Publications by authors named "Liu Cao"

202 Publications

Autophagy receptor CCDC50 tunes the STING-mediated interferon response in viral infections and autoimmune diseases.

Cell Mol Immunol 2021 Aug 27. Epub 2021 Aug 27.

MOE Key Laboratory of Tropical Disease Control, Centre for Infection and Immunity Study (CIIS), School of Medicine, Sun Yat-sen University, Shenzhen, China.

DNA sensing and timely activation of interferon (IFN)-mediated innate immunity are crucial for the defense against DNA virus infections and the clearance of abnormal cells. However, overactivation of immune responses may lead to tissue damage and autoimmune diseases; therefore, these processes must be intricately regulated. STING is the key adaptor protein, which is activated by cyclic GMP-AMP, the second messenger derived from cGAS-mediated DNA sensing. Here, we report that CCDC50, a newly identified autophagy receptor, tunes STING-directed type I IFN signaling activity by delivering K63-polyubiquitinated STING to autolysosomes for degradation. Knockout of CCDC50 significantly increases herpes simplex virus 1 (HSV-1)- or DNA ligand-induced production of type I IFN and proinflammatory cytokines. Ccdc50-deficient mice show increased production of IFN, decreased viral replication, reduced cell infiltration, and improved survival rates compared with their wild-type littermates when challenged with HSV-1. Remarkably, the expression of CCDC50 is downregulated in systemic lupus erythematosus (SLE), a chronic autoimmune disease. CCDC50 levels are negatively correlated with IFN signaling pathway activation and disease severity in human SLE patients. CCDC50 deficiency potentiates the cGAS-STING-mediated immune response triggered by SLE serum. Thus, our findings reveal the critical role of CCDC50 in the immune regulation of viral infections and autoimmune diseases and provide insights into the therapeutic implications of CCDC50 manipulation.
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http://dx.doi.org/10.1038/s41423-021-00758-wDOI Listing
August 2021

Berberine modulates deacetylation of PPARγ to promote adipose tissue remodeling and thermogenesis via AMPK/SIRT1 pathway.

Int J Biol Sci 2021 25;17(12):3173-3187. Epub 2021 Jul 25.

College of Basic Medical Science, Institute of Translational Medicine, Key Laboratory of Medical Cell Biology, Ministry of Education, Key Laboratory of Liaoning Province, China Medical University, Shenyang, Liaoning Province, P.R. China, 110122.

Pharmacological stimulation of adipose tissue remodeling and thermogenesis to increase energy expenditure is expected to be a viable therapeutic strategy for obesity. Berberine has been reported to have pharmacological activity in adipose tissue to anti-obesity, while the mechanism remains unclear. Here, we observed that berberine significantly reduced the body weight and insulin resistance of high-fat diet mice by promoting the distribution of brown adipose tissue and thermogenesis. We have further demonstrated that berberine activated energy metabolic sensing pathway AMPK/SIRT1 axis to increase the level of PPARγ deacetylation, which leads to promoting adipose tissue remodeling and increasing the expression of the thermogenic protein UCP-1. These findings suggest that berberine that enhances the AMPK/SIRT1 pathway can act as a selective PPARγ activator to promote adipose tissue remodeling and thermogenesis. This study proposes a new mechanism for the regulation of berberine in adipose tissue and offers a great prospect for berberine in obesity treatment.
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http://dx.doi.org/10.7150/ijbs.62556DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8375237PMC
July 2021

ATM at the crossroads of reactive oxygen species and autophagy.

Int J Biol Sci 2021 22;17(12):3080-3090. Epub 2021 Jul 22.

College of Basic Medical Science, Key Laboratory of Medical Cell Biology, Ministry of Education, Key Laboratory of Liaoning Province, China Medical University, Shenyang, Liaoning Province, 110122, P. R. China.

Reactive oxygen species (ROS) are generally small, short-lived and highly reactive molecules, initially thought to be a pathological role in the cell. A growing amount of evidence in recent years argues for ROS functioning as a signaling intermediate to facilitate cellular adaptation in response to pathophysiological stress through the regulation of autophagy. Autophagy is an essential cellular process that plays a crucial role in recycling cellular components and damaged organelles to eliminate sources of ROS in response to various stress conditions. A large number of studies have shown that DNA damage response (DDR) transducer ataxia-telangiectasia mutated (ATM) protein can also be activated by ROS, and its downstream signaling pathway is involved in autophagy regulation. This review aims at providing novel insight into the regulatory mechanism of ATM activated by ROS and its molecular basis for inducing autophagy, and revealing a new function that ATM can not only maintain genome homeostasis in the nucleus, but also as a ROS sensor trigger autophagy to maintain cellular homeostasis in the cytoplasm.
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http://dx.doi.org/10.7150/ijbs.63963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8375236PMC
July 2021

Live attenuated coronavirus vaccines deficient in N7-Methyltransferase activity induce both humoral and cellular immune responses in mice.

Emerg Microbes Infect 2021 Dec;10(1):1626-1637

State Key Laboratory of Virology, Modern Virology Research Center, Institute for Vaccine Research, RNA Institute, College of Life Sciences, Wuhan University, Wuhan, People's Republic of China.

Coronaviruses (CoVs) can infect a variety of hosts, including humans, livestock and companion animals, and pose a serious threat to human health and the economy. The current COVID-19 pandemic, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has killed millions of people. Unfortunately, effective treatments for CoVs infection are still lacking, suggesting the importance of coronavirus vaccines. Our previous work showed that CoV nonstuctural protein 14 (nsp14) functions as (guanine-N7)-methyltransferase (N7-MTase), which is involved in RNA cap formation. Moreover, we found that N7-MTase is well conserved among different CoVs and is a universal target for developing antivirals against CoVs. Here, we show that N7-MTase of CoVs can be an ideal target for designing live attenuated vaccines. Using murine hepatitis virus strain A59 (MHV-A59), a representative and well-studied model of coronaviruses, we constructed N7-MTase-deficient recombinant MHV D330A and Y414A. These two mutants are highly attenuated in mice and exhibit similar replication efficiency to the wild-type (WT) virus in the cell culture. Furthermore, a single dose immunization of D330A or Y414A can induce long-term humoral immune responses and robust CD4 and CD8 T cell responses, which can provide full protection against the challenge of a lethal-dose of MHV-A59. Collectively, this study provides an ideal strategy to design live attenuated vaccines for coronavirus by abolishing viral RNA N7-MTase activity. This approach may apply to other RNA viruses that encode their own conservative viral N7-methyltransferase.
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http://dx.doi.org/10.1080/22221751.2021.1964385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8381960PMC
December 2021

Genome-wide analysis of protein-protein interactions and involvement of viral proteins in SARS-CoV-2 replication.

Cell Biosci 2021 Jul 22;11(1):140. Epub 2021 Jul 22.

The Center for Infection and Immunity Study and Molecular Cancer Research Center, School of Medicine, Sun Yat-Sen University, Guangming Science City, Shenzhen, 518107, China.

Background: Analysis of viral protein-protein interactions is an essential step to uncover the viral protein functions and the molecular mechanism for the assembly of a viral protein complex. We employed a mammalian two-hybrid system to screen all the viral proteins of SARS-CoV-2 for the protein-protein interactions.

Results: Our study detected 48 interactions, 14 of which were firstly reported here. Unlike Nsp1 of SARS-CoV, Nsp1 of SARS-CoV-2 has the most interacting partners among all the viral proteins and likely functions as a hub for the viral proteins. Five self-interactions were confirmed, and five interactions, Nsp1/Nsp3.1, Nsp3.1/N, Nsp3.2/Nsp12, Nsp10/Nsp14, and Nsp10/Nsp16, were determined to be positive bidirectionally. Using the replicon reporter system of SARS-CoV-2, we screened all viral Nsps for their impacts on the viral replication and revealed Nsp3.1, the N-terminus of Nsp3, significantly inhibited the replicon reporter gene expression. We found Nsp3 interacted with N through its acidic region at N-terminus, while N interacted with Nsp3 through its NTD, which is rich in the basic amino acids. Furthermore, using purified truncated N and Nsp3 proteins, we determined the direct interactions between Nsp3 and N protein.

Conclusions: Our findings provided a basis for understanding the functions of coronavirus proteins and supported the potential of interactions as the target for antiviral drug development.
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http://dx.doi.org/10.1186/s13578-021-00644-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8295636PMC
July 2021

MS2Planner: improved fragmentation spectra coverage in untargeted mass spectrometry by iterative optimized data acquisition.

Bioinformatics 2021 07;37(Suppl_1):i231-i236

Computational Biology Department, Carnegie Mellon University, Pittsburgh, PA 15213, USA.

Motivation: Untargeted mass spectrometry experiments enable the profiling of metabolites in complex biological samples. The collected fragmentation spectra are the metabolite's fingerprints that are used for molecule identification and discovery. Two main mass spectrometry strategies exist for the collection of fragmentation spectra: data-dependent acquisition (DDA) and data-independent acquisition (DIA). In the DIA strategy, all the metabolites ions in predefined mass-to-charge ratio ranges are co-isolated and co-fragmented, resulting in multiplexed fragmentation spectra that are challenging to annotate. In contrast, in the DDA strategy, fragmentation spectra are dynamically and specifically collected for the most abundant ions observed, causing redundancy and sub-optimal fragmentation spectra collection. Yet, DDA results in less multiplexed fragmentation spectra that can be readily annotated.

Results: We introduce the MS2Planner workflow, an Iterative Optimized Data Acquisition strategy that optimizes the number of high-quality fragmentation spectra over multiple experimental acquisitions using topological sorting. Our results showed that MS2Planner increases the annotation rate by 38.6% and is 62.5% more sensitive and 9.4% more specific compared to DDA.

Availability And Implementation: MS2Planner code is available at https://github.com/mohimanilab/MS2Planner. The generation of the inclusion list from MS2Planner was performed with python scripts available at https://github.com/lfnothias/IODA_MS.

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btab279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8336448PMC
July 2021

Passive Immunization of Chickens with Anti-Enterobactin Egg Yolk Powder for Control.

Vaccines (Basel) 2021 Jun 1;9(6). Epub 2021 Jun 1.

Department of Animal Science, The University of Tennessee, Knoxville, TN 37996, USA.

Enterobactin (Ent) is a highly conserved and important siderophore for the growth of many Gram-negative bacterial pathogens. Therefore, targeting Ent for developing innovative intervention strategies has attracted substantial research interest in recent years. Recently, we developed a novel Ent conjugate vaccine that has been demonstrated to be effective for controlling Gram-negative pathogens using both in vitro and in vivosystems. In particular, active immunization of chickens with the Ent conjugate vaccine elicited strong immune responses and significantly reduced intestinal colonization of , the leading foodborne bacterial pathogen. Given that hyperimmune egg yolk immunoglobulin Y (IgY) has been increasingly recognized as a promising and practical non-antibiotic approach for passive immune protection against pathogens in livestock, in this study, we assessed the efficacy of oral administration of broiler chickens with the anti-Ent hyperimmune egg yolk powder to control colonization in the intestine. However, supplementation of feed with 2% (/) of anti-Ent egg yolk powder failed to reduce colonization when compared to the control group. Consistent with this finding, the ELISA titers of the specific IgY in cecum, ileum, duodenum, gizzard, and serum contents were similar between the two groups throughout the trial. Chicken intestinal microbiota also did not change in response to the egg yolk powder treatment. Subsequently, to examine ex vivo stability of the egg yolk IgY, the chicken gizzard and duodenum contents from two independent sources were spiked with the egg yolk antibodies, incubated at 42 °C for different lengths of time, and subjected to ELISA analysis. The specific IgY titers were dramatically decreased in gizzard contents (up to 2048-fold) but were not changed in duodenum contents. Collectively, oral administration of broiler chickens with the anti-Ent egg yolk powder failed to confer protection against intestinal colonization of , which was due to instability of the IgY in gizzard contents as demonstrated by both in vivo and ex vivo evidence.
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http://dx.doi.org/10.3390/vaccines9060569DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8230082PMC
June 2021

Prediction of harmful algal blooms in large water bodies using the combined EFDC and LSTM models.

J Environ Manage 2021 Oct 23;295:113060. Epub 2021 Jun 23.

College of Water Sciences, Beijing Normal University, Beijing, 100875, China.

Harmful algal blooms (HABs) is a worldwide water environmental problem. HABs usually happens in short time and is difficult to be controlled. Early warning of HABs using data-driven models is prospective in making time for taking precaution against HABs. High-frequency water quality monitoring data are necessary to improve the reliability of the model, but it is expensive. This research used environmental fluid dynamics code (EFDC) to extend one-point data obtained by only one instrument to the whole 249 ha water area instead of multi-instruments monitoring, followed by Long short-term memory (LSTM) to predict the HABs in the whole water body. Correlation analysis and principal component analysis were used to reduce the data dimension and improve model accuracy. Finally, the LSTM model was calibrated to predict chlorophyll-a (Chl-a) for the next 1 to 3 time steps. The Nash-Sutcliffe efficiency coefficient (NSE) and mean absolute percentage error (MAPE) of EFDC-LSTM were 0.797-0.991 and 2.74-13.16%, respectively, suggesting the promising utilization of this model in early warning systems for HABs. EFDC-LSTM achieves high-precision HABs forecasting in a cost-effective manner, providing a reliable way to detect HABs in advance.
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http://dx.doi.org/10.1016/j.jenvman.2021.113060DOI Listing
October 2021

Endogenous reverse transcriptase and RNase H-mediated antiviral mechanism in embryonic stem cells.

Cell Res 2021 Sep 22;31(9):998-1010. Epub 2021 Jun 22.

Centre for Infection and Immunity Study (CIIS), School of Medicine (Shenzhen), Sun Yat-sen University, Guangzhou, Guangdong, China.

Nucleic acid-based systems play important roles in antiviral defense, including CRISPR/Cas that adopts RNA-guided DNA cleavage to prevent DNA phage infection and RNA interference (RNAi) that employs RNA-guided RNA cleavage to defend against RNA virus infection. Here, we report a novel type of nucleic acid-based antiviral system that exists in mouse embryonic stem cells (mESCs), which suppresses RNA virus infection by DNA-mediated RNA cleavage. We found that the viral RNA of encephalomyocarditis virus can be reverse transcribed into complementary DNA (vcDNA) by the reverse transcriptase (RTase) encoded by endogenous retrovirus-like elements in mESCs. The vcDNA is negative-sense single-stranded and forms DNA/RNA hybrid with viral RNA. The viral RNA in the heteroduplex is subsequently destroyed by cellular RNase H1, leading to robust suppression of viral growth. Furthermore, either inhibition of the RTase activity or depletion of endogenous RNase H1 results in the promotion of virus proliferation. Altogether, our results provide intriguing insights into the antiviral mechanism of mESCs and the antiviral function of endogenized retroviruses and cellular RNase H. Such a natural nucleic acid-based antiviral mechanism in mESCs is referred to as ERASE (endogenous RTase/RNase H-mediated antiviral system), which is an addition to the previously known nucleic acid-based antiviral mechanisms including CRISPR/Cas in bacteria and RNAi in plants and invertebrates.
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http://dx.doi.org/10.1038/s41422-021-00524-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217788PMC
September 2021

Adipose-derived stem cells regulate metabolic homeostasis and delay aging by promoting mitophagy.

FASEB J 2021 07;35(7):e21709

Department of Plastic Surgery, China Medical University the First Hospital, Shenyang, P.R. China.

Tissues undergo a process of degeneration as the body ages. Mesenchymal stem cells (MSCs) have been found to have major potential in delaying the aging process in tissues and organs. However, the mechanism underlying the anti-aging effects of MSC is not clear which limits clinical applications. In this study, we used adipose-derived mesenchymal stem cells (ADSCs) to perform anti-aging treatments on senescent cells and progeroid animal models. Following intervention with ADSCs, replicative senescence was delayed and metabolic homeostasis was transformed from catabolism to anabolism. Metabolomic tests were used to analyze different metabolites. We found that ADSCs acted to accelerate mitophagy which eliminated intracellular ROS and improved the quality of mitochondria. These processes acted to regulate the cellular metabolic homeostasis and ultimately delayed the process of aging. Allogeneic stem cell therapy in a Progeria animal model (DNA polymerase gamma (POLG) knockin, mitochondrial dysfunction) also showed that ADSC therapy can improve alopecia and kyphosis by promoting mitophagy. Our research confirms for the first time that allogeneic stem cell therapy can improve aging-related symbols and phenotypes through mitochondrial quality control. These results are highly significant for the future applications of stem cells in aging-related diseases.
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http://dx.doi.org/10.1096/fj.202100332RDOI Listing
July 2021

Particle counting based on high-order Fano resonance in an optofluidic microcavity.

Appl Opt 2021 Jun;60(16):4856-4860

We demonstrate particle counting based on high-order Fano resonance (FR) in an optofluidic microcavity. The high-order FR excited by a thin fiber taper can penetrate the liquid core of a microcapillary. An optical pulse is generated due to the resonant spectrum shift when a particle crosses the microcavity. Analogous to other methods, such a pulse can be used for particle counting. The sampled particles of PS microspheres and super-absorbent polymer broken beads are used for particle-counting experiments. All results confirm the feasibility of such a counting method.
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http://dx.doi.org/10.1364/AO.423321DOI Listing
June 2021

MolDiscovery: learning mass spectrometry fragmentation of small molecules.

Nat Commun 2021 06 17;12(1):3718. Epub 2021 Jun 17.

Carnegie Mellon University, Pittsburgh, PA, USA.

Identification of small molecules is a critical task in various areas of life science. Recent advances in mass spectrometry have enabled the collection of tandem mass spectra of small molecules from hundreds of thousands of environments. To identify which molecules are present in a sample, one can search mass spectra collected from the sample against millions of molecular structures in small molecule databases. The existing approaches are based on chemistry domain knowledge, and they fail to explain many of the peaks in mass spectra of small molecules. Here, we present molDiscovery, a mass spectral database search method that improves both efficiency and accuracy of small molecule identification by learning a probabilistic model to match small molecules with their mass spectra. A search of over 8 million spectra from the Global Natural Product Social molecular networking infrastructure shows that molDiscovery correctly identify six times more unique small molecules than previous methods.
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http://dx.doi.org/10.1038/s41467-021-23986-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8211649PMC
June 2021

Prenatal phthalate exposure reduction through an integrated intervention strategy.

Environ Sci Pollut Res Int 2021 Jun 4. Epub 2021 Jun 4.

School of Laboratory Medicine, Hubei University of Chinese Medicine, 16 Huangjia Lake West Road, Wuhan, 430065, China.

Pregnancy represents a sensitive susceptibility window to phthalate esters (PAEs). In this study, we develop an intervention strategy for reducing the exposure of pregnant women to phthalates. Thirty-five pregnant women, who initially underwent maternity examination, were recruited from an ongoing longitudinal prospective prenatal cohort study. The intervention strategy integrates diet, lifestyle, and environmental factors. Participants were encouraged to modify their behaviors and habits according to the intervention strategy at three different periods. Urine samples were collected from the participants after antenatal examination every month, for 8 months, to measure ten PAE metabolites. Mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono-n-butyl phthalate (MnBP), and mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP) declined significantly after the 1st intervention, while mono-isobutyl phthalate (MiBP) and mono-methyl phthalate (MMP) noticeably decreased after the 2nd intervention. The sum of the molar concentrations of MEHP, MEHHP, MEOHP, and MECPP reduced by 20 to 40% during subsequent intervention. In addition, the sum of the molar concentrations of MEP, MnBP, MMP, and MiBP as well as the sum of the molar concentrations of the ten metabolites also reduced. Our findings suggest that intervention through written recommendations can effectively reduce the burden of phthalates during pregnancy.
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http://dx.doi.org/10.1007/s11356-021-14613-yDOI Listing
June 2021

A Convenient and Biosafe Replicon with Accessory Genes of SARS-CoV-2 and Its Potential Application in Antiviral Drug Discovery.

Virol Sin 2021 May 17. Epub 2021 May 17.

The Center for Infection and Immunity Study, School of Medicine, Sun Yat-sen University, Guangming Science City, Shenzhen, 518107, China.

SARS-CoV-2 causes the pandemic of COVID-19 and no effective drugs for this disease are available thus far. Due to the high infectivity and pathogenicity of this virus, all studies on the live virus are strictly confined in the biosafety level 3 (BSL3) laboratory but this would hinder the basic research and antiviral drug development of SARS-CoV-2 because the BSL3 facility is not commonly available and the work in the containment is costly and laborious. In this study, we constructed a reverse genetics system of SARS-CoV-2 by assembling the viral cDNA in a bacterial artificial chromosome (BAC) vector with deletion of the spike (S) gene. Transfection of the cDNA into cells results in the production of an RNA replicon that keeps the capability of genome or subgenome replication but is deficient in virion assembly and infection due to the absence of S protein. Therefore, such a replicon system is not infectious and can be used in ordinary biological laboratories. We confirmed the efficient replication of the replicon by demonstrating the expression of the subgenomic RNAs which have similar profiles to the wild-type virus. By mutational analysis of nsp12 and nsp14, we showed that the RNA polymerase, exonuclease, and cap N7 methyltransferase play essential roles in genome replication and sgRNA production. We also created a SARS-CoV-2 replicon carrying a luciferase reporter gene and this system was validated by the inhibition assays with known anti-SARS-CoV-2 inhibitors. Thus, such a one-plasmid system is biosafe and convenient to use, which will benefit both fundamental research and development of antiviral drugs.
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http://dx.doi.org/10.1007/s12250-021-00385-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8127439PMC
May 2021

MicroRNA-370 carried by M2 macrophage-derived exosomes alleviates asthma progression through inhibiting the FGF1/MAPK/STAT1 axis.

Int J Biol Sci 2021 23;17(7):1795-1807. Epub 2021 Apr 23.

Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang 110004, China.

Emerging evidence has suggested the functions of exosomes in allergic diseases including asthma. By using a mouse model with asthma induced by ovalbumin (OVA), we explored the roles of M2 macrophage-derived exosomes (M2Φ-Exos) in asthma progression. M2Φ-Exos significantly alleviated OVA-induced fibrosis and inflammatory responses in mouse lung tissues, as well as inhibited abnormal proliferation, invasion, and fibrosis-related protein production in platelet derived growth factor (PDGF-BB) treated primary mouse airway smooth muscle cells (ASMCs). The OVA administration in mice or the PDGF-BB treatment in ASMCs reduced the expression of miR-370, which was detected in M2Φ-Exos by miRNA sequencing. However, treating the mice or ASMCs with M2Φ-Exos reversed the inhibitory effect of OVA or PDGF-BB on miR-370 expression. We identified that the target of miR-370 was fibroblast growth factor 1 (). Downregulation of miR-370 by Lv-miR-370 inhibitor or overexpression of FGF1 by Lv-FGF1 blocked the protective roles of M2Φ-Exos in asthma-like mouse and cell models. M2Φ-Exos were found to inactivate the MAPK signaling pathway, which was recovered by miR-370 inhibition or FGF1 overexpression. Collectively, we conclude that M2Φ-Exos carry miR-370 to alleviate asthma progression through downregulating FGF1 expression and the MAPK/STAT1 signaling pathway. Our study may offer a novel insight into asthma treatment.
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http://dx.doi.org/10.7150/ijbs.59715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120458PMC
April 2021

A review on China's constructed wetlands in recent three decades: Application and practice.

J Environ Sci (China) 2021 Jun 11;104:53-68. Epub 2020 Dec 11.

State Key Laboratory of Environmental Aquatic Chemistry, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China; University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address:

Constructed wetlands (CWs) have been introduced to and developed in China for environmental engineering over the most prosperous three decades (1990-2020). To study the origin, development process, and future trend of CWs, this review summarized a wide range of literatures between 1990 and 2020 by Chinese authors. Firstly, the publication number over years, research highlights, and the author contributions with the most published papers in this field were conducted through bibliometric analysis. Secondly, the most principal components of CWs, substrates and macrophytes were summarized and analyzed. Thirdly, the typical application cases from traditional CWs, pond systems to combined pond-wetland systems were presented. In China, CWs were predominately distributed in the east of the so-called 'Hu Huanyong Line'. Therefore CWs were limited by the socio-economic level and climatic conditions. It is unquestionable that the overall level of China's CWs has improved significantly, and one of the most prominent features has started towards the plural pattern development. There has been a trend of large-scale or low-cost CW application in the recent years. However, lifecycle research and management are required for better strategies in the future.
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http://dx.doi.org/10.1016/j.jes.2020.11.032DOI Listing
June 2021

CoS nanoparticles-embedded porous carbon: A highly efficient sorbent for mercury capture from nonferrous smelting flue gas.

J Hazard Mater 2021 06 25;412:124970. Epub 2020 Dec 25.

School of Metallurgy and Environment, Central South University, Changsha 410083, China; Chinese National Engineering Research Center for Control & Treatment of Heavy Metal Pollution, Changsha 410083, China. Electronic address:

In this study, a novel CoS nanoparticles-embedded porous carbon (CoS-PC) was designed as an effective reusable sorbent for Hg capture from smelting flue gas. Some flue gas components can create more active sites on CoS-PC for Hg adsorption, but compete with Hg for the same sulfur sites over nano CoS/CoS (CoS) and CoS/CoS embedded porous carbon (CoS-PC), which can be ascribed to the difference in crystal structure between CoS and CoS/CoS. Therefore, CoS-PC shows much better Hg capture ability than CoS and CoS-PC under smelting flue gas. O, SO and HCl improve Hg adsorption on CoS-PC mainly through creating Co site, but HO has neglectable effect on Hg capture. CoS-PC shows a remarkably large Hg adsorption capacity of 43.18 mg/g, which is greatly higher than the representative metal sulfides for Hg removal from smelting flue gas. During Hg adsorption, Co is the primary site to directly interact with Hg, and the adsorbed mercury exists as HgS. CoS-PC exhibits an excellent recyclability for capturing Hg, which is mainly assigned to the replenishment of consumed Co site by O, SO and HCl. Therefore, CoS nanoparticles-embedded porous carbon is an efficient, sustainable and highly recyclable sorbent for Hg recovery from smelting flue gas.
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http://dx.doi.org/10.1016/j.jhazmat.2020.124970DOI Listing
June 2021

The deacetylation-phosphorylation regulation of SIRT2-SMC1A axis as a mechanism of antimitotic catastrophe in early tumorigenesis.

Sci Adv 2021 Feb 24;7(9). Epub 2021 Feb 24.

Department of Pathology, School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35249-7331, USA.

Improper distribution of chromosomes during mitosis can contribute to malignant transformation. Higher eukaryotes have evolved a mitotic catastrophe mechanism for eliminating mitosis-incompetent cells; however, the signaling cascade and its epigenetic regulation are poorly understood. Our analyses of human cancerous tissue revealed that the NAD-dependent deacetylase SIRT2 is up-regulated in early-stage carcinomas of various organs. Mass spectrometry analysis revealed that SIRT2 interacts with and deacetylates the structural maintenance of chromosomes protein 1 (SMC1A), which then promotes SMC1A phosphorylation to properly drive mitosis. We have further demonstrated that inhibition of SIRT2 activity or continuously increasing SMC1A-K579 acetylation causes abnormal chromosome segregation, which, in turn, induces mitotic catastrophe in cancer cells and enhances their vulnerability to chemotherapeutic agents. These findings suggest that regulation of the SIRT2-SMC1A axis through deacetylation-phosphorylation permits escape from mitotic catastrophe, thus allowing early precursor lesions to overcome oncogenic stress.
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http://dx.doi.org/10.1126/sciadv.abe5518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904255PMC
February 2021

PolG Inhibits Gastric Cancer Glycolysis and Viability by Suppressing PKM2 Phosphorylation.

Cancer Manag Res 2021 16;13:1559-1570. Epub 2021 Feb 16.

Department of Plastic Surgery, China Medical University the First Hospital, Shenyang, 110001, Liaoning Province, People's Republic of China.

Purpose: Gastric cancer (GC) is the fifth most frequently diagnosed cancer and the third leading cause of cancer-related death. There is a critical need for the development of novel therapies in GC. DNA polymerase gamma (PolG) has been implicated in mitochondrial homeostasis and affects the development of numerous types of cancer, however, its effects on GC and molecular mechanisms remain to be fully determined. The aim of the present research was to clarify the effects of PolG on GC and its possible molecular mechanism of action.

Methods: The GSE62254 dataset was used to predict the effect of PolG on prognostic value in GC patients. Lentivirus-mediated transduction was used to silence PolG expression. Western blot analysis evinced the silencing effect. Co-immunoprecipitation (Co-IP) analysis was performed to explore the potential molecular mechanism of action. Analysis of the glycolysis process in GC cells was also undertaken. Cell proliferation was determined using a CCK-8 (Cell Counting Kit-8) proliferation assay. Cell migration was detected using the Transwell device. Animal experiments were used to measure in vivo xenograft tumor growth.

Results: GC patients with low PolG expression have worse overall survival (OS) and progression-free survival (PFS). PolG binds to PKM2 and affects the activation of Tyr105-site phosphorylation, thus interfering with the glycolysis of GC cells. In vitro tumor formation experiments in mice also confirmed that PolG silencing of GC has a stronger proliferation ability. PolG can suppress GC cell growth both in vivo and in vitro.

Conclusion: Our study reveals a potential molecular mechanism between PolG and the energy metabolic process of GC tumor cells for the first time, suggesting PolG as an independent novel potential therapeutic target for tumor therapy, and providing new ideas for clinical GC treatment.
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http://dx.doi.org/10.2147/CMAR.S292306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7896732PMC
February 2021

Remdesivir Metabolite GS-441524 Effectively Inhibits SARS-CoV-2 Infection in Mouse Models.

J Med Chem 2021 Feb 1. Epub 2021 Feb 1.

Shenzhen Key Laboratory of Small Molecule Drug Discovery and Synthesis, Department of Chemistry, College of Science, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China.

The outbreak of coronavirus disease 2019 (COVID-19) has resulted in a global pandemic due to the rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). At the time of this manuscript's publication, remdesivir is the only COVID-19 treatment approved by the United States Food and Drug Administration. However, its effectiveness is still under question due to the results of the large Solidarity Trial conducted by the World Health Organization. Herein, we report that the parent nucleoside of remdesivir, GS-441524, potently inhibits the replication of SARS-CoV-2 in Vero E6 and other cell lines. Challenge studies in both an AAV-hACE2 mouse model of SARS-CoV-2 and in mice infected with murine hepatitis virus, a closely related coronavirus, showed that GS-441524 was highly efficacious in reducing the viral titers in CoV-infected organs without notable toxicity. Our results support that GS-441524 is a promising and inexpensive drug candidate for treating of COVID-19 and other CoV diseases.
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http://dx.doi.org/10.1021/acs.jmedchem.0c01929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7875336PMC
February 2021

Comparative analysis of impact of human occupancy on indoor microbiomes.

Front Environ Sci Eng 2021 10;15(5):89. Epub 2020 Dec 10.

Department of Civil and Environmental Engineering, The University of Tennessee, Knoxville, TN 37996 USA.

Educational facilities serve as community hubs and consequently hotspots for exposure to pathogenic microorganisms. Therefore, it is of critical importance to understand processes shaping the indoor microbiomes in educational facilities to protect public health by reducing potential exposure risks of students and the broader community. In this study, the indoor surface bacterial microbiomes were characterized in two multifunctional university buildings with contrasting levels of human occupancy, of which one was recently constructed with minimal human occupancy while the other had been in full operation for six years. Higher levels of human occupancy in the older building were shown to result in greater microbial abundance in the indoor environment and greater proportion of the indoor surface bacterial microbiomes contributed from human-associated microbiota, particularly the skin microbiota. It was further revealed that human-associated microbiota had greater influence on the indoor surface bacterial microbiomes in areas of high occupancy than areas of low occupancy. Consistent with minimal impact from human occupancy in a new construction, the indoor microbiomes in the new building exhibited significantly lower influence from human-associated microbiota than in the older building, with microbial taxa originating from soil and plants representing the dominant constituents of the indoor surface bacterial microbiomes. In contrast, microbial taxa in the older building with extensive human occupancy were represented by constituents of the human microbiota, likely from occupants. These findings provide insights into processes shaping the indoor microbiomes which will aid the development of effective strategies to control microbial exposure risks of occupants in educational facilities.
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http://dx.doi.org/10.1007/s11783-020-1383-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7783699PMC
December 2020

Dual-mode endogenous and exogenous sensitization of tumor radiotherapy through antifouling dendrimer-entrapped gold nanoparticles.

Theranostics 2021 1;11(4):1721-1731. Epub 2021 Jan 1.

State Key Laboratory for Modification of Chemical Fiber and Polymer Materials, College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai 201620, People's Republic of China.

Development of a powerful sensitization system to alleviate radioresistance for enhanced tumor radiotherapy (RT) remains to be explored. Herein, we present a unique dual-mode endogenous and exogenous nanosensitizer based on dendrimer-entrapped gold nanoparticles (Au DENPs) to realize enhanced tumor RT. Generation 5 poly(amidoamine) dendrimers partially modified with 1,3-propanesultone were used for templated synthesis of Au NPs, and the created zwitterionic Au DENPs were adopted for serum-enhanced delivery of siRNA to lead to the knockdown of hypoxia-inducible factor-1α (HIF-1α) protein and downstream genes to relieve tumor invasion. The Au DENPs/siRNA polyplexes were also used for dual-mode endogenous and exogenous sensitization of tumor RT . Due to the dual-mode endogenous sensitization through HIF-1α gene silencing and the exogenous sensitization through the existing Au component, enhanced RT of cancer cells and a tumor model can be realized, which was confirmed by enhanced cytotoxic reactive oxygen species (ROS) generation and double-strand DNA damage verified from the γ-HAX protein expression in tumor cells . By integrating the advantages of HIF-1α gene silencing-induced downregulation of downstream genes and the dual-mode sensitization-enhanced RT, simultaneous inhibition of primary tumors and metastasis can be readily realized. The developed zwitterionic Au DENPs may be used as a promising platform for dual-mode endogenously and exogenously sensitized RT of other tumor types.
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http://dx.doi.org/10.7150/thno.54930DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7778585PMC
August 2021

The ATM and ATR kinases regulate centrosome clustering and tumor recurrence by targeting KIFC1 phosphorylation.

Nat Commun 2021 01 4;12(1):20. Epub 2021 Jan 4.

Translational Medicine Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 201620, Shanghai, China.

Drug resistance and tumor recurrence are major challenges in cancer treatment. Cancer cells often display centrosome amplification. To maintain survival, cancer cells achieve bipolar division by clustering supernumerary centrosomes. Targeting centrosome clustering is therefore considered a promising therapeutic strategy. However, the regulatory mechanisms of centrosome clustering remain unclear. Here we report that KIFC1, a centrosome clustering regulator, is positively associated with tumor recurrence. Under DNA damaging treatments, the ATM and ATR kinases phosphorylate KIFC1 at Ser26 to selectively maintain the survival of cancer cells with amplified centrosomes via centrosome clustering, leading to drug resistance and tumor recurrence. Inhibition of KIFC1 phosphorylation represses centrosome clustering and tumor recurrence. This study identified KIFC1 as a prognostic tumor recurrence marker, and revealed that tumors can acquire therapeutic resistance and recurrence via triggering centrosome clustering under DNA damage stresses, suggesting that blocking KIFC1 phosphorylation may open a new vista for cancer therapy.
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http://dx.doi.org/10.1038/s41467-020-20208-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7782532PMC
January 2021

The Regulatory Effect of SIRT1 on Extracellular Microenvironment Remodeling.

Int J Biol Sci 2021 1;17(1):89-96. Epub 2021 Jan 1.

College of Basic Medical Science, Institute of Translational Medicine, Key Laboratory of Medical Cell Biology, Ministry of Education, Key Laboratory of Liaoning Province, China Medical University, Shenyang, Liaoning Province, P.R. China, 110122.

The sirtuins family is well known by its unique nicotinamide adenine dinucleotide (NAD)-dependent deacetylase function. The most-investigated member of the family, Sirtuin 1 (SIRT1), accounts for deacetylating a broad range of transcription factors and coregulators, such as p53, the Forkhead box O (FOXO), and so on. It serves as a pivotal regulator in various intracellular biological processes, including energy metabolism, DNA damage response, genome stability maintenance and tumorigenesis. Although the most attention has been focused on its intracellular functions, the regulatory effect on extracellular microenvironment remodeling of SIRT1 has been recognized by researchers recently. SIRT1 can regulate cell secretion process and participate in glucose metabolism, neuroendocrine function, inflammation and tumorigenesis. Here, we review the advances in the understanding of SIRT1 on remodeling the extracellular microenvironment, which may provide new ideas for pathogenesis investigation and guidance for clinical treatment.
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http://dx.doi.org/10.7150/ijbs.52619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757024PMC
January 2021

Micro-Nanostructure of Coal and Adsorption-Diffusion Characteristics of Methane.

J Nanosci Nanotechnol 2021 Jan;21(1):422-430

School of Civil Engineering, Qingdao University of Technology, Qingdao, 266520, China.

The adsorption and diffusion characteristics of coal are important parameters for coalbed methane (CBM) extraction and mine gas control. However, the adsorption test can only obtain the apparent adsorption amount, and it cannot obtain the actual adsorption amount, which leads to a large error during the calculation of the coal diffusion coefficient. Taking the anthracite coal in the Jiulishan Mine as the research object, the micro-nanostructure and instantaneous apparent methane adsorption isotherms of the primary structure coal and tectonic coal were determined by low-temperature CO₂ adsorption, mercury intrusion and methane diffusion kinetics tests, and the instantaneous apparent adsorption isotherms of methane were corrected to the instantaneous actual adsorption isotherm by the Langmuir model. The results demonstrate that the micro-nanopore, Density Function Theory (DFT) pore volume and specific surface area values below 1-2 nm in tectonic coal are larger than those in the primary structure coal, which is the fundamental reason why the ultimate adsorption capacity of tectonic coal is larger than that of the primary structure coal. The apparent adsorption amounts of the tectonic coal and the primary structure coal reach the maximum at 8 MPa and 10 MPa, respectively. Thereafter, the instantaneous isotherms of the apparent adsorption amount decrease with increasing of gas pressure. However, the instantaneous isotherms of the actual adsorption amount tend to be stable. The diffusion coefficient undergoes a rapid decay with time under low gas pressure, and undergoes a slow decay with under the high gas pressure.
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http://dx.doi.org/10.1166/jnn.2021.18733DOI Listing
January 2021

Sarcopenia affects clinical efficacy of immune checkpoint inhibitors in non-small cell lung cancer patients: A systematic review and meta-analysis.

Int Immunopharmacol 2020 Nov 18;88:106907. Epub 2020 Sep 18.

Department of Thoracic Surgery, The First Hospital of China Medical University, No.155, North Nanjing Street, Shenyang 110001, Liaoning, China. Electronic address:

Background: The clinical impact of sarcopenia on the immune checkpoint inhibitor's (ICI) efficacy and immune-related adverse events in non-small cell lung cancer (NSCLC) patients is unclear. Therefore, the purpose of this study is to evaluate the association between sarcopenia and clinical outcomes of ICI immunotherapy.

Methods: A systematic literature search of PubMed, Embase, Cochrane CENTRAL, and conference databases was conducted for the relevant studies. The primary outcomes were progression-free survival (PFS) and overall survival (OS) measured by hazard ratio (HR) with 95% confidence interval (CI), and the secondary outcomes were disease control rate, overall response rate, and immune-related adverse events measured by relative risk (RR) with 95% CI. Subgroup and sensitivity analysis were performed.

Results: Pre-immunotherapy sarcopenia was significantly associated with worse OS (HR = 1.61, 95% CI = 1.24-2.10) and PFS (HR = 1.98, 95% CI = 1.32-2.97). Development or worsening of sarcopenia during immunotherapy also predicted worse OS and PFS. Both pre-immunotherapy sarcopenia (RR = 0.70, 95% CI = 0.56-0.86) and development or worsening of sarcopenia (RR = 0.62, 95% CI = 0.40-0.96) resulted in a lower disease control rate. Sarcopenia tended toward a lower overall response rate, although there was no significant difference (RR = 0.54, 95% CI = 0.19-1.53). Moreover, sarcopenia did not increase immune-related adverse events (RR = 0.99, 95% CI = 0.21-4.67).

Conclusion: Sarcopenia was associated with worse treatment response and shorter long-term efficacy in NSCLC patients treated with ICI immunotherapy. Moreover, sarcopenia does not increase the rate of immune-related adverse events.
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http://dx.doi.org/10.1016/j.intimp.2020.106907DOI Listing
November 2020

Understanding building-occupant-microbiome interactions toward healthy built environments: A review.

Front Environ Sci Eng 2021 22;15(4):65. Epub 2020 Oct 22.

Department of Civil and Environmental Engineering, University of Tennessee, Knoxville, TN 37996 USA.

Built environments, occupants, and microbiomes constitute a system of ecosystems with extensive interactions that impact one another. Understanding the interactions between these systems is essential to develop strategies for effective management of the built environment and its inhabitants to enhance public health and well-being. Numerous studies have been conducted to characterize the microbiomes of the built environment. This review summarizes current progress in understanding the interactions between attributes of built environments and occupant behaviors that shape the structure and dynamics of indoor microbial communities. In addition, this review also discusses the challenges and future research needs in the field of microbiomes of the built environment that necessitate research beyond the basic characterization of microbiomes in order to gain an understanding of the causal mechanisms between the built environment, occupants, and microbiomes, which will provide a knowledge base for the development of transformative intervention strategies toward healthy built environments. The pressing need to control the transmission of SARS-CoV-2 in indoor environments highlights the urgency and significance of understanding the complex interactions between the built environment, occupants, and microbiomes, which is the focus of this review.
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http://dx.doi.org/10.1007/s11783-020-1357-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596174PMC
October 2020

E3 Ubiquitin ligase NEDD4 family‑regulatory network in cardiovascular disease.

Int J Biol Sci 2020 21;16(14):2727-2740. Epub 2020 Aug 21.

Department of Cardiology, the First Hospital of China Medical University, Shenyang, Liaoning, P.R. China.

Protein ubiquitination represents a critical modification occurring after translation. E3 ligase catalyzes the covalent binding of ubiquitin to the protein substrate, which could be degraded. Ubiquitination as an important protein post-translational modification is closely related to cardiovascular disease. The NEDD4 family, belonging to HECT class of E3 ubiquitin ligases can recognize different substrate proteins, including PTEN, ENaC, Nav1.5, SMAD2, PARP1, Septin4, ALK1, SERCA2a, TGFβR3 and so on, via the WW domain to catalyze ubiquitination, thus participating in multiple cardiovascular-related disease such as hypertension, arrhythmia, myocardial infarction, heart failure, cardiotoxicity, cardiac hypertrophy, myocardial fibrosis, cardiac remodeling, atherosclerosis, pulmonary hypertension and heart valve disease. However, there is currently no review comprehensively clarifying the important role of NEDD4 family proteins in the cardiovascular system. Therefore, the present review summarized recent studies about NEDD4 family members in cardiovascular disease, providing novel insights into the prevention and treatment of cardiovascular disease. In addition, assessing transgenic animals and performing gene silencing would further identify the ubiquitination targets of NEDD4. NEDD4 quantification in clinical samples would also constitute an important method for determining NEDD4 significance in cardiovascular disease.
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http://dx.doi.org/10.7150/ijbs.48437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7586430PMC
August 2020

Hypoxia-autophagy axis induces VEGFA by peritoneal mesothelial cells to promote gastric cancer peritoneal metastasis through an integrin α5-fibronectin pathway.

J Exp Clin Cancer Res 2020 Oct 20;39(1):221. Epub 2020 Oct 20.

Institute of Translational Medicine, Key Laboratory of Cell Biology of Ministry of Public Health, Key Laboratory of Medical Cell Biology of Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, Shenyang, 110001, Liaoning, China.

Background: Peritoneal metastasis (PM) is an important pathological process in the progression of gastric cancer (GC). The metastatic potential of tumor and stromal cells is governed by hypoxia, which is a key molecular feature of the tumor microenvironment. Mesothelial cells also participate in this complex and dynamic process. However, the molecular mechanisms underlying the hypoxia-driven mesothelial-tumor interactions that promote peritoneal metastasis of GC remain unclear.

Methods: We determined the hypoxic microenvironment in PM of nude mice by immunohistochemical analysis and screened VEGFA by human growth factor array kit. The crosstalk mediated by VEGFA between peritoneal mesothelial cells (PMCs) and GC cells was determined in GC cells incubated with conditioned medium prepared from hypoxia-treated PMCs. The association between VEGFR1 and integrin α5 and fibronectin in GC cells was enriched using Gene Set Enrichment Analysis and KEGG pathway enrichment analysis. In vitro and xenograft mouse models were used to evaluate the impact of VEGFA/VEGFR1 on gastric cancer peritoneal metastasis. Confocal microscopy and immunoprecipitation were performed to determine the effect of hypoxia-induced autophagy.

Results: Here we report that in the PMCs of the hypoxic microenvironment, SIRT1 is degraded via the autophagic lysosomal pathway, leading to increased acetylation of HIF-1α and secretion of VEGFA. Under hypoxic conditions, VEGFA derived from PMCs acts on VEGFR1 of GC cells, resulting in p-ERK/p-JNK pathway activation, increased integrin α5 and fibronectin expression, and promotion of PM.

Conclusions: Our findings have elucidated the mechanisms by which PMCs promote PM in GC in hypoxic environments. This study also provides a theoretical basis for considering autophagic pathways or VEGFA as potential therapeutic targets to treat PM in GC.
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http://dx.doi.org/10.1186/s13046-020-01703-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576728PMC
October 2020
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