluated using MTT and BrdU assays. The candidate upstream miRNAs of HMGB1 were screened using miRcode, miRWalk, miRanda and Target scan, verified using real-time PCR assays. The interaction between TP73-AS1 and miR-200a was confirmed using Luciferase report gene assays. The proten levels of HMGB1 signaling-related factors in response to co-processing TP73-AS1 knockdown and miR-200a inhibition were determined using Western blot assays and ELISA. Further, miR-200a, HMGB1 mRNA and RAGE mRNA and their correlations in HCC tissues were determined.
TP73-AS1 was upregulated in HCC tissues and cell lines. High TP73-AS1 expression was correlated with worse clinicopathological features, poorer prognosis and shorter survival. Knockdown of TP73-AS1 inhibited the HCC proliferation and the expression levels of HMGB1, RAGE and NF-κB in HCC cells. By using online tools, we screened out several candidate upstream miRNAs of HMGB1, among which miR-200a overexpression inhibited HMGB1 mRNA expression the most significantly. By using luciferase assays, we confirmed that miR-200a could directly bind to TP73-AS1 and the 3'UTR of HMGB1; TP73-AS1 competed with HMGB1 for miR-200a binding. MiR-200a inhibition could up-regulate HMGB1, RAGE, NF-κB expression as well as NF-κB regulated cytokines levels, which could be partially restored by si-TP73-AS1. In HCC tissues, miR-200a was down-regulated while HMGB1 and RAGE were up-regulated; TP73-AS1 was inversely correlated with miR-200a, while positively correlated with HMGB1 and RAGE, respectively.
Our data indicated that TP73-AS1 might be an oncogenic lncRNA that promoted proliferation of HCC and could be regarded as a therapeutic target in human HCC.
Emerging studies have suggested that the Hippo pathway is involved in the tumorigenesis of hepatocellular carcinoma (HCC). However, the key regulator of the Hippo pathway in liver tumor metabolic ...reprogramming remains elusive. Here, we provide evidence that high mobility group box 1 (HMGB1), a chromosomal protein, plays a role in the regulation of the Hippo pathway during liver tumorigenesis. Cre/loxP recombination‐mediated HMGB1 depletion in hepatocytes blocks diethylnitrosamine‐induced liver cancer initiation in mice, whereas short hairpin RNA‐mediated gene silencing of HMGB1 inhibits HCC cell proliferation. Mechanistically, the binding of HMGB1 to GA‐binding protein alpha promotes the expression of yes‐associated protein (YAP), a major downstream effector of the Hippo pathway that contributes to liver tumorigenesis by inducing hypoxia‐inducible factor 1α (HIF1α)‐dependent aerobic glycolysis. Like wild‐type YAP‐complementary DNA, YAP‐5SA‐S94A can restore HIF1α DNA binding activity, glycolysis‐associated gene expression, and HIF1α–YAP complex formation in YAP‐knockdown HCC cell lines. In contrast, verteporfin, a reagent targeting the interface between YAP and TEA domain transcription factor, has the ability to block YAP–HIF1α complex formation. Notably, genetic or pharmacologic inhibition of the HMGB1–YAP–HIF1α pathway confers protection against excessive glycolysis and tumor growth in mice. Conclusion: These findings demonstrate that HMGB1 plays a novel role in modulating the YAP‐dependent HIF1α pathway and shed light on the development of metabolism‐targeting therapeutics for HCC chemoprevention. (Hepatology 2018;67:1823‐1841)
Rechargeable aqueous zinc‐ion batteries (ZIBs) have attracted escalating attention recently, owing to their energy density, decreasing cost, advanced safety, and environmental benignity. ...Nevertheless, ZIBs still lack suitable cathode materials with stable cycling performance, owing to the high polarization of zinc ion. Therefore, developing candidate materials with excellent properties remains a great challenge. Herein, we successfully synthesize a novel Mn3O4@N‐doped carbon matrix composite nanorods (Mn3O4@NC Nrs) by using MnOOH nanorods (the self‐sacrifice templates) and polypyrrole (carbon and nitrogen source). Benefiting from the N‐doped carbon shell and the synergetic effect of Zn2+ and Mn2+ in the electrolyte, the Mn3O4@NC Nrs show superior cycling stability and long cycling features for ZIBs. Specifically, the zinc cell conducts a high reversible capacity of 280 mAh g−1 at 100 mA g−1 and retains a high reversible capacity of 97 mAh g−1 at 1000 mA g−1 after 700 cycles. In addition, the work provides a new approach to fabricate long‐term and high‐rate capability cathodes for ZIBs.
Rod for your own back: Mn3O4 on a new type of N‐doped carbon matrix support is prepared as a cathode material for zinc‐ion batteries. The N‐doped carbon matrix can relieve volume expansion and enhance the electron conductivity during the charge‐discharge process. Therefore, the Mn3O4@NC composite nanorods exhibit excellent electrochemical performances.
Background
Clear cell type hepatocellular carcinoma (HCC) is an uncommon neoplasm with an ambivalent prognosis compared to common type HCC.
Methods
First, patients with clear cell or common type HCC ...were enrolled from the Surveillance, Epidemiology, and End Results (SEER) database, and their demographic and clinical characteristics were identified. Next, overall survival (OS), disease‐specific survival (DSS), and subgroup analysis of the two types of HCC were performed. Next, we utilized a competing risk model to focus on cancer‐caused death. Finally, propensity score matching (PSM) was employed to reduce the confounding factors based on the histopathological type, and sensitivity analysis was conducted.
Results
A total of 205 cases of clear cell type HCC and 29,954 cases of common type HCC were enrolled in our study. Patients with clear cell type HCC were older and predominantly female than those with common type HCC. OS and DSS were not significantly different between the two groups, and histopathological type was not a prognostic factor of HCC, as verified by the competing risk model. Patient characteristics adjusted by PSM and sensitivity analysis confirmed this conclusion. In subgroup analysis, patients with clear cell type HCC at grade III ~ IV and with lymph nodes metastasis had a better prognosis compared to common type HCC.
Conclusions
This study revealed that the prognosis of clear cell type HCC is similar to common type HCC. Tumor differentiation grade and status of lymph node metastasis affect the prognosis of HCC.
Patients with HCC‐clear and HCC‐NOS were enrolled from the SEER database to identify demographic and clinical characteristics. Prognostic analyses were performed using OS, DSS, multivariate regression analysis, subgroup analysis, etc. Competing risk model and PSM were introduced for reducing confounding factors. Sensitivity analysis was included for conclusion validation.
Osteoarthritis (OA) is an inflammatory disease of the joints that causes progressive disability in the elderly. Reactive oxygen species (ROS) play an important role in OA development; they may ...activate the NLRP3 inflammasome, thereby inducing the secretion of proinflammatory IL-1β and IL-18, leading to the aggravation of the downstream inflammatory response. Nrf2 is a key transcription factor that regulates the expression of antioxidant enzymes that protect against oxidative stress and tissue damage. We aimed to explore the underlying mechanism of OA development by investigating NLRP3, ASC, Nrf2, and HO-1 expression in synovia and their regulatory networks in OA.
Human total knee replacement samples were subjected to histology and micro-CT analysis to determine the pathological changes in the cartilage and subchondral bone and to assess the expression of inflammation-related markers in the synovial tissue by immunohistochemistry (IHC), qRT-PCR, and Western blot. To investigate these pathological changes in an OA animal model, adult Sprague-Dawley rats were subjected to anterior cruciate ligament transection and medial meniscectomy. Articular cartilage and subchondral bone changes and synovial tissue were also determined by the same methods used for the human samples. Finally, SW982 cells were stimulated with lipopolysaccharide (LPS) as an in vitro inflammatory cell model. The correlation between NLRP3 and Nrf2 expression was confirmed by knocking down NLRP3 or Nrf2.
Cartilage destruction and subchondral bone sclerosis were found in the OA patients and OA model rats. Significantly increased expression levels of NLRP3, ASC, Nrf2, and HO-1 were found in the synovial tissue from OA patients. NLRP3, ASC, Nrf2, and HO-1 expression in the synovium was also upregulated in the OA group compared with the sham group. Furthermore, the NLRP3, Nrf2, HO-1, IL-1β, and IL-18 expression in LPS-treated SW982 cells was increased in a dose-dependent manner. As expected, the expression of NLRP3 was upregulated, and the expression of IL-1β and IL-18 was downregulated after Nrf2 silencing. However, knocking down NLRP3 did not affect the expression of Nrf2.
ROS-induced oxidative stress may be the main cause of NLRP3 inflammasome activation and subsequent release of downstream factors during OA development. Nrf2/HO-1 signaling could be a key pathway for the activation of the NLRP3 inflammasome, which may contribute to the progression of OA. Herein, we discovered a novel role of Nrf2/HO-1 signaling in the production of NLRP3, which may facilitate the prevention and treatment of OA.
Acute liver failure (ALF) is a severe liver disease with a high mortality rate without effective therapeutic drugs. Ferroptosis is a form of programmed cell death that plays an important role in ALF. ...In this study, we aimed to identify ferroptosis-related genes in ALF, thereby predicting promising compounds to treat ALF. First, mRNA microarray data were utilized to identify the ferroptosis-related differentially expressed genes (DEGs). Hub genes were screened in the protein-protein interaction network and validated. Subsequently, potential drugs to treat ALF were predicted. One of the predicted drugs was tested in an ALF model of mice. Ferroptosis examination and molecular docking were analyzed to explore the mechanism. A total of 37 DEGs were identified, ten hub genes were extracted, and their expression in ALF was validated. The predicted drug niclosamide mitigated lipopolysaccharide/D-galactosamine-induced hepatotoxicity, and decreased mortality of mice in the ALF model. Mechanically, niclosamide may combine with signal transducer and activator of transcription 3 to inhibit ALF progression by suppressing ferroptosis. This study may help advance our understanding of the role of ferroptosis in ALF, and niclosamide may be promising for therapeutic efficacy in patients with ALF.
•Alkali activated slag paste and mortar specimens were cured at 7–30°C.•Curing at below normal temperature retards the setting and shrinkage of AAS.•Curing at below normal temperature has little ...influence on later strength.•Paste becomes more compact with the increases of the curing temperature.•AAS paste cured at below-normal temperature for long age can develop to highly compact structure.
This work experimentally investigated the effects of curing temperatures (7, 15, 20 and 30°C) on the setting time, strength development, shrinkage, and microstructure of alkali activated slag (AAS). The results indicated that the impact of the curing temperature was much more significant on the setting time of AAS than on that of ordinary Portland cement (OPC), and 7°C curing could prolong the initial and final setting times of AAS without significant decrease of later strength, and increase the long-term strengths. The shrinkage of AAS were slightly reduced or retarded by curing at below normal temperature. There is no significant difference in the types of hydration products in the AAS pastes cured at 7–30°C for 28days, whereas the paste cured for same ages became more compact with lower porosity and finer pore size distribution as the curing temperature was increased.
During the Earth's magnetic reversal, the dipole component of the magnetic field weakens, and the non‐dipole component becomes dominant, resulting in a far more complex magnetospheric topology than ...that of a dipole. In this study, we used a particle tracing technique to investigate the motion of ions within an irregular magnetosphere during the Matuyama‐Brunhes magnetic polarity reversal. Compared to the scenario in which the geomagnetic field is dominated by a dipole component, earthward‐moving particles can be hardly “trapped” in the inner magnetosphere when the geomagnetic field experiences the polarity reversal, and particles can directly precipitate into the Earth's atmosphere on a global scale. It suggests that under an irregular magnetospheric configuration, the traditional trapped region of particles (e.g., radiation belt or ring current) no longer exists.
Plain Language Summary
During the Earth's paleomagnetic reversal, the strength of the Earth's magnetic field was approximately 10% of its current value, accompanied by a weakening of the dipole component and an enhancement of the non‐dipole component. Under the superposition of this non‐axisymmetric multipole magnetic field, the magnetospheric structures may undergo significant changes. How charged particles travel in such an irregular magnetosphere and how different their trajectories are compared to the well‐known textbook scenario are still unknown. In this study, by utilizing global MHD simulations and test‐particle tracing techniques, we trace the charged particle's trajectory within the magnetosphere during the Matuyama‐Brunhes magnetic polarity reversal. We found that under an irregular magnetosphere in the middle stage of the geomagnetic reversal, particles in the inner magnetosphere cannot be constantly trapped around the Earth. The traditional trapped region (e.g., radiation belt or ring current) no longer exists. Particles moving Earthward do not gain the same acceleration effect as those under the present‐day magnetic field topology, resulting in a globally distributed pattern of particle precipitation. These differences can affect the global energy deposition and particle distribution in near‐Earth space.
Key Points
We simulated charged particles' trajectories in the magnetosphere during the Matuyama‐Brunhes reversal
Particles cannot be “trapped” in an irregular magnetosphere
The irregular geomagnetic field results in global particle precipitation
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