Increasing evidence supports that ferroptosis plays an important role in tumor growth inhibition. Sorafenib, originally identified as an inhibitor of multiple oncogenic kinases, has been shown to ...induce ferroptosis in hepatocellular carcinoma (HCC). However, some hepatoma cell lines are less sensitive to sorafenib-induced ferroptotic cell death. Glutathione S-transferase zeta 1 (GSTZ1), an enzyme in the catabolism of phenylalanine, suppresses the expression of the master regulator of cellular redox homeostasis nuclear factor erythroid 2-related factor 2 (NRF2). This study aimed to investigate the role and underlying molecular mechanisms of GSTZ1 in sorafenib-induced ferroptosis in HCC. GSTZ1 was significantly downregulated in sorafenib-resistant hepatoma cells. Mechanistically, GSTZ1 depletion enhanced the activation of the NRF2 pathway and increased the glutathione peroxidase 4 (GPX4) level, thereby suppressing sorafenib-induced ferroptosis. The combination of sorafenib and RSL3, a GPX4 inhibitor, significantly inhibited GSTZ1-deficient cell viability and promoted ferroptosis and increased ectopic iron and lipid peroxides. In vivo, the combination of sorafenib and RSL3 had a synergic therapeutic effect on HCC progression in Gstz1
mice. In conclusion, this finding demonstrates that GSTZ1 enhanced sorafenib-induced ferroptosis by inhibiting the NRF2/GPX4 axis in HCC cells. Combination therapy of sorafenib and GPX4 inhibitor RSL3 may be a promising strategy in HCC treatment.
Aberrant glucose metabolism and elevated O-linked β-N-acetylglucosamine modification (O-GlcNAcylation) are hallmarks of hepatocellular carcinoma (HCC). Loss of phosphoenolpyruvate carboxykinase 1 ...(PCK1), the major rate-limiting enzyme of hepatic gluconeogenesis, increases hexosamine biosynthetic pathway (HBP)-mediated protein O-GlcNAcylation in hepatoma cell and promotes cell growth and proliferation. However, whether PCK1 deficiency and hyper O-GlcNAcylation can induce HCC metastasis is largely unknown. Here, gain- and loss-of-function studies demonstrate that PCK1 suppresses HCC metastasis in vitro and in vivo. Specifically, lysine acetyltransferase 5 (KAT5), belonging to the MYST family of histone acetyltransferases (HAT), is highly modified by O-GlcNAcylation in PCK1 knockout hepatoma cells. Mechanistically, PCK1 depletion suppressed KAT5 ubiquitination by increasing its O-GlcNAcylation, thereby stabilizing KAT5. KAT5 O-GlcNAcylation epigenetically activates TWIST1 expression via histone H4 acetylation, and enhances MMP9 and MMP14 expression via c-Myc acetylation, thus promoting epithelial-mesenchymal transition (EMT) in HCC. In addition, targeting HBP-mediated O-GlcNAcylation of KAT5 inhibits lung metastasis of HCC in hepatospecific Pck1-deletion mice. Collectively, our findings demonstrate that PCK1 depletion increases O-GlcNAcylation of KAT5, epigenetically induces TWIST1 expression and promotes HCC metastasis, and link metabolic enzyme, post-translational modification (PTM) with epigenetic regulation.
Abstract
Accumulating mutations in the SARS-CoV-2 Spike (S) protein can increase the possibility of immune escape, challenging the present COVID-19 prophylaxis and clinical interventions. Here, 3 ...receptor binding domain (RBD) specific monoclonal antibodies (mAbs), 58G6, 510A5 and 13G9, with high neutralizing potency blocking authentic SARS-CoV-2 virus display remarkable efficacy against authentic B.1.351 virus. Surprisingly, structural analysis has revealed that 58G6 and 13G9 both recognize the steric region S
470–495
on the RBD, overlapping the E484K mutation presented in B.1.351. Also, 58G6 directly binds to another region S
450–458
in the RBD. Significantly, 58G6 and 510A5 both demonstrate prophylactic efficacy against authentic SARS-CoV-2 and B.1.351 viruses in the transgenic mice expressing human ACE2 (hACE2), protecting weight loss and reducing virus loads. Together, we have evidenced 2 potent neutralizing Abs with unique mechanism targeting authentic SARS-CoV-2 mutants, which can be promising candidates to fulfill the urgent needs for the prolonged COVID-19 pandemic.
To evaluate long-term effect of biochar application on yield-scaled greenhouse gas emissions (YSGE) in a paddy rice cropping system, a 4-year field experiment by static chamber - gas chromatograph ...method was conducted in South China. Principal component analysis and terminal restriction fragment length polymorphism (T-RFLP) and real-time qPCR was used to unravel the microbial mechanisms of biochar addition. Six treatments were included: control (CK), application of 5tha−1 biochar (BC1), application of 10tha−1 biochar (BC2), application of 10tha−1 biochar (BC3), rice straw return at 2400kgha−1(RS) and inoculated rice straw return at 2400kgha−1(RI). The results indicated that biochar amendment significantly decreased methane (CH4) and gross greenhouse gas (GHG) emissions. This may primarily be ascribed to the stimulated biodiversity and abundance of methanotrophic microbes, increased soil pH and improved aeration by reducing bulk density after biochar incorporation. Compared with CK, RS and RI, 26.18%, 70.02%, 66.47% of CH4 flux and 26.14%, 70.16%, 66.46% of gross GHG emissions were reduced by biochar (mean of three biochar treatments), respectively. Furthermore, biochar significantly increased harvest index of double rice production (p<0.05). In comparison with CK, RS and RI, 29.14%, 68.04%, 62.28% of YSGE was reduced by biochar, respectively, and the highest biochar addition rate (20tha−1) contributed most to the mitigation of GHG emissions (36.24% decrease compared to CK) and improvement of rice yield (7.65% increase compared to CK). Results of our study suggested that long-term application of biochar should be the potential way to mitigate GHGs emissions and simultaneously improve rice productivity in the paddy rice system.
Relative change ratio of different biochar amendments and rice straw residues to CK treatment during the rice growing seasons from 2012 to 2015.
* and *** stand for significant at 0.05 and 0.001 probability level, respectively. Display omitted
•Biochar addition significantly reduced YSGE in paddy rice field.•Biochar stimulated biodiversity and abundance of methanotrophic microbes.•Biochar increased soil pH and aeration by reducing soil bulk density.•Genetic techniques excavated the microbial mechanisms of biochar effect.•Long-term effect of biochar favors both food security and low carbon agriculture.
Two open-top chambers (OTCs) experiments were conducted to assess the impacts of 2-year and 10-year warming on soil biochemistry in the alpine meadow on the Qinghai-Tibet Plateau (QTP) of China. The ...soil warming at 0.8–1.1 °C above the control in the two experiments did not significantly affect soil pH, bulk density, total carbon, nitrogen, phosphorus, organic carbon, available phosphorus, NO3-N, microbial biomass C, N, P, and cellulase, catalase, phosphatase activities. NH4-N and soil urease were significantly increased, but soil moisture was significantly reduced from both short and long-term warming. These findings suggested that short and long-term experimental warming might have the similar effects on soil nutrient levels, microbial biomass and enzyme activities in an alpine meadow ecosystem on the QTP.
•Impacts of short- and long-term warming on soil of alpine meadow were assessed.•Short- and long-term warming did not significantly affect most of soil biochemistry.•Both short- and long-term warming significantly increased NH4-N and soil urease.•Both short- and long-term warming significantly reduced soil moisture.
Solute carrier family 27 member 5 (SLC27A5/FATP5) is involved in fatty acid transport and bile acid metabolism; however, little is known about its role in human diseases. Here, we first show that ...SLC27A5 expression is downregulated in hepatocellular carcinoma (HCC) by DNA hypermethylation, and reduced SCL27A5 expression contributes to tumor progression and poor prognosis. Both gain- and loss-of-function studies demonstrated that SLC27A5 has an antiproliferative effect on HCC cells in vitro and in vivo. Knockout of SLC27A5 increases polyunsaturated lipids, leading to increased NADP
/NADPH ratio, ROS production as well as lipid peroxidation and the subsequent accumulation of 4-hydroxy-2-nonenal (4-HNE) in hepatoma cells. Mass spectrometry analysis found that 4-HNE directly modifies cysteine residues (Cys513, 518) on KEAP1, thus leading KEAP1/NRF2 pathway activation and increases the expression levels of NRF2 target genes, such as TXNRD1. Further, SLC27A5 expression negatively correlates with TXNRD1 expression in hepatoma cells and clinical HCC samples, and blockade of NRF2/TXNRD1 using genetic approaches or inhibitors sensitizes SLC27A5-deficient hepatoma cells to sorafenib treatment. Collectively, we demonstrated that SLC27A5 acts as a novel tumor suppressor by suppressing TXNRD1 expression via the KEAP1/NRF2 pathway in HCC. Combination therapy of sorafenib and NRF2/TXNRD1 inhibitors may be a promising strategy in personalized HCC treatment.
The combined impacts of modified nitrogen (N) fertilizers and water saving irrigation (WSI) on greenhouse gas (GHG) emissions and grain yield of rice paddies have not previously been documented. GHG ...emissions from rice paddies under modified N fertilizers and WSI deserve attention because water and N are being used extensively to attain higher grain yield. A field experiment was conducted to evaluate the influence of modified N fertilizers and WSI on methane (CH4) and nitrous oxide (N2O) emissions and grain yield in rice paddies. Four treatments were applied: urea with conventional irrigation (U+CI), urea with shallow water depth with alternate wetting-drying water saving irrigation (U+SWD), polymer-coated controlled release urea with SWD (CRU+SWD), and nitrapyrin-urea composition plus hydroquinone with SWD (NU+HQ+SWD). Compared to U+CI, CH4 emissions significantly decreased by 26% and 31%, and N2O emissions increased by 52% and 42% under U+SWD in the early and late rice growing seasons respectively (p<0.05). Although SWD increased N2O emissions, total GHG emissions (TGHG) reduced by 20% and 25% in the two rice seasons under U+SWD, and GHG emission intensity (GHGI) decreased by 24% on average. Modified N fertilizer applications also affected grain yield and GHG emissions under SWD. Compared with U+SWD, CRU+SWD and NU+HQ+SWD reduced CH4, N2O emissions and TGHG by 28–49%, 12–44% and 26–45%, respectively, while grain yield increased by 6–35%. Reduction in CH4 emissions occurred because, compared to urea, CRU and NU+HQ can inhibit CH4 production and transport by controlling development of invalid tillers, while their nitrogen release patterns were more favorable for CH4 consumption. In summary, modified N fertilizers in combination with SWD are a win-win strategy to improve grain production while reducing GHG emissions in the rice cropping system.
•Water saving irrigation significantly reduced CH4 and total GHG emissions in rice paddies.•Modified N fertilizers significantly reduced CH4 emissions by influencing CH4 production, oxidation, and transport.•Combination of water saving irrigation and modified N fertilizers further reduce GHG emissions while improving rice yield.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative virus of the coronavirus disease 2019 (COVID-19) pandemic. To establish a safe and convenient assay system for studying ...entry inhibitors and neutralizing antibodies against SARS-CoV-2, we constructed a codon-optimized, full-length C-terminal mutant spike (S) gene of SARS-CoV-2. We generated a luciferase (Luc)-expressing pseudovirus containing the wild-type or mutant S protein of SARS-CoV-2 in the envelope-defective HIV-1 backbone. The key parameters for this pseudovirus-based assay, including the S mutants and virus incubation time, were optimized. This pseudovirus contains a Luc reporter gene that enabled us to easily quantify virus entry into angiotensin-converting enzyme 2 (ACE2)-expressing 293T cells. Cathepsin (Cat)B/L inhibitor E−64d could significantly block SARS-CoV-2 pseudovirus infection in 293T-ACE2 cells. Furthermore, the SARS-CoV-2 spike pseudotyped virus could be neutralized by sera from convalescent COVID-19 patients or recombinant ACE2 with the fused Fc region of human IgG1. Thus, we developed a pseudovirus-based assay for SARS-CoV-2, which will be valuable for evaluating viral entry inhibitors and neutralizing antibodies against this highly pathogenic virus.
Grassland cover is strongly influenced by climate change. The response of grassland cover to climate change becomes complex with background climate. There have been some advances in research on the ...sensitivity of grassland vegetation to climate change around the world, but the differences in climate sensitivity among grassland types are still unclear in alpine grassland. Therefore, we applied MODIS NDVI data and trend analysis methods to quantify the spatial and temporal variation of grassland vegetation cover on the Qinghai-Tibet Plateau. Then, we used multiple regression models to analyze the sensitivity of fractional vegetation cover (FVC) to climatic factors (Temperature, Precipitation, Solar radiation, Palmer drought severity index) and summarized the potential mechanisms of vegetation sensitivity to different climatic gradients. Our results showed (1) a significant increasing trend in alpine desert FVC from 2000–2018 (1.12 × 10−3/a, R2 = 0.56, p < 0.001) but no significant trend in other grassland types. (2) FVC sensitivity to climatic factors varied among grassland types, especially in the alpine desert, which had over 60% of the area with positive sensitivity to temperature, precipitation and PDSI. (3) The sensitivity of grassland FVC to heat factors decreases with rising ambient temperature while the sensitivity to moisture increases. Similarly, the sensitivity to moisture decreases while the sensitivity to thermal factors increases along the moisture gradient. Furthermore, the results suggest that future climate warming will promote grassland in cold and wet areas of the Qinghai-Tibet Plateau and may suppress vegetation in warmer areas. In contrast, the response of the alpine desert to future climate is more stable. Studying the impact of climate variation at a regional scale could enhance the adaptability of vegetation in future global climates.
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