Publications by authors named "Yulin Liao"

194 Publications

Circ-Ddx60 contributes to the antihypertrophic memory of exercise hypertrophic preconditioning.

J Adv Res 2022 Jun 16. Epub 2022 Jun 16.

Department of Cardiology, State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Lab of Shock and Microcirculation, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; National Clinical Research Center of Kidney Disease, Guangdong Provincial Institute of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China. Electronic address:

Introduction: We previously reported a phenomenon called exercise hypertrophic preconditioning (EHP), the underlying mechanisms of which need further clarification.

Objectives: We aimed to investigate whether circular RNAs (circRNAs) are involved in EHP.

Methods: CircRNA sequencing of myocardial tissue was performed in male C57BL/6 mice with EHP and sedentary. Bioinformatics analysis and Sanger sequencing were used to screen hub circRNA expression and to detect full-length circRNAs, respectively. Loss-of-function analyses were conducted to assess the effects of circ-Ddx60 (c-Ddx) on EHP. After 21 days of swimming training or resting, mice underwent transverse aortic constriction (TAC) or sham surgery. Echocardiography, invasive hemodynamic measurement and histological analysis were used to evaluate cardiac remodeling and function. The presence of interaction between c-Ddx and proteins was investigated using comprehensive identification of RNA-binding proteins by mass spectrometry (ChIRP-MS).

Results: In this study, we identified a novel circRNA, named c-Ddx that was preferentially expressed in myocardial tissue and significantly up-regulated in EHP mice. Silencing of c-Ddx attenuated the antihypertrophic effect of EHP and worsened heart failure in mice that underwent TAC. ChIRP-MS and molecular docking analysis validated the combination of c-Ddx and eukaryotic elongation factor 2 (eEF2). Mechanistically, c-Ddx silencing inhibited the increase of phosphorylation of eEF2 and its upstream AMP-activated protein kinase (AMPK) induced by EHP.

Conclusions: C-Ddx contributes to the antihypertrophic memory of EHP by binding and activating eEF2, which would provide opportunity to search new therapeutic targets for pathological hypertrophy of heart.
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http://dx.doi.org/10.1016/j.jare.2022.06.005DOI Listing
June 2022

Evaluation of stromal cell infiltration in the tumor microenvironment enable prediction of treatment sensitivity and prognosis in colon cancer.

Comput Struct Biotechnol J 2022 30;20:2153-2168. Epub 2022 Apr 30.

Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, PR China.

Current clinical factors for screening candidates that might benefit from adjuvant chemotherapy in colon cancer are inadequate. Tumor microenvironment, especially the stromal components, has the potential to determine treatment response. However, clinical translation of the tumor-associated stromal characterization into a practical biomarker for helping treatment decision has not been established. Using machine learning, we established a novel 31-gene signature, called stromal cell infiltration intensity score (SIIS), to distinguish patients characterized by the enrichment of abundant stromal cells in five colon cancer datasets from GEO (N = 990). Patients with high-SIIS were at higher risk for recurrence and mortality, and could not benefit from adjuvant chemotherapy due to their intrinsic drug resistance; however, the opposite was reported for patients with low-SIIS. The role of SIIS in detection of patients with high stromal cell infiltration and reduced drug efficiency was consistently validated in the TCGA-COAD cohort (N = 382), Sun Yat-sen University Cancer Center cohort (N = 30), and could also be observed in TCGA pan-cancer settings (N = 4898) and four independent immunotherapy cohorts (N = 467). Based on multi-omics data analysis and the CRISPR library screen, we reported that lack of gene mutation, hypomethylation in ADCY4 promoter region, activation of WNT-PCP pathway and SIAH2-GPX3 axis were potential mechanisms responsible for the chemoresistance of patients within high-SIIS group. Our findings demonstrated that SIIS provide an important reference for those making treatment decisions for such special patients.
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http://dx.doi.org/10.1016/j.csbj.2022.04.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9118126PMC
April 2022

Optimal dose of physical exercise for preventing cardiac and renal dysfunction, data from NHANES survey.

Eur J Prev Cardiol 2022 May 17. Epub 2022 May 17.

Department of Cardiology, State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Shock and Microcirculation, National Clinical Research Center of Kidney Disease, Guangdong Provincial Institute of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.

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http://dx.doi.org/10.1093/eurjpc/zwac096DOI Listing
May 2022

Pancreatic Adverse Events Associated With Immune Checkpoint Inhibitors: A Large-Scale Pharmacovigilance Analysis.

Front Pharmacol 2022 1;13:817662. Epub 2022 Apr 1.

Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China.

Immune checkpoint inhibitors (ICIs) are considered cornerstones of oncology treatment with durable anti-tumor efficacy, but the increasing use of ICIs is associated with the risk of developing immune-related adverse events (irAEs). Although ICI-associated pancreatic adverse events (AEs) have been reported in patients treated with ICIs, the clinical features and spectrum of pancreatic AEs are still not well-defined. Therefore, this study aimed to identify the association between pancreatic AEs and ICIs treatments and to characterize the main features of ICI-related pancreatic injury (ICIPI) based on the Food and Drug Administration Adverse Event Reporting System (FAERS) database.

Methods: Data from the first quarter of 2015 to the first quarter of 2021 in the database were extracted to conduct a disproportionality analysis. The selection of AEs related to the pancreas relied on previous studies and preferred terms from the Medical Dictionary for Regulatory Activities. Two main disproportionality analyses-the reporting odds ratio (ROR) and information component (IC)-were used to evaluate potential associations between ICIs and pancreatic AEs.

Results: In total, 2,364 cases of pancreatic AEs in response to ICIs were extracted from the FAERS database, of which, 647 were identified as ICI-associated pancreatitis and 1,293 were identified as ICI-associated diabetes mellitus. Generally, significant signals can be detected between pancreatic AEs and all ICIs treatments (ROR = 3.30, IC = 1.71). For monotherapy, the strongest signal associated with pancreatitis was reported for anti-PD-L1 (ROR = 1.75, IC = 0.76), whereas that with diabetes mellitus was reported for anti-PD-1 (ROR = 6.39, IC = 2.66). Compared with monotherapy, combination therapy showed stronger associations with both ICI-associated pancreatitis (ROR = 2.35, IC = 1.20 . ROR = 1.52, IC = 0.59) and ICI-associated diabetes mellitus (ROR = 9.53, IC = 3.23 . ROR = 5.63, IC = 2.48), but lower fatality proportion.

Conclusions: ICIs were significantly associated with the over-reporting frequency of pancreatic AEs, in which combination therapy posed a higher reporting frequency. Therefore, patients should be informed of these potential toxicities before ICIs medications are administered.
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http://dx.doi.org/10.3389/fphar.2022.817662DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9012537PMC
April 2022

CX3CL1 Worsens Cardiorenal Dysfunction and Serves as a Therapeutic Target of Canagliflozin for Cardiorenal Syndrome.

Front Pharmacol 2022 18;13:848310. Epub 2022 Mar 18.

Department of Cardiology, State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Shock and Microcirculation, Nanfang Hospital, Southern Medical University, Guangzhou, China.

The prognosis of cardiorenal dysfunction induced by diabetes mellitus (DM), which belongs to cardiorenal syndrome type 5, is poor and its pathogenesis remains elusive. We have reported that CX3CL1 exacerbated heart failure and direct inhibition of CX3CL1 improved cardiac function. Emerging evidence supports that CX3CL1 is involved in renal impairment. Here we attempt to clarify whether CX3CL1 might be a therapeutic target for cardiorenal dysfunction in diabetes. We found that cardiac and renal CX3CL1 protein levels were significantly increased in both streptozotocin-induced diabetic mice and in non-obese diabetic mice, and that hyperglycemia led to persistent CX3CL1 expression in the heart and kidneys even after it was controlled by insulin. In cultured cardiac and renal cells, soluble CX3CL1 accelerated mitochondrial-dependent apoptosis via activation of the RhoA/ROCK1-Bax signaling pathway and promoted fibrosis through cellular phenotypic trans-differentiation mediated by the TGF-β/Smad pathway. In the two diabetic mouse models, knockout of CX3CL1 receptor CX3CR1 or treatment with an CX3CL1 neutralizing antibody significantly improved cardiorenal dysfunction by inhibiting apoptosis, mitochondrial dysfunction, and fibrosis. Moreover, sodium glucose cotransporter 2 inhibitor canagliflozin significantly downregulated cardiac and renal CX3CL1 expression and improved cardiorenal dysfunction. These findings indicate that CX3CL1 could be a new therapeutic target for diabetes-induced cardiorenal dysfunction.
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http://dx.doi.org/10.3389/fphar.2022.848310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8971671PMC
March 2022

Comparative Respiratory Tract Microbiome Between Carbapenem-Resistant Colonization and Ventilator Associated Pneumonia.

Front Microbiol 2022 4;13:782210. Epub 2022 Mar 4.

State Key Laboratory for Turbulence and Complex Systems, Department of Biomedical Engineering, College of Future Technology and Center for Quantitative Biology, Peking University, Beijing, China.

Background: Carbapenem-resistant (CRAB) is a common cause of ventilator-associated pneumonia (VAP) in intensive care unit (ICU) patients, but its infection and colonization state are difficult to distinguish. If the judgment is wrong, it may aggravate the abuse of antibiotics and further accelerate the evolution of drug resistance. We sought to provide new clues for the diagnosis, pathogenesis and treatment of CRAB VAP based on lower respiratory tract (LRT) microbiota.

Methods: A prospective study was conducted on patients with mechanical ventilation from July 2018 to December 2019 in a tertiary hospital. Multi-genomics studies (16S rRNA amplicon, metagenomics, and whole-genome sequencing [WGS]) of endotracheal deep aspirate (ETA) were performed.

Results: Fifty-two ICU patients were enrolled, including 24 with CRAB VAP (CRAB-I), 22 with CRAB colonization (CRAB-C), and six CRAB-negative patients (infection-free) (CRAB-N). Diversity of pulmonary microbiota was significantly lower in CRAB-I than in CRAB-C or CRAB-N (mean Shannon index, 1.79 vs. 2.73 vs. 4.81, < 0.05). Abundances of 11 key genera differed between the groups. was most abundant in CRAB-I (76.19%), moderately abundant in CRAB-C (59.14%), and least abundant in CRAB-N (11.25%), but its interactions with other genera increased in turn. Metagenomics and WGS analysis showed that virulence genes were more abundant in CRAB-I than in CRAB-C. Multi-locus sequence typing (MLST) of 46 CRAB isolates revealed that the main types were ST208 (30.43%) and ST938 (15.22%), with no difference between CRAB-I and CRAB-C.

Conclusion: Lower respiratory tract microbiota dysbiosis including elevated relative abundance of and reduced bacterial interactions, and virulence enrichment may lead to CRAB VAP.
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http://dx.doi.org/10.3389/fmicb.2022.782210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8931608PMC
March 2022

Nitrogen application practices to reduce cadmium concentration in rice (Oryza sativa L.) grains.

Environ Sci Pollut Res Int 2022 Mar 1. Epub 2022 Mar 1.

Key Laboratory for Agro-Ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, 410125, China.

Cadmium (Cd) pollution in paddy soils creates challenges in rice grain production, thereby threatening food security. The effectiveness of different base-tillering-panicle urea application ratios and the combined basal application of urea and Chinese milk vetch (CMV, Astragalus sinicus L.) in minimizing Cd accumulation in rice grains was explored in a Cd-contaminated acidic soil via a field experiment. The results indicated that under similar nitrogen (N) application rates, an appropriate amount of urea applied at the panicle stage or the combined basal application of urea and CMV decreased Cd absorption by rice roots and its accumulation in rice grains, as compared with that of conventional N application (control). Furthermore, under a 3:4:3 base-tillering-panicle urea application ratio or under a high basal application of CMV (37,500 kg hm), Cd concentrations in brown rice were significantly lower (40.7% and 34.1%, respectively) than that of control. Cadmium transport coefficient from root to straw was significantly higher than that of control when an appropriate amount of urea was applied at the panicle stage or when urea and CMV were applied basally, whereas the Cd transport coefficient from straw to brown rice was relatively lower. Moreover, soil pH, or the CEC and CaCl-Cd concentrations under different N fertilizer treatment was not significantly different. However, the rice grain yield increased by 29.4% with basal application of a high CMV amount compared with that of control. An appropriate amount of urea applied at the panicle stage or the combined basal application of urea and CMV decreased Cd absorption by rice roots and inhibited its transport from straw to brown rice, thus reducing Cd concentration in brown rice. Therefore, combined with the key phase of Cd accumulation in rice, a reasonable urea application ratio or a basal application of high CMV amounts could effectively reduce Cd concentration in brown rice.
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http://dx.doi.org/10.1007/s11356-022-19381-xDOI Listing
March 2022

Evolution of tumor microenvironment in colorectal liver metastases under treatment stress.

Cancer Commun (Lond) 2022 05 15;42(5):471-475. Epub 2022 Jan 15.

Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, P. R. China.

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http://dx.doi.org/10.1002/cac2.12259DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9118053PMC
May 2022

A Modified Surgical Ventricular Reconstruction in Post-infarction Mice Persistently Alleviates Heart Failure and Improves Cardiac Regeneration.

Front Cardiovasc Med 2021 24;8:789493. Epub 2021 Dec 24.

Department of Cardiology, State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Shock and Microcirculation, National Clinical Research Center of Kidney Disease, Guangdong Provincial Institute of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China.

Large ventricular aneurysm secondary to myocardial infarction (MI) results in severe heart failure (HF) and limits the effectiveness of regeneration therapy, which can be improved by surgical ventricular reconstruction (SVR). However, the conventional SVR procedures do not yield optimal long-term outcome in post-MI rodents. We hypothesized that a modified SVR procedure without aggressive purse string suture would persistently alleviate HF and improve cardiac regeneration in post-MI mice. Adult male C57 mice were subjected to MI or sham surgery. Four weeks later, mice with MI underwent SVR or 2nd open-chest operation alone. SVR was performed by plicating the aneurysm with a single diagonal linear suture from the upper left ventricle (LV) to the right side of the apex. Cardiac remodeling, heart function and myocardial regeneration were evaluated. Three weeks after SVR, the scar area, LV volume, and heart weight/body weight ratio were significantly smaller, while LV ejection fraction, the maximum rising and descending rates of LV pressure, LV contractility and global myocardial strain were significantly higher in SVR group than in SVR-control group. The inhibitory effects of SVR on LV remodeling and HF persisted for at least eight-week. SVR group exhibited improved cardiac regeneration, as reflected by more Ki67-, Aurora B- and PH3-positive cardiomyocytes and a higher vessel density around the plication area of the infarcted LV. SVR with a single linear suture results in a significant and sustained reduction in LV volume and improvement in both LV systolic and diastolic function as well as cardiac regeneration.
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http://dx.doi.org/10.3389/fcvm.2021.789493DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8740235PMC
December 2021

A Bibliometric and Visualized Analysis of Cardiac Regeneration Over a 20-Year Period.

Front Cardiovasc Med 2021 13;8:789503. Epub 2021 Dec 13.

State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Shock and Microcirculation, Department of Cardiology, National Clinical Research Center of Kidney Disease, Guangdong Provincial Institute of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China.

Recent research has suggested that cardiac regeneration may have the widely applicable potential of treating heart failure (HF). A comprehensive understanding of the development status of this field is conducive to its development. However, no bibliometric analysis has summarized this field properly. We aimed to analyze cardiac regeneration-related literature over 20 years and provide valuable insights. Publications were collected from the Web of Science Core Collection (WoSCC). Microsoft Excel, VOSviewer, CiteSpace, and alluvial generator were used to analyze and present the data. The collected 11,700 publications showed an annually increasing trend. The United States and Harvard University were the leading force among all the countries and institutions. The majority of articles were published in Circulation Research, and Circulation was the most co-cited journal. According to co-citation analysis, burst detection and alluvial flow map, cardiomyocyte proliferation, stem cells, such as first-and second-generation, extracellular vesicles especially exosomes, direct cardiac reprogramming, macrophages, microRNAs, and inflammation have become more and more popular recently. Cardiac regeneration remains a research hotspot and develops rapidly. How to modify cardiac regeneration endogenously and exogenously may still be the hotspot in the future and should be discussed more deeply.
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http://dx.doi.org/10.3389/fcvm.2021.789503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8710530PMC
December 2021

CircRNA Chordc1 protects mice from abdominal aortic aneurysm by contributing to the phenotype and growth of vascular smooth muscle cells.

Mol Ther Nucleic Acids 2022 Mar 10;27:81-98. Epub 2021 Nov 10.

Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, China.

Circular RNAs (circRNAs) have important potential in modulating vascular smooth muscle cell (VSMC) activity, but their roles in abdominal aortic aneurysm (AAA) are unknown. We performed hybridization and immunohistochemistry and determined that circChordc1 (cysteine and histidine-rich domain containing 1) was markedly downregulated in aneurysm tissue compared with normal arteries. A gene gain and loss strategy was used to confirm that circChordc1 transformed VSMCs into a contracted phenotype and improved their growth, which significantly suppressed aneurysm formation and reduced the risk of rupture in mouse models of angiotensin (Ang) II- and CaCl-induced AAA. RNA pull-down, immunoprecipitation, and immunoblotting indicated that circChordc1 facilitated the VSMC phenotype and growth determination by binding to vimentin and ANXA2 (annexin A2), which not only increased vimentin phosphorylation to promote its degradation but also promoted the interaction between ANXA2 and glycogen synthase kinase 3 beta (GSK3β) to induce the nuclear entry of β-catenin. Thus, our present study revealed that circChordc1 optimized the VSMC phenotype and improved their growth by inducing vimentin degradation and increasing the activity of the GSK3β/β-catenin pathway, thereby extenuating vascular wall remodeling and reversing pathological aneurysm progression.
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http://dx.doi.org/10.1016/j.omtn.2021.11.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8649900PMC
March 2022

Response by He et al to Letter Regarding Article, "Antihypertrophic Memory After Regression of Exercise-Induced Physiological Myocardial Hypertrophy Is Mediated by the Long Noncoding RNA Mhrt779".

Circulation 2021 10 18;144(16):e271-e272. Epub 2021 Oct 18.

Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China.

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http://dx.doi.org/10.1161/CIRCULATIONAHA.121.056310DOI Listing
October 2021

LncRNA Snhg1-driven self-reinforcing regulatory network promoted cardiac regeneration and repair after myocardial infarction.

Theranostics 2021 13;11(19):9397-9414. Epub 2021 Sep 13.

Department of Cardiology and National Key Lab for Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.

Most current cardiac regeneration approaches result in very limited cell division and little new cardiomyocyte (CM) mass. Positive feedback loops are vital for cell division, but their role in CM regeneration remains unclear. We aimed to determine whether the lncRNA small nucleolar RNA host gene 1 Snhg1 (Snhg1) could form a positive feedback loop with c-Myc to induce cardiac regeneration. Quantitative PCR and hybridization experiments were performed to determine the Snhg1 expression patterns in fetal and myocardial infarction (MI) hearts. Gain- and Loss-of-function assays were conducted to explore the effect of Snhg1 on cardiomyocyte (CM) proliferation and cardiac repair following MI. We further constructed CM-specific Snhg1 knockout mice to confirm the proliferative effect exerted by Snhg1 using CRISPR/Cas9 technology. RNA sequencing and RNA pulldown were performed to explore how Snhg1 mediated cardiac regeneration. Chromatin immunoprecipitation and luciferase reporter assays were used to demonstrate the positive feedback loop between Snhg1 and c-Myc. Snhg1 expression was increased in human and mouse fetal and myocardial infarction (MI) hearts, particularly in CMs. Overexpression of Snhg1 promoted CM proliferation, angiogenesis, and inhibited CM apoptosis after myocardial infarction, which further improved post-MI cardiac function. Antagonism of Snhg1 in early postnatal mice inhibited CM proliferation and impaired cardiac repair after MI. Mechanistically, Snhg1 directly bound to phosphatase and tensin homolog (PTEN) and induced PTEN degradation, activating the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway to promote CM proliferation. The c-Myc protein, one of downstream targets of PI3K/AKT signaling, functioned as a transcription factor by binding to the promoter regions of Snhg1. Perturbation of the positive feedback between Snhg1 and c-Myc by mutation of the binding sequence significantly affected Snhg1-induced CM proliferation. Snhg1 effectively elicited CM proliferation and improved cardiac function post-MI by forming a positive feedback loop with c-Myc to sustain PI3K/Akt signaling activation, and thus may be a promising cardiac regeneration strategy in treating heart failure post-MI.
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http://dx.doi.org/10.7150/thno.57037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8490501PMC
February 2022

Co-utilizing milk vetch, rice straw, and lime reduces the Cd accumulation of rice grain in two paddy soils in south China.

Sci Total Environ 2022 Feb 28;806(Pt 2):150622. Epub 2021 Sep 28.

Key Laboratory of Plant Nutrition and Fertilizer, Ministry of Agriculture and Rural Affairs, Institute of Agricultural Resources and Regional Planning, Chinese Academy of Agricultural Sciences, Beijing 100081, China. Electronic address:

The danger posed by cadmium (Cd) pollution to rice production is continuously increasing. Co-utilizing milk vetch (Astragalus sinicus L.) and rice straw is a good practice for rice yield and soil fertility in south China. However, its effects on Cd availability in soil-rice systems remain unclear. A micro-plot trial of two typical paddy soils (alluvial sandy soil and reddish clayey soil) in south China was conducted to investigate the effects of milk vetch, rice straw, lime, and their combined application on Cd availability and the related mechanisms. Soil chemical properties, CaCl-extractable Cd (CaCl-Cd), total content of Cd (Total-Cd), Cd fractionation (BCR sequential-extraction method), and Cd accumulation in rice were measured. Results showed that the co-utilization of milk vetch, rice straw, and lime (GRFL) decreased the Cd content in rice grain by 91.43% and 15.63% in early rice of two soils, respectively. Cd was not detected in late rice grains. CaCl-Cd decreased by 0.025 mg kg in late rice of alluvial sandy soil, 0.057 and 0.044 mg kg decreased in early and late rice of reddish clayey soil, and Total-Cd decreased by 19.4% and 9.1% for early rice of two soils, respectively. Co-utilizing milk vetch, rice straw, and lime changed the distribution of different chemical forms of Cd, decreased the content of bioavailable Cd in soil by reducing the Aci-Cd and RedCd, and benefited the formation of more stable residual fraction (ResCd). Redundancy analysis showed that the improvement in soil pH, dissolved organic matter (DOM), and other soil properties was the main cause of the transformation of Cd form. Among the soil properties, pH and DOM had the greatest impacts on Cd availability. In conclusion, co-utilizing milk vetch and rice straw can alleviate the danger of soil Cd in rice production, and this effect could be strengthened by applying lime.
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http://dx.doi.org/10.1016/j.scitotenv.2021.150622DOI Listing
February 2022

Circular RNA Cdyl promotes abdominal aortic aneurysm formation by inducing M1 macrophage polarization and M1-type inflammation.

Mol Ther 2022 02 20;30(2):915-931. Epub 2021 Sep 20.

Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 1838 Guangzhou Avenue North, Guangzhou 510515, China; Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou 510005, China; Guangdong Provincial Key Laboratory of Shock and Microcirculation, Guangzhou 510515, China. Electronic address:

Macrophage polarization plays a crucial role in regulating abdominal aortic aneurysm (AAA) formation. Circular RNAs (circRNAs) are important regulators of macrophage polarization during the development of cardiovascular diseases. How-ever, the roles of circRNAs in regulating AAA formation through modulation of macrophage polarization remain unknown. In the present study, we compared circRNA microarray data under two distinct polarizing conditions (M1 and M2 macrophages) and identified an M1-enriched circRNA, circCdyl. Loss- and gain-of-function assay results demonstrated that circCdyl overexpression accelerated angiotensin II (Ang II)- and calcium chloride (CaCl)-induced AAA formation by promoting M1 polarization and M1-type inflammation, while circCdyl deficiency showed the opposite effects. RNA pulldown, mass spectrometry analysis, and RNA immunoprecipitation (RIP) assays were conducted to elucidate the underlying mechanisms by which circCdyl regulates AAA formation and showed that circCdyl promotes vascular inflammation and M1 polarization by inhibiting interferon regulatory factor 4 (IRF4) entry into the nucleus, significantly inducing AAA formation. In addition, circCdyl was shown to act as a let-7c sponge, promoting C/EBP-δ expression in macrophages to induce M1 polarization. Our results indicate an important role for circCdyl-mediated macrophage polarization in AAA formation and provide a potent therapeutic target for AAA treatment.
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http://dx.doi.org/10.1016/j.ymthe.2021.09.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8821928PMC
February 2022

Single-cell analysis of a tumor-derived exosome signature correlates with prognosis and immunotherapy response.

J Transl Med 2021 09 8;19(1):381. Epub 2021 Sep 8.

Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China.

Background: Tumor-derived exosomes (TEXs) are involved in tumor progression and the immune modulation process and mediate intercellular communication in the tumor microenvironment. Although exosomes are considered promising liquid biomarkers for disease diagnosis, it is difficult to discriminate TEXs and to develop TEX-based predictive biomarkers.

Methods: In this study, the gene expression profiles and clinical information were collected from The Cancer Genome Atlas (TCGA) database, IMvigor210 cohorts, and six independent Gene Expression Omnibus datasets. A TEXs-associated signature named TEXscore was established to predict overall survival in multiple cancer types and in patients undergoing immune checkpoint blockade therapies.

Results: Based on exosome-associated genes, we first constructed a tumor-derived exosome signature named TEXscore using a principal component analysis algorithm. In single-cell RNA-sequencing data analysis, ascending TEXscore was associated with disease progression and poor clinical outcomes. In the TCGA Pan-Cancer cohort, TEXscore was elevated in tumor samples rather than in normal tissues, thereby serving as a reliable biomarker to distinguish cancer from non-cancer sources. Moreover, high TEXscore was associated with shorter overall survival across 12 cancer types. TEXscore showed great potential in predicting immunotherapy response in melanoma, urothelial cancer, and renal cancer. The immunosuppressive microenvironment characterized by macrophages, cancer-associated fibroblasts, and myeloid-derived suppressor cells was associated with high TEXscore in the TCGA and immunotherapy cohorts. Besides, TEXscore-associated miRNAs and gene mutations were also identified. Further experimental research will facilitate the extending of TEXscore in tumor-associated exosomes.

Conclusions: TEXscore capturing tumor-derived exosome features might be a robust biomarker for prognosis and treatment responses in independent cohorts.
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http://dx.doi.org/10.1186/s12967-021-03053-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8424990PMC
September 2021

CircSEC24A promotes tumor progression through sequestering miR-455-3p in hepatocellular carcinoma.

Neoplasma 2021 Aug 31. Epub 2021 Aug 31.

Department of Clinical Laboratory, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China.

Hepatocellular carcinoma (HCC) ranks third in the cause of death due to cancer. Circular RNA circSEC24 Homolog A (circSEC24A) has been uncovered to be upregulated in liver cancer. However, the function of circSEC24A in HCC is indistinct. We analyzed the microarray datasets GSE78520 and GSE94508 to search for differentially expressed circRNAs associated with HCC. Expression of circSEC24A, microRNA (miR)-455-3p, and protein phosphatase, Mg2+/Mn2+ dependent 1F (PPM1F) mRNA was detected by quantitative real-time polymerase chain reaction (RT-qPCR). Loss-of-function experiments were conducted to validate the biological function of circSEC24A in HCC cells in vitro and in vivo. Protein levels were evaluated by western blotting and immunohistochemistry (IHC). The relationship between circSEC24A or PPM1F and miR-455-3p was verified by a dual-luciferase reporter and/or RNA immunoprecipitation (RIP) assays. circSEC24A was overexpressed in HCC. circSEC24A silencing decreased xenograft tumor growth in vivo and repressed proliferation, metastasis, invasion, epithelial-to-mesenchymal transition (EMT), induced cell cycle arrest, and apoptosis of HCC cells in vitro. circSEC24A acted as a molecular sponge to sequester miR-455-3p, resulting in elevating the expression of PPM1F. miR-455-3p inhibitor reversed the suppressive impact of circSEC24A silencing on malignant behaviors of HCC cells. PPM1F overexpression offsets the inhibitory effect of miR-455-3p mimic on malignant behaviors of HCC cells. circSEC24A sponged miR-455-3p to elevate the PPM1F expression, resulting in accelerating malignant behaviors of HCC cells. The study provided a potential therapeutic target for patients with HCC.
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http://dx.doi.org/10.4149/neo_2021_210305N285DOI Listing
August 2021

Tumor microenvironment evaluation promotes precise checkpoint immunotherapy of advanced gastric cancer.

J Immunother Cancer 2021 08;9(8)

Department of Oncology, Southern Medical University Nanfang Hospital, Guangzhou, Guangdong, China

Background: Durable efficacy of immune checkpoint blockade (ICB) occurred in a small number of patients with metastatic gastric cancer (mGC) and the determinant biomarker of response to ICB remains unclear.

Methods: We developed an open-source TMEscore R package, to quantify the tumor microenvironment (TME) to aid in addressing this dilemma. Two advanced gastric cancer cohorts (RNAseq, N=45 and NanoString, N=48) and other advanced cancer (N=534) treated with ICB were leveraged to investigate the predictive value of TMEscore. Simultaneously, multi-omics data from The Cancer Genome Atlas of Stomach Adenocarcinoma (TCGA-STAD) and Asian Cancer Research Group (ACRG) were interrogated for underlying mechanisms.

Results: The predictive capacity of TMEscore was corroborated in patient with mGC cohorts treated with pembrolizumab in a prospective phase 2 clinical trial (NCT02589496, N=45, area under the curve (AUC)=0.891). Notably, TMEscore, which has a larger AUC than programmed death-ligand 1 combined positive score, tumor mutation burden, microsatellite instability, and Epstein-Barr virus, was also validated in the multicenter advanced gastric cancer cohort using NanoString technology (N=48, AUC=0.877). Exploration of the intrinsic mechanisms of TMEscore with TCGA and ACRG multi-omics data identified TME pertinent mechanisms including mutations, metabolism pathways, and epigenetic features.

Conclusions: Current study highlighted the promising predictive value of TMEscore for patients with mGC. Exploration of TME in multi-omics gastric cancer data may provide the impetus for precision immunotherapy.
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http://dx.doi.org/10.1136/jitc-2021-002467DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8356190PMC
August 2021

Comprehensive analyses reveal TKI-induced remodeling of the tumor immune microenvironment in EGFR/ALK-positive non-small-cell lung cancer.

Oncoimmunology 2021 16;10(1):1951019. Epub 2021 Jul 16.

Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.

Tyrosine kinase inhibitors (TKI) play a pivotal role in the treatment of non-small-cell lung cancer (NSCLC) with mutations in epidermal growth factor receptor (EGFR) and rearrangements in anaplastic lymphoma kinase (ALK). However, the influences of TKIs on the tumor immune microenvironment (TIM), especially dynamic changes of responders, have not yet been fully elucidated. Therefore, RNA sequencing and whole-exome sequencing were performed on EGFR/ALK-positive NSCLC samples before and after TKI treatment. In combination with neoantigen and mutational-load estimations, xCell and single-sample gene set enrichment analysis (ssGSEA) were used to assess tumor immune-cell infiltration and activity. Furthermore, weighted-gene correlation network analysis and the bottleneck method were used to identify the hub genes that affected treatment-related immune responses. We found that TKI treatment remodeled the TIM in treatment-responsive samples. Profound increases in the rate of anti-tumor cell infiltration and cytotoxicity was observed following TKI treatment, while antigen presentation was limited in ALK-rearranged samples. However, no significant change in anti-tumor cell infiltration or cytotoxicity was found between pre-treatment and post-progression samples. Subsequently, we found that neurofilament heavy (NEFH) mutations were enriched in samples after TKI treatment and were associated with reduced neutrophil infiltration. The cytotoxicity of EGFR-mutant NSCLCs with co-driver TP53 mutation and ALK-rearranged samples with wild-type TP53 seems to be more easily induced by TKI. Finally, the immune-associated score generated by hub genes was positively correlated with immune infiltration, immune activation, and a favorable prognosis. In conclusion, the dynamic changes in the TIM provide clues to drug selection and timing for TKI-immunotherapy combinations.
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http://dx.doi.org/10.1080/2162402X.2021.1951019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8288040PMC
October 2021

Depression accelerates gastric cancer invasion and metastasis by inducing a neuroendocrine phenotype via the catecholamine/β -AR/MACC1 axis.

Cancer Commun (Lond) 2021 10 20;41(10):1049-1070. Epub 2021 Jul 20.

Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, P. R. China.

Background: Depression is a common, easily ignored, accompanied disease of gastric cancer (GC) patients and is often observed with elevated plasma catecholamine levels. Depression frequently promotes GC progression and leads to poor clinical outcomes; however, the molecular mechanisms underlying depression-induced GC progression remain poorly understood. We aimed to study the effects of depression on GC progression and explore possible mechanisms mediating the action of depression-associated catecholamines on GC.

Methods: Depression states of GC patients were graded using the Patient Health Questionnaire-9, and plasma catecholamine levels were examined by high performance liquid chromatography coupled with tandem mass spectrometry. Migrative and invasive GC cells were examined using transwell assays, and metastatic GC niches were imaged using bioluminescence technology in a depression mouse model established with chronic unpredictable mild stress. Mouse depression-like behaviors were assessed through sucrose preference, forced swimming, and tail suspension tests. Characteristics of the neuroendocrine phenotype were observed via RT-PCR, Western blotting, flow cytometry, and transmission electron microscopy.

Results: Fifty-one GC patients (age: 53.61 ± 1.79 years; cancer duration: 3.71 ± 0.33 months; depression duration: 2.37 ± 0.38 months; male-to-female ratio: 1.55:1) were enrolled in the study. Depression grade was significantly higher in GC patients showing higher plasma levels of catecholamines (epinephrine: P = 0.018; noradrenaline: P = 0.009), higher oncogene metastasis-associated in colon cancer-1 (MACC1) level (P = 0.018), and metastasis (P < 0.001). Further, depression-associated catecholamine specifically bound to the beta-2 adrenergic receptor (β -AR) and upregulated MACC1 expression, and thus promoting neuroendocrine phenotypic transformation through direct binding between MACC1 and synaptophysin. Eventually, the neuroendocrine phenotypic transformation accelerated GC invasion in vitro and metastasis in vivo. However, β -AR antagonist ICI-118,551 or MACC1 silencing effectively blocked the catecholamine-induced neuroendocrine phenotypic transformation and eliminated depression-enhanced GC migration and invasion. Moreover, β -AR blocking or MACC1 silencing prevented GC metastasis attributed to a neuroendocrine phenotype in a depression mouse model.

Conclusions: Catecholamine-induced neuroendocrine phenotypes of GC cells led to depression-accelerated GC invasion and metastasis via the β -AR/MACC1 axis, while β -AR antagonist or MACC1 silencing could reverse it, showing promising potential therapeutic strategies for improving the outcome of GC patients with comorbid depression.
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http://dx.doi.org/10.1002/cac2.12198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8504143PMC
October 2021

IOBR: Multi-Omics Immuno-Oncology Biological Research to Decode Tumor Microenvironment and Signatures.

Front Immunol 2021 2;12:687975. Epub 2021 Jul 2.

Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China.

Recent advances in next-generation sequencing (NGS) technologies have triggered the rapid accumulation of publicly available multi-omics datasets. The application of integrated omics to explore robust signatures for clinical translation is increasingly emphasized, and this is attributed to the clinical success of immune checkpoint blockades in diverse malignancies. However, effective tools for comprehensively interpreting multi-omics data are still warranted to provide increased granularity into the intrinsic mechanism of oncogenesis and immunotherapeutic sensitivity. Therefore, we developed a computational tool for effective Immuno-Oncology Biological Research (IOBR), providing a comprehensive investigation of the estimation of reported or user-built signatures, TME deconvolution, and signature construction based on multi-omics data. Notably, IOBR offers batch analyses of these signatures and their correlations with clinical phenotypes, long non-coding RNA (lncRNA) profiling, genomic characteristics, and signatures generated from single-cell RNA sequencing (scRNA-seq) data in different cancer settings. Additionally, IOBR integrates multiple existing microenvironmental deconvolution methodologies and signature construction tools for convenient comparison and selection. Collectively, IOBR is a user-friendly tool for leveraging multi-omics data to facilitate immuno-oncology exploration and to unveil tumor-immune interactions and accelerating precision immunotherapy.
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http://dx.doi.org/10.3389/fimmu.2021.687975DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8283787PMC
October 2021

CRIP1 cooperates with BRCA2 to drive the nuclear enrichment of RAD51 and to facilitate homologous repair upon DNA damage induced by chemotherapy.

Oncogene 2021 08 14;40(34):5342-5355. Epub 2021 Jul 14.

Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, PR China.

Homologous recombination (HR) repair is an important determinant of chemosensitivity. However, the mechanisms underlying HR regulation remain largely unknown. Cysteine-rich intestinal protein 1 (CRIP1) is a member of the LIM/double-zinc finger protein family and is overexpressed and associated with prognosis in several tumor types. However, to date, the functional role of CRIP1 in cancer biology is poorly understood. Here we found that CRIP1 downregulation causes HR repair deficiency with concomitant increase in cell sensitivity to cisplatin, epirubicin, and the poly ADP-ribose polymerase (PARP) inhibitor olaparib in gastric cancer cells. Mechanistically, upon DNA damage, CRIP1 is deubiquitinated and upregulated by activated AKT signaling. CRIP1, in turn, promotes nuclear enrichment of RAD51, which is a prerequisite step for HR commencement, by stabilizing BRCA2 to counteract FBXO5-targeted RAD51 degradation and by binding to the core domain of RAD51 (RAD51) in coordination with BRCA2, to facilitate nuclear export signal masking interactions between BRCA2 and RAD51. Moreover, through mass spectrometry screening, we found that KPNA4 is at least one of the carriers controlling the nucleo-cytoplasmic distribution of the CRIP1-BRCA2-RAD51 complex in response to chemotherapy. Consistent with these findings, RAD51 inhibitors block the CRIP1-mediated HR process, thereby restoring chemotherapy sensitivity of gastric cancer cells with high CRIP1 expression. Analysis of patient specimens revealed an abnormally high level of CRIP1 expression in GC tissues compared to that in the adjacent normal mucosa and a significant negative association between CRIP1 expression and survival time in patient cohorts with different types of solid tumors undergoing genotoxic treatments. In conclusion, our study suggests an essential function of CRIP1 in promoting HR repair and facilitating gastric cancer cell adaptation to genotoxic therapy.
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http://dx.doi.org/10.1038/s41388-021-01932-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8390368PMC
August 2021

Differences in the clinical presentation, management, and in-hospital outcomes of acute aortic dissection in patients with and without end-stage renal disease.

BMC Nephrol 2021 07 8;22(1):257. Epub 2021 Jul 8.

1Department of Cardiology, First Affiliated Hospital, Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Jiangxi Branch Center of National Geriatric Disease Clinical Medical Research Center, Gannan Medical University, Ganzhou, 341000, China.

Background: Few studies have evaluated the clinical presentation, management, and outcomes of patients with end-stage renal disease (ESRD) presenting with acute aortic dissection (AAD) in real-world clinical practice. Thus, this study investigated the clinical characteristics, management, and outcomes of AAD patients with ESRD.

Methods: A total of 217 patients were included. We evaluated the differences in the clinical features, management, and in-hospital outcomes of patients with and without a history of ESRD presenting with AAD.

Results: A history of ESRD was present in 71 of 217 patients. Patients with ESRD had atypical clinical manifestations (p < 0.001) and were more likely to be managed medically compared with patients without ESRD (p = 0.002). Hypertension and type B aortic dissection were significantly more common among patients with ESRD. Moreover, patients with ESRD had lower leucocyte and platelet counts than patients without ESRD in laboratory findings (p < 0.001). However, hospitalization days and in-hospital mortality were similar between the two groups (p > 0.05). Multivariate analysis identified Type A aortic dissection as an independent predictor of in-hospital mortality among patients without ESRD (OR, 13.68; 95% CI, 1.92 to 98.90; P = 0.006).

Conclusions: This study highlights differences in the clinical characteristics, management, and outcomes of AAD patients with ESRD. These patients usually have atypical symptoms and more comorbid conditions and are managed more conservatively. However, these patients have no in-hospital survival disadvantage over those without ESRD. Further studies are needed to better understand and optimize care for patients with ESRD presenting with AAD.
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http://dx.doi.org/10.1186/s12882-021-02432-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8265107PMC
July 2021

Growth differentiation factor 11 attenuates cardiac ischemia reperfusion injury via enhancing mitochondrial biogenesis and telomerase activity.

Cell Death Dis 2021 07 2;12(7):665. Epub 2021 Jul 2.

Department of Cardiology, State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Shock and Microcirculation, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.

It has been reported that growth differentiation factor 11 (GDF11) protects against myocardial ischemia/reperfusion (IR) injury, but the underlying mechanisms have not been fully clarified. Considering that GDF11 plays a role in the aging/rejuvenation process and that aging is associated with telomere shortening and cardiac dysfunction, we hypothesized that GDF11 might protect against IR injury by activating telomerase. Human plasma GDF11 levels were significantly lower in acute coronary syndrome patients than in chronic coronary syndrome patients. IR mice with myocardial overexpression GDF11 (oe-GDF11) exhibited a significantly smaller myocardial infarct size, less cardiac remodeling and dysfunction, fewer apoptotic cardiomyocytes, higher telomerase activity, longer telomeres, and higher ATP generation than IR mice treated with an adenovirus carrying a negative control plasmid. Furthermore, mitochondrial biogenesis-related proteins and some antiapoptotic proteins were significantly upregulated by oe-GDF11. These cardioprotective effects of oe-GDF11 were significantly antagonized by BIBR1532, a specific telomerase inhibitor. Similar effects of oe-GDF11 on apoptosis and mitochondrial energy biogenesis were observed in cultured neonatal rat cardiomyocytes, whereas GDF11 silencing elicited the opposite effects to oe-GDF11 in mice. We concluded that telomerase activation by GDF11 contributes to the alleviation of myocardial IR injury through enhancing mitochondrial biogenesis and suppressing cardiomyocyte apoptosis.
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http://dx.doi.org/10.1038/s41419-021-03954-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8253774PMC
July 2021

Characterizing a long-term chronic heart failure model by transcriptomic alterations and monitoring of cardiac remodeling.

Aging (Albany NY) 2021 04 23;13(10):13585-13614. Epub 2021 Apr 23.

Department of Cardiology, State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Lab of Shock and Microcirculation, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.

The long-term characteristics of transcriptomic alterations and cardiac remodeling in chronic heart failure (CHF) induced by myocardial infarction (MI) in mice are not well elucidated. This study aimed to reveal the dynamic changes in the transcriptome and cardiac remodeling in post-MI mice over a long time period. Monitoring C57BL/6 mice with MI for 8 months showed that approximately 44% of mice died of cardiac rupture in the first 2 weeks and others survived to 8 months with left ventricular (LV) aneurysm. The transcriptomic profiling analysis of cardiac tissues showed that the Integrin and WNT pathways were activated at 8 months after MI while the metabolism-related pathways were inversely inhibited. Subsequent differential analysis at 1 and 8 months post-MI revealed significant enrichments in biological processes, including consistent regulation of metabolism-related pathways. Moreover, echocardiographic monitoring showed a progressive increase in LV dimensions and a decrease in the LV fractional shortening during the first 4 weeks, and these parameters progressed at a lower rate till 8 months. A similar trend was found in the invasive LV hemodynamics, cardiac morphological and histological analyses. These results suggested that mouse MI model is ideal for long-term studies, and transcriptomic findings may provide new CHF therapeutic targets.
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http://dx.doi.org/10.18632/aging.202879DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8202904PMC
April 2021

Substituting chemical P fertilizer with organic manure: effects on double-rice yield, phosphorus use efficiency and balance in subtropical China.

Sci Rep 2021 04 21;11(1):8629. Epub 2021 Apr 21.

Soil and Fertilizer Institute of Hunan Province, Hunan Academy of Agricultural Sciences, 730 Yuanda No.2 Rd, Furong District, Changsha, 410125, China.

Organic manure is an ideal alternative fertilizer to provide phosphorus (P) but is not fully recycled in subtropical China. In order to identify if it can replace chemical P fertilizer, a 35-year field trail in a paddy soil under double-rice cropping system was conducted to assess the effects of substituting chemical P fertilizer with pig manure (NKM) on rice yield, phosphorus use efficiency (PUE) and P balance. The N, P and K input under NKM was 1.2, 0.8 and 1.2 times of the combined chemical fertilizer treatment (NPK), respectively. The NKM treatment reached the same level of grain yield with NPK after 20 years' application, and showed significantly 4.0% decreased double-rice grain yield compared with NPK over the 35 years. The NKM treatment reduced the crop P uptake leading to decreased PUE compared with NPK. Long-term P budget showed that NKM may result in higher potential of P loss than NPK. Thus, substituting chemical P fertilizer with organic manure under this rate of nutrient input slightly sacrificed the crop yield and may increase the P loss. Considering the benefits of soil fertility, adjusting the substitution rate with a more balanced NPK input might be alternative in subtropical China.
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http://dx.doi.org/10.1038/s41598-021-87851-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8060255PMC
April 2021

Immunosuppressive Microenvironment Revealed by Immune Cell Landscape in Pre-metastatic Liver of Colorectal Cancer.

Front Oncol 2021 23;11:620688. Epub 2021 Mar 23.

Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China.

Colorectal cancer, the fourth leading cause of cancer mortality, is prone to metastasis, especially to the liver. The pre-metastatic microenvironment comprising various resident stromal cells and immune cells is essential for metastasis. However, how the dynamic evolution of immune components facilitates pre-metastatic niche formation remains unclear. Utilizing RNA-seq data from our orthotopic colorectal cancer mouse model, we applied single sample gene set enrichment analysis and Cell type Identification By Estimating Relative Subsets Of RNA Transcripts to investigate the tumor microenvironment landscape of pre-metastatic liver, and define the exact role of myeloid-derived suppressor cells (MDSCs) acting in the regulation of infiltrating immune cells and gene pathways activation. Flow cytometry analysis was conducted to quantify the MDSCs levels in human and mice samples. In the current work, based on the high-throughput transcriptome data, we depicted the immune cell infiltration pattern of pre-metastatic liver and highlighted MDSCs as the dominant altered cell type. Notably, flow cytometry analysis showed that high frequencies of MDSCs, was detected in the pre-metastatic liver of orthotopic colorectal cancer tumor-bearing mice, and in the peripheral blood of patients with stage I-III colorectal cancer. MDSCs accumulation in the liver drove immunosuppressive factors secretion and immune checkpoint score upregulation, consequently shaping the pre-metastatic niche with sustained immune suppression. Metabolic reprogramming such as upregulated glycolysis/gluconeogenesis and HIF-1 signaling pathways in the primary tumor was also demonstrated to correlate with MDSCs infiltration in the pre-metastatic liver. Some chemokines were identified as a potential mechanism for MDSCs recruitment. Collectively, our study elucidates the alterations of MDSCs during pre-metastatic niche transformation, and illuminates the latent biological mechanism by which primary tumors impact MDSC aggregation in the targeted liver.
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http://dx.doi.org/10.3389/fonc.2021.620688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8021849PMC
March 2021

Loss of FoxO3a prevents aortic aneurysm formation through maintenance of VSMC homeostasis.

Cell Death Dis 2021 04 7;12(4):378. Epub 2021 Apr 7.

Department of Cardiology, Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, First Affiliated Hospital of Gannan Medical University, Gannan Medical University, University Town, Ganzhou Development District, 341000, Ganzhou, China.

Vascular smooth muscle cell (VSMC) phenotypic switching plays a critical role in the formation of abdominal aortic aneurysms (AAAs). FoxO3a is a key suppressor of VSMC homeostasis. We found that in human and animal AAA tissues, FoxO3a was upregulated, SM22α and α-smooth muscle actin (α-SMA) proteins were downregulated and synthetic phenotypic markers were upregulated, indicating that VSMC phenotypic switching occurred in these diseased tissues. In addition, in cultured VSMCs, significant enhancement of FoxO3a expression was found during angiotensin II (Ang II)-induced VSMC phenotypic switching. In vivo, FoxO3a overexpression in C57BL/6J mice treated with Ang II increased the formation of AAAs, whereas FoxO3a knockdown exerted an inhibitory effect on AAA formation in ApoE mice infused with Ang II. Mechanistically, FoxO3a overexpression significantly inhibited the expression of differentiated smooth muscle cell (SMC) markers, activated autophagy, the essential repressor of VSMC homeostasis, and promoted AAA formation. Our study revealed that FoxO3a promotes VSMC phenotypic switching to accelerate AAA formation through the P62/LC3BII autophagy signaling pathway and that therapeutic approaches that decrease FoxO3a expression may prevent AAA formation.
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http://dx.doi.org/10.1038/s41419-021-03659-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8027644PMC
April 2021

Novel biomarkers for post-contrast acute kidney injury identified from long non-coding RNA expression profiles.

Int J Biol Sci 2021 17;17(3):882-896. Epub 2021 Feb 17.

Department of Cardiology, Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510000, Guangdong, China.

Post-contrast acute kidney injury (PC-AKI) is a severe complication of cardiac catheterization. Emerging evidence indicated that long non-coding RNAs (lncRNAs) could serve as biomarkers for various diseases. However, the lncRNA expression profile and potential biomarkers in PC-AKI remain unclear. This study aimed to investigate novel lncRNA biomarkers for the early detection of PC-AKI. lncRNA profile in the kidney tissues of PC-AKI rats was evaluated through RNA sequencing. Potential lncRNA biomarkers were identified through human-rat homology analysis, kidney and blood filtering in rats and verified in 112 clinical samples. The expression patterns of the candidate lncRNAs were detected in HK-2 cells and rat models to evaluate their potential for early detection. In total, 357 lncRNAs were found to be differentially expressed in PC-AKI. We identified lnc-HILPDA and lnc-PRND were conservative and remarkably upregulated in both kidneys and blood from rats and the blood of PC-AKI patients; these lncRNAs can precisely distinguish PC-AKI patients (area under the curve (AUC) values of 0.885 and 0.875, respectively). The combination of these two lncRNAs exhibited improved accuracy for predicting PC-AKI, with 100% sensitivity and 83.93% specificity. Time-course experiments showed that the significant difference was first noted in the blood of PC-AKI rats at 12 h for lnc-HILPDA and 24 h for lnc-PRND. Our study revealed that lnc-HILPDA and lnc-PRND may serve as the novel biomarkers for early detection and profoundly affect the clinical stratification and strategy guidance of PC-AKI.
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http://dx.doi.org/10.7150/ijbs.45294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7975710PMC
January 2022

Long noncoding RNA (lncRNA) induces chemoresistance of gastric cancer via autophagy activation.

Autophagy 2021 12 25;17(12):4083-4101. Epub 2021 Mar 25.

Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.

Chemotherapy is currently the main treatment for unresectable or advanced postoperative gastric cancers. However, its efficacy is negatively affected by the occurrence of chemoresistance, which severely affects patient prognosis. Recently, dysregulation in autophagy has been suggested as a potential mechanism for chemoresistence, and long noncoding RNA (lncRNA) also shows its regulatory role in cancer drug resistance. Using RNA sequencing, we found that lncRNA was highly expressed in drug-resistant gastric cancer cells. In-vitro and in-vivo experiments showed that activated autophagy and induced drug resistance in gastric cancer cells by targeting ATG14. Bioinformatics and experimental results showed that regulated the expression of ATG14 through direct binding to enhance stabilization of mRNA and via blocking the degradation of mRNA through competitively binding with microRNA (miRNA) . Therefore, increased the expression of ATG14, contributing to activation of autophagy and chemoresistance. Furthermore, it was confirmed that and ATG14 were highly expressed in gastric cancer patients resistant to chemotherapy, and this was closely associated with patient prognosis. In conclusion, is involved in the regulation of autophagy and chemoresistance in gastric cancer cells by targeting ATG14. It may be a suitable new target for enhancing chemosensitivity and improving prognosis. 3-MA: 3-methyladenine; 5-Fu: 5-fluorouracil; ATG: autophagy related; C-CASP3: cleaved caspase 3; C-CASP7: cleaved caspase 7; C-PARP: cleaved PARP; CQ: chloroquine; CR: complete response; DIG: digoxigenin; ESR1: estrogen receptor 1; FBS: fetal bovine serum; FISH: fluorescence in situ hybridization; IHC: immunohistochemistry; ISH: in situ hybridization; lncRNA: long noncoding RNA; miRNA: microRNA; MUT: mutant; NC: negative control; OXA: oxaliplatin; PBS: phosphate-buffered saline; PD: progressive disease; PFA: paraformaldehyde; PR: partial response; qPCR: quantitative polymerase chain reaction; RAPA: rapamycin; SD: stable disease; TEM: transmission electron microscopy; WT: wild type.
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http://dx.doi.org/10.1080/15548627.2021.1901204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8726636PMC
December 2021
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