Publications by authors named "Lili Li"

599 Publications

GOLM1 suppresses autophagy-mediated anti-tumor immunity in hepatocellular carcinoma.

Signal Transduct Target Ther 2021 Sep 17;6(1):335. Epub 2021 Sep 17.

Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA.

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http://dx.doi.org/10.1038/s41392-021-00673-6DOI Listing
September 2021

Methods to Identify Immunogenic Peptides in SARS-CoV-2 Spike and Protective Monoclonal Antibodies in COVID-19 Patients.

Small Methods 2021 Jul 19;5(7):2100058. Epub 2021 Jun 19.

Department of Microbiology Immunology & Molecular Genetics University of California Los Angeles Los Angeles CA 90095 USA.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the associated COVID-19 diseases are an emerging threat to global public health. Although considerable scientific research on the immune, especially antibody, responses to SARS-CoV-2 infection have been conducted, additional dominant epitopes and protective antibodies are needed for diagnosis and treatment of COVID-19 patients. Here, two different phage libraries are used to identify immunogenic epitopes across the spike protein and monoclonal antibodies from COVID-19 patients. Three peptides are further characterized in the receptor-binding motif (RBM) and measured their antibody levels in COVID-19 patients, from which one identifies one most immunodominant epitope with the highest antibody response in COVID-19 patients and in immunized mice. More importantly, monoclonal antibodies specifically binding to this peptide isolated from COVID-19 patients have therapeutic potential to neutralize SARS-CoV-2 infection. Thus, the approaches to systemically identify immunogenic peptides and directly identify human monoclonal antibodies from patients will provide useful diagnostic and therapeutic tools for COVID-19 and other emerging infectious diseases.
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http://dx.doi.org/10.1002/smtd.202100058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8420616PMC
July 2021

PRG5 Knockout Precipitates Late-Onset Hypersusceptibility to Pilocarpine-Induced Juvenile Seizures by Exacerbating Hippocampal Zinc Signaling-Mediated Mitochondrial Damage.

Front Neurosci 2021 27;15:715555. Epub 2021 Aug 27.

Division of Brain Science, Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, China.

Introduction: Epileptogenesis is understood as the plastic process that produces a persistent reorganization of the brain's neural network after a precipitating injury (recurrent neonatal seizures, for instance) with a latent period, finally leading to neuronal hyperexcitability. Plasticity-related genes (PRGs), also known as lipid phosphate phosphatase-related proteins (PLPPRs), are regulators of mitochondrial membrane integrity and energy metabolism. This study was undertaken to determine whether PRG5 gene knockout contributes to the delayed hypersensitivity induced by developmental seizures and the aberrant sprouting of hippocampal mossy fibers, and to determine whether it is achieved through the mitochondrial pathway. Here, we developed a "twist" seizure model by coupling pilocarpine-induced juvenile seizures with later exposure to penicillin to test the long-term effects of PRG5 knockout on seizure latency through comparison with wild-type (WT) mice. Hippocampal mossy fiber sprouting (MFS) was detected by Timm staining. In order to clarify the mechanism of the adverse reactions triggered by PRG5 knockout, hippocampal HT22 neuronal cultures were exposed to glutamate, with or without PRG5 interference. Mitochondrial function, oxidative stress indicators and zinc ion content were detected.

Results: PRG5 gene knockout significantly reduced the seizure latency, and aggravated the lowered seizure threshold induced by developmental seizures. Besides, knockout of the PRG5 gene reduced the MFS scores to a certain extent. Furthermore, PRG5 gene silencing significantly increases the zinc ion content in hippocampal neurons, impairs neuronal activity and mitochondrial function, and exacerbates glutamate-induced oxidative stress damage.

Conclusion: In summary, PRG5 KO is associated with significantly greater hypersusceptibility to juvenile seizures in PRG5 mice compared with WT mice. These effects may be related to the hippocampal zinc signaling. The effects do not appear to be related to changes in MFS because KO mice with juvenile seizures had the shortest seizure latencies but exhibited less MFS than WT mice with juvenile seizures.
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http://dx.doi.org/10.3389/fnins.2021.715555DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8430038PMC
August 2021

The gut microbiota and its products: Establishing causal relationships with obesity related outcomes.

Obes Rev 2021 Sep 6. Epub 2021 Sep 6.

Yantai Institute of Coastal Zone Research, Chinese Academy of Sciences, Yantai, China.

Gut microorganisms not only participate in the metabolism of carbohydrate, lipids, protein, and polypeptides in the intestine but also directly affect the metabolic phenotypes of the host. Although many studies have described the apparent effects of gut microbiota on human health, the development of metagenomics and culturomics in the past decade has generated a large amount of evidence suggesting a causal relationship between gut microbiota and obesity. The interaction between the gut microbiota and host is realized by microbial metabolites with multiple biological functions. We concentrated here on several representative beneficial species connected with obesity as well as the mechanisms, with particular emphasis on microbiota-dependent metabolites. Finally, we consider the potential clinical significance of these relationships to fuel the conception and realization of novel therapeutic and preventive strategies.
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http://dx.doi.org/10.1111/obr.13341DOI Listing
September 2021

Epithelial Bone Morphogenic Protein 2 and 4 Are Indispensable for Tooth Development.

Front Physiol 2021 16;12:660644. Epub 2021 Aug 16.

Department of Stomatology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.

The and expressed in root mesenchyme were essential for the patterning and cellular differentiation of tooth root. The role of the epithelium-derived Bmps in tooth root development, however, had not been reported. In this study, we found that the double abrogation of and from mouse epithelium caused short root anomaly (SRA). The ; ; mice exhibited a persistent Hertwig's Epithelial Root Sheath (HERS) with the reduced cell death, and the down-regulated BMP-Smad4 and Erk signaling pathways. Moreover, the expression in the HERS, the Shh-Gli1 signaling, and expression in the root mesenchyme of the ; ; mice were also decreased, indicating a disrupted epithelium- mesenchyme interaction between HERS and root mesenchyme. Such disruption suppressed the and expression in the root mesenchyme, indicating an impairment on the differentiation and maturation of root odontoblasts. The impaired differentiation and maturation of root odontoblasts could be rescued partially by transgenic . Therefore, although required in a low dosage and with a functional redundancy, the epithelial Bmp2 and Bmp4 were indispensable for the HERS degeneration, as well as the differentiation and maturation of root mesenchyme.
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http://dx.doi.org/10.3389/fphys.2021.660644DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8415269PMC
August 2021

MIG/CXCL9 exacerbates the progression of metabolic-associated fatty liver disease by disrupting Treg/Th17 balance.

Exp Cell Res 2021 Aug 27;407(2):112801. Epub 2021 Aug 27.

Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, PR China. Electronic address:

CD4CD25 regulatory T (Treg) cells and Th17 cells play important roles in the progression of metabolic-associated fatty liver disease (MAFLD). However, the contribution of monokine induced by interferon-gamma (MIG)/CXCL9 to the Treg/Th17 imbalance in MAFLD is only partially understood. In the present study, we detected increased levels of MIG/CXCL9 and a Treg/Th17 imbalance in the setting of metabolic-associated steatohepatitis (MASH). Recombinant adeno-associated virus-mediated gene transfer and silencing of MIG/CXCL9 expression in mice alleviated MASH and increased the Treg/Th17 ratio. Furthermore, the percentage of Th17 cells, but not Treg cells, differentiated from splenic CD4 T cells was significantly increased by administration of MIG/CXCL9. MIG/CXCL9 also promoted Th17 cell proliferation, and its effects were dose dependent. Levels of phosphorylated c-Jun N-terminal kinase (JNK) decreased dramatically when MIG/CXCL9 was inhibited in a murine MASH model. In cultured Treg cells, phosphorylated JNK levels decreased dose-dependently in response to MIG/CXCL9 inhibition, but increased in cultured Th17 cells. This effect was blocked in the presence of a JNK inhibitor. These findings underline the fundamental importance of MIG/CXCL9 in maintaining the Treg/Th17 balance in MAFLD and provide the foundations for a novel approach to preventing and treating MAFLD.
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http://dx.doi.org/10.1016/j.yexcr.2021.112801DOI Listing
August 2021

Silencing YKL-40 gene can inhibit inflammatory factor expression and affects the effect of THP-1 cells on endometrial cancer.

Arch Gynecol Obstet 2021 Aug 21. Epub 2021 Aug 21.

The Fourth Affiliated Hospital of Guangxi Medical University, Liuzhou, China.

Purpose: To investigate the effect of silencing the YKL-40 gene on the expression of inflammatory factors and the effect of silencing the YKL-40 gene of THP-1 cells on endometrial cancer.

Methods: We used a siRNA targeting a sequence in YKL-40 (si-YKL-40) to transfect HEC-1A and THP-1 cells. Quantitative real-time polymerase chain reaction assay was performed to investigate the mRNA levels of YKL-40, IL-8 and MMP-9 in HEC-1A and THP-1 cells. Migration, and invasion assays were performed to identify the effects of co-culture with THP-1 cells that silenced YKL-40 gene on the migration and invasion capacity of HEC-1A cells. Tube formation ability were detected by Matrigel-based angiogenesis assay.

Results: We successfully transfected HEC-1A and THP-1 cells with lentivirus to silence the YKL-40 gene. Compared with the blank control group and NC group, the expression of YKL-40, IL-8 and MMP-9 which were examined by qRT-PCR in YKL-40-siRNA group was significantly reduced in the two cell lines; after co-cultured with the supernatant of transfected THP-1 cells, the migration and invasion ability of HEC-1A cells in YKL-40-siRNA group was significantly reduced; the number of tubes in the YKL-40-siRNA group was significantly reduced, the spacing between the tubes was significantly increased, and the structure of tubes was incomplete.

Conclusion: Silencing the YKL-40 gene in THP-1 cells can inhibit the expression of inflammatory factors, the invasion and migration of human endometrial cancer cells and the capacity of vitro angiogenic. And YKL-40 gene as a marker of inflammation may be an effective therapeutic target for endometrial cancer.
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http://dx.doi.org/10.1007/s00404-021-06194-5DOI Listing
August 2021

Network analysis of miRNA targeting m6A-related genes in patients with esophageal cancer.

PeerJ 2021 29;9:e11893. Epub 2021 Jul 29.

Department of Radiation Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Background: We investigated the miRNA-m6A related gene network and identified a miRNA-based prognostic signature in patients with esophageal cancer using integrated genomic analysis.

Methods: We obtained expression data for m6A-related genes and miRNAs from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets. Survival analysis was conducted to identify potential prognostic biomarkers. LASSO Cox regression was performed to construct the overall survival (OS) associated prediction signature. We used the Kaplan-Meier (K-M) curve and receiver operating characteristic (ROC) curves to explore the signature's efficiency and accuracy. Interactions between the m6A-related genes and miRNAs were identified in starBase3.0 and used to construct the miRNA-m6A related gene network.

Results: We found that HNRNPC, YTHDF, ZC3H13, YTHDC2, and METTL14 were dysregulated in esophageal cancer tissues. Multivariate Cox regression analysis revealed that HNRNPC may be an independent risk factor for OS. Five hundred twenty-two potential upstream miRNAs were obtained from starBase3.0. Four miRNAs (miR-186, miR-320c, miR-320d, and miR-320b) were used to construct a prognostic signature, which could serve as a prognostic predictor independent from routine clinicopathological features. Finally, we constructed a key miRNA-m6A related gene network and used one m6A-related gene and four miRNAs associated with the prognosis. The results of our bioinformatics analysis were successfully validated in the human esophageal carcinoma cell lines KYSE30 and TE-1.

Conclusion: Our study identified a 4-miRNA prognostic signature and established a key miRNA-m6A related gene network. These tools may reliably assist with esophageal cancer patient prognosis.
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http://dx.doi.org/10.7717/peerj.11893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8325912PMC
July 2021

Thermal Comfort Index for Lactating Water Buffaloes under Hot and Humid Climate.

Animals (Basel) 2021 Jul 11;11(7). Epub 2021 Jul 11.

Key Laboratory of Buffalo Genetics, Breeding and Reproduction Technology, Ministry of Agriculture and Guangxi Buffalo Research Institute, Chinese Academy of Agricultural Sciences, Nanning 530001, China.

Heat stress results in serious performance losses and adversely affects animal health and welfare under various production systems. This study was conducted to develop a thermal comfort model for lactating buffaloes under hot and humid climate. Twenty Nili-Ravi buffaloes were randomly enrolled for this one-year study. Physiological parameters including rectal temperature (RT), respiratory rate (RR), and body surface temperature (BST) and environmental variables such as wet bulb temperature (WBT), dew point temperature (DPT), and black globe temperature (BGT) were recorded twice a week on each Tuesday and Thursday ( = 1602 and 1560, respectively) at 8:00 am and 2:30 pm. Moreover, ambient temperature (AT, °C) and relative humidity (RH, %), at an interval of every 30 min were recorded. We used a typical correlation analysis to build the index models for thermal comfort. The results revealed that AT positively correlated with BGT, WBT, DPT, BST, RT, and RR, while RH negatively correlated with RT. Moreover, a physiological index model consisting of BST, RT and RR (P1 = 0.578 × BST + 0.047 × RT + 0.429 × RR) and an environmental index model (E1 = 0.881 × AT + 0.194 × RH + 0.455 × BGT - 0.347 × WBT + 0.032 × DPT) proved to be a more accurate index as a pair to reveal the state of thermal comfort in lactating buffaloes. Moreover, these models correlated well with physiological variables, indicating that this this pair of index models can be used to effectively evaluate the thermal comfort in buffaloes.
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http://dx.doi.org/10.3390/ani11072067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8300202PMC
July 2021

Tissue distribution and developmental changes of PTEN in the immune organs of chicken and effect of IBDV infection on it.

Poult Sci 2021 Sep 27;100(9):101356. Epub 2021 Jun 27.

College of Animal Science and Veterinary Medicine, Henan Institute of Science and Technology, Xinxiang, 453003, Henan, China. Electronic address:

Phosphatase and tensin homolog (PTEN), a tumor suppressor gene, functions in antiviral innate immunity and regulates the development and function of T cells and B cells. However, limited information about PTEN is available in poultry. In the present study, quantitative real-time polymerase chain reaction and immunohistochemistry staining were used to study the tissue distribution and developmental changes of PTEN in the main immune organs of chicken. The effects of infectious bursal disease virus (IBDV) infection on PTEN mRNA expression in the bursa of Fabricius (BF) of chickens were also investigated. The results are as follows. 1) The order of PTEN mRNA expression levels at the 18th d of hatching (E18) was: muscle and immune organs (spleen and thymus) > visceral organs (heart, lung, kidney, and liver) > hypothalamus and digestive tracts (duodenum, jejunum, ileum, cecum, proventriculus, BF [originates from cloaca], and cecum tonsil [locates at the lamina propria of cecum]). However, at the 15th d of raising (D15), the PTEN mRNA expression in the heart was the highest among all the tissues, followed by those in the liver, proventriculus, and kidney. The PTEN mRNA expression levels in the rest tissues were very low and were only 1.20 to 19.47% as much as that in the heart (P < 0.05). 2) The changes in the expression of PTEN mRNA in the BF, spleen, and thymus from E15 to D15 had no obvious regularity. PTEN-immunopositive (PTEN-ip) cells in the BF were distributed in epithelium mucosa, bursal follicles and interfollicles before hatching, but only in bursal follicles after hatching. PTEN-ip cells in the spleen were expressed in the periarterial lymphatic sheath from E18 to D15. Most of PTEN-ip cells distributed in the thymic medulla and only a few distributed in the thymic cortex during the whole experiment. 3) Chicken with IBDV infection had a remarkable decrease in PTEN mRNA expression from 1 d postinfection (dpi) to 7 dpi. Although PTEN mRNA level was reversed at 7 dpi, it was still significantly lower than that at 0 dpi (P < 0.05). These findings suggest that the PTEN of chicken might play important roles in the development of embryos and T/B lymphocytes, and the downregulation of PTEN in chickens infected with IBDV might be a mechanism of IBDV evasion from host immunity. Strategies designed to restore PTEN expression may be a therapy for preventing chickens from IBDV infection.
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http://dx.doi.org/10.1016/j.psj.2021.101356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8350381PMC
September 2021

Duzhong Fang Attenuates the POMC-Derived Neuroinflammation in Parkinsonian Mice.

J Inflamm Res 2021 23;14:3261-3276. Epub 2021 Jul 23.

State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, People's Republic of China.

Background: Neuroinflammation and microglia reactivity are now recognized to be features of Parkinson's disease (PD). Thus, microglia phenotype is a potential new target for developing treatments against PD. Duzhong Fang (DZF) is a traditional Chinese medicine (TCM) prescription. The theory of TCM argues that Duzhong Fang, nourishing yin and tonifying yang, may treat PD. However, its modern pharmacological studies and the underlying mechanisms are unclear.

Methods: First, MPTP was used to establish a parkinsonian mouse model, and behavioral testing was used to evaluate the locomotor dysfunction. Then, HPLC, immunohistochemical staining, and Western blot assays were performed to evaluate the survival of dopaminergic neurons. Molecular biological and immunofluorescence staining were used to evaluate the neuroinflammation and microglial activation. In addition, RNA-seq transcriptomics was used to analyze differentially expressed genes and verify by RT-PCR.

Results: In the present study, we first confirmed that DZF can alleviate neuroinflammation and ameliorate dyskinesia in parkinsonian mice. Then, further studies found that DZF can regulate microglial morphology and reactivity and act on the POMC gene. POMC is an upstream target for regulating inflammation and proinflammatory cytokines, and DZF can directly inhibit the POMC level and restore the homeostatic signature of microglia in parkinsonian mice.

Conclusion: This study found that POMC may have a potential role as a therapeutic target for PD. DZF may inhibit neuroinflammation and play an anti-PD effect by down-regulating the expression of POMC.
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http://dx.doi.org/10.2147/JIR.S316314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8315774PMC
July 2021

GTPase ROP6 negatively modulates phosphate deficiency through inhibition of PHT1;1 and PHT1;4 in Arabidopsis thaliana.

J Integr Plant Biol 2021 Jul 20. Epub 2021 Jul 20.

State Key Laboratory of Crop Stress Biology for Arid Areas and College of Life Sciences, Northwest A&F University, Yangling, 712100, China.

Phosphorus, an essential macroelement for plant growth and development, is a major limiting factor for sustainable crop yield. The Rho of plant (ROP) GTPase is involved in regulating multiple signal transduction processes in plants, but potentially including the phosphate deficiency signaling pathway remains unknown. Here, we identified that the rop6 mutant exhibited a dramatic tolerant phenotype under Pi-deficient conditions, with higher phosphate accumulation and lower anthocyanin content. In contrast, the rop6 mutant was more sensitive to arsenate (As(V)) toxicity, the analog of Pi. Immunoblot analysis displayed that the ROP6 protein was rapidly degraded through ubiquitin/26S proteasome pathway under Pi-deficient conditions. In addition, pull-down assay using GST-RIC1 demonstrated that the ROP6 activity was decreased obviously under Pi-deficient conditions. Strikingly, protein-protein interaction and two-voltage clamping assays demonstrated that ROP6 physically interacted with and inhibited the key phosphate uptake transporters PHT1;1 and PHT1;4 in vitro and in vivo. Moreover, genetic analysis showed that ROP6 functioned upstream of PHT1;1 and PHT1;4. Thus, we conclude that GTPase ROP6 modulates the uptake of phosphate by inhibiting the activities of PHT1;1 and PHT1;4 in Arabidopsis.
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http://dx.doi.org/10.1111/jipb.13153DOI Listing
July 2021

A Novel HCC Prognosis Predictor EEF1E1 Is Related to Immune Infiltration and May Be Involved in EEF1E1/ATM/p53 Signaling.

Front Oncol 2021 2;11:700972. Epub 2021 Jul 2.

Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Background: EEF1E1 has been reported to play a role in ovarian cancer, breast cancer, non-small cell lung cancer and other cancers, but its role and mechanism in hepatocellular carcinoma (HCC) are still unknown.

Methods: EEF1E1 expression in human HCC was analyzed the GTEx and TCGA database. Logistic regression analysis was used to analyze the clinicopathological correlation of EEF1E1 expression. The correlation between EEF1E1 expression and patients' prognosis was analyzed in HCC, shown by forest plots, nomogram and Kaplan-Meier curves. Hazard ratio (HR) with 95% confidence intervals and log-rank -value were calculated multivariate/univariate survival analyses. Moreover, the correlation between EEF1E1 and tumor immune infiltration was analyzed using the gsva package with the ssgsea algorithm. Pearson correlation was used to investigate the correlation between EEF1E1 expression and p53 pathway genes expression. Two third-party databases were used to validate the content of EEF1E1 protein and mRNA expression patterns and prognosis analysis. The immunohistochemistry and multiplex immunohistochemistry was used to verify the bio-informatics results.

Results: EEF1E1 mRNA and protein expression in tumor was statistically higher than normal (EEF1E1 mRNA: < 0.001; EEF1E1 protein: < 0.01). Results from paired t-test (cancer and adjacent tissues) exhibited consistent trend (t = 7.572, < 0.001). Immunohistochemistry showed that EEF1E1 is highly expressed in cancer. The expression of EEF1E1 was positively correlated with body weight, BMI, tumor status, vascular invasion, AFP, logistic grade, T stage and pathological stage. The univariate Cox model revealed that high EEF1E1 expression was strongly associated with worse OS (HR=2.581; 95% CI: 1.782-3.739; < 0.001), as was T stage, pathologic stage, Histologic grade. High EEF1E1 expression was the only independent prognostic factor associated with OS (HR=2.57; 95% CI: 1.715-3.851; < 0.001) in the multivariate analysis. EEF1E1 was significantly correlated with various immune cells, including cytotoxic cells, DC, macrophages, neutrophils, NK cd56bright, TFH, Tgd, Th17, Th2, Treg. Multiplex immunohistochemistry showed that the EEF1E1 protein level is positively correlated to the CD3, CD4, PD1 and is negatively correlated to the CD8. The expression level of EEF1E1 in HCC was significantly correlated with the key genes involved in the p53 pathway. The expression of EEF1E1, ATM, p53 and CASPASE3 in HCC tissues was significantly higher than that in adjacent tissues.

Conclusion: EEF1E1 is highly expressed in cancer tissues in HCC. EEF1E1's high expression is significantly correlated with worse prognosis and immune cell infiltration of HCC. EEF1E1 may be participating in EEF1E1/ATM/p53 signaling pathway in HCC.
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http://dx.doi.org/10.3389/fonc.2021.700972DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8285289PMC
July 2021

Cancer cells escape p53's tumor suppression through ablation of ZDHHC1-mediated p53 palmitoylation.

Oncogene 2021 Sep 19;40(35):5416-5426. Epub 2021 Jul 19.

Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.

The inactivation of tumor-suppressor genes contributes heavily to oncogenesis. The mutation of TP53 has been well-studied and recognized as a major factor in the development of tumors. Yet other means of p53 inactivation has not been well-elucidated. We previously identified a hypermethylated gene ZDHHC1 that suppresses tumor growth when the expression was restored, but the specific mechanism was yet to be found. The protein product of ZDHHC1 is an S-palmitoyltransferase and we have identified p53 as a substrate for ZDHHC1-mediated palmitoylation, specifically at the C135, C176, and C275 residues. The novel form of post-translational modification of p53 is required for the nuclear translocation of the tumor suppressor. p53 recruited DNMT3A to ZDHHC1 promoter and is responsible for the hypermethylation of ZDHHC1. The epigenetic feedback loop formed by ZDHHC1 and p53 sheds light on the inactivation of p53 without the presence of genetic mutations.
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http://dx.doi.org/10.1038/s41388-021-01949-5DOI Listing
September 2021

Publisher Correction: Leveraging breeding programs and genomic data in Norway spruce (Picea abies L. Karst) for GWAS analysis.

Genome Biol 2021 Jul 15;22(1):210. Epub 2021 Jul 15.

Umeå Plant Science Centre, Department Forest Genetics and Plant Physiology, Swedish University of Agricultural Sciences, SE-90183, Umeå, Sweden.

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http://dx.doi.org/10.1186/s13059-021-02421-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8281665PMC
July 2021

Nasopharyngeal carcinoma: an evolving paradigm.

Nat Rev Clin Oncol 2021 Jun 30. Epub 2021 Jun 30.

State Key Laboratory of Translational Oncology, Sir YK Pao Centre for Cancer, Department of Clinical Oncology, Hong Kong Cancer Institute, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR.

The past three decades have borne witness to many advances in the understanding of the molecular biology and treatment of nasopharyngeal carcinoma (NPC), an Epstein-Barr virus (EBV)-associated cancer endemic to southern China, southeast Asia and north Africa. In this Review, we provide a comprehensive, interdisciplinary overview of key research findings regarding NPC pathogenesis, treatment, screening and biomarker development. We describe how technological advances have led to the advent of proton therapy and other contemporary radiotherapy approaches, and emphasize the relentless efforts to identify the optimal sequencing of chemotherapy with radiotherapy through decades of clinical trials. Basic research into the pathogenic role of EBV and the genomic, epigenomic and immune landscape of NPC has laid the foundations of translational research. The latter, in turn, has led to the development of new biomarkers and therapeutic targets and of improved approaches for individualizing immunotherapy and targeted therapies for patients with NPC. We provide historical context to illustrate the effect of these advances on treatment outcomes at present. We describe current preclinical and clinical challenges and controversies in the hope of providing insights for future investigation.
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http://dx.doi.org/10.1038/s41571-021-00524-xDOI Listing
June 2021

Smad3 gene C-terminal phosphorylation site mutation exacerbates CCl-induced hepatic fibrogenesis by promoting pSmad2L/C-mediated signaling transduction.

Naunyn Schmiedebergs Arch Pharmacol 2021 08 30;394(8):1779-1786. Epub 2021 Jun 30.

Department of Pharmacology, Key Laboratory of Anti-Inflammatory and Immunopharmacology, Ministry of Education, Anhui Medical University, 81 Meishan Road, Hefei, 230032, China.

Current researches have confirmed that Smads, mediators of TGF-β signaling, are strictly controlled by domain-specific site phosphorylation in the process of hepatic disease. Usually, Smad3 phospho-isoform pSmad3L and pSmad3C are reversible and antagonistic; pSmad2L/C could act together with pSmad3L by stimulating PAI-1 expression and ECM synthesis to transmit fibrogenic signals. Our recent study found that pSmad3C mutation is supposed to perform a vigorous role on the early phase of liver injury and abates salvianolic acid B's anti-hepatic fibrotic-carcinogenesis. However, whether pSmad3C mutation expedites pSmad2L/C-mediated signaling transduction during hepatic fibrogenesis remains vague. Presently, Smad3 gene C-terminal phosphorylation site mutation heterozygote (pSmad3C) mice were constructed to probe if and how pSmad3C retards CCl-induced hepatic fibrogenesis by inhibiting pSmad2L/C-mediated signaling transduction. Twelve 6-week-old pSmad3C C57BL/6J mice were intraperitoneally injection with CCl for 6 weeks to induce liver fibrogenesis. Results showed that pSmad3C mutation aggravates the relative liver weight, biochemical parameters, collagenous fibers and fibrotic septa formation, contributes to fibrogenesis in HT-CCl mice. Furthermore, fibrotic-related proteins TGF-β, pSmad2C, pSmad2L, and PAI-1 were also increased in CCl-induced pSmad3C mice. These results suggest that pSmad3C mutation exacerbates hepatic fibrogenesis which relates to intensifying pSmad2L/C-mediated signaling transduction.
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http://dx.doi.org/10.1007/s00210-021-02114-1DOI Listing
August 2021

ADP-ribosyltransferase PARP11 suppresses Zika virus in synergy with PARP12.

Cell Biosci 2021 Jun 29;11(1):116. Epub 2021 Jun 29.

Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA, 90095, USA.

Background: Zika virus (ZIKV) infection and ZIKV epidemic have been continuously spreading silently throughout the world and its associated microcephaly and other serious congenital neurological complications poses a significant global threat to public health. Type I interferon response to ZIKV infection in host cells suppresses viral replication by inducing the expression of interferon-stimulated genes (ISGs).

Methods: The study aims to demonstrate the anti-ZIKV mechanism of PARP11. PARP11 knock out and overexpressing A549 cell lines were constructed to evaluate the anti-ZIKV function of PARP11. PARP11, PARP12 and PARP11PARP12 HEK293T cell lines were constructed to explain the synergistic effect of PARP11 and PARP12 on NS1 and NS3 protein degradation. Western blotting, immunofluorescence and immunoprecipitation assay were performed to illustrate the interaction between PARP11 and PARP12.

Results: Both mRNA and protein levels of PARP11 were induced in WT but not IFNAR1 cells in response to IFNα or IFNβ stimulation and ZIKV infection. ZIKV replication was suppressed in cells expressed PARP11 but was enhanced in PARP11 cells. PARP11 suppressed ZIKV independently on itself PARP enzyme activity. PARP11 interacted with PARP12 and promoted PARP12-mediated ZIKV NS1 and NS3 protein degradation.

Conclusion: We identified ADP-ribosyltransferase PARP11 as an anti-ZIKV ISG and found that it cooperated with PARP12 to enhance ZIKV NS1 and NS3 protein degradation. Our findings have broadened the understanding of the anti-viral function of ADP-ribosyltransferase family members, and provided potential therapeutic targets against viral ZIKV infection.
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http://dx.doi.org/10.1186/s13578-021-00628-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8240438PMC
June 2021

Memory-Based Event-Triggered Output Regulation for Networked Switched Systems With Unstable Switching Dynamics.

IEEE Trans Cybern 2021 Jun 24;PP. Epub 2021 Jun 24.

This article studies an event-triggered asynchronous output regulation problem (EAORP) for networked switched systems (NSSs) with unstable switching dynamics (USDs) including all modes unstable and partial switching instants destabilization, which means that the Lyapunov function increases both on the activation intervals of all subsystems and at some switching instants. First, a memory-based mode-compared event-triggered mechanism for switched systems is proposed to effectively shorten asynchronous intervals, which employs historical sampled outputs and compares the mode of the current sampled instant and the adjacent sampled instant. Then, the maximum average dwell time for a novel switching signal is derived with a constraint on the ratio of total destabilizing switchings to total stabilizing switchings, which relaxes the requirement of the regular arrangement of destabilizing and stabilizing switchings. Moreover, with the help of different coordinate transformations in the EAORP, the discretized Lyapunov functions are no longer needed when synthesizing the NSSs with USDs, and the asynchronous switching situation is also discussed. Afterward, by designing a dynamic output feedback controller, sufficient conditions are given to solve the EAORP for NSSs with USDs subject to network-induced delays, packet disorders, and packet losses. Finally, the effectiveness of the proposed methods is verified via a switched RLC circuit.
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http://dx.doi.org/10.1109/TCYB.2021.3081927DOI Listing
June 2021

Astragaloside IV inhibits hepatocellular carcinoma by continually suppressing the development of fibrosis and regulating pSmad3C/3L and Nrf2/HO-1 pathways.

J Ethnopharmacol 2021 Oct 19;279:114350. Epub 2021 Jun 19.

Department of Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immunopharmacology, Ministry of Education, Hefei 230032, China. Electronic address:

Ethnopharmacological Relevance: Astragalus is a medicinal herb used in China for the prevention and treatment of diseases such as diabetes and cancer. As one of the main active ingredients of astragalus, Astragaloside IV (AS-IV) has a wide range of pharmacological effects, including anti-inflammation and anti-cancer effects.

Aim Of The Study: Different phosphorylated forms of Smad3 differentially regulate the progression of hepatic carcinoma. The phosphorylation of the COOH-terminal of Smad3 (pSmad3C) and activation of the Nrf2/HO-1 pathway inhibits hepatic carcinoma, while phosphorylation of the linker region of Smad3 (pSmad3L) promotes progression. Thus, pSmad3C/3L and Nrf2/HO-1 pathways are potential targets for drug of anti-cancer development. AS-IV is anti-apoptotic and can inhibit hepatocellular carcinoma cell (HCC) proliferation, invasion, and tumor growth in nude mice. However, it is not clear whether AS-IV has a therapeutic effect on inhibiting the progression of primary liver cancer by regulating the pSmad3C/3L and Nrf2/HO-1 pathway. The purpose of this study is to investigate whether AS-IV inhibits hepatocellular carcinoma by regulating pSmad3C/3L and Nrf2/HO-1 pathway.

Materials And Methods: primary liver cancer in mice induced by DEN/CCl/CHOH (DCC) and HSC-T6/HepG2 cell models activated by TGF-β was investigated for the mechanisms of AS-IV. In vivo assays included liver biopsy, histopathology and post-mortem analysis included immunohistochemistry, immunofluorescent, and Western blotting analysis, and in vitro assays included immunofluorescent, and Western blotting analysis.

Results: AS-IV significantly inhibited the development of primary liver cancer, reflecting improved liver biopsy, histopathology. The incidence and multiplicity of primary liver cancer were markedly decreased by AS-IV treatment at the 20th week. AS-IV had observable effects on the TGF-β/Smad and Nrf2/HO-1 expression in vivo, especially up-regulated pSmad3C, pNrf2, HO-1, and NQO1, while it down-regulated pSmad2C, pSmad2L, pSmad3L, PAI-1, and α-SMA at the 12th week and the 20th week. Furthermore, in vitro analysis further confirmed that AS-IV regulated the expression of pSmad3C/3L and Nrf2/HO-1 pathway in HSC-T6 and HepG2 cells activated by TGF-β.

Conclusion: AS-IV administration delays the occurrence of primary liver cancer by continually suppressing the development of fibrosis, the mechanism of the therapeutic effect involving the regulation of the pSmad3C/3L and Nrf2/HO-1 pathways, especially in regulation reversibility and antagonism of pSmad3C and pSmad3L and promoting the phosphorylation of Nrf2.
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http://dx.doi.org/10.1016/j.jep.2021.114350DOI Listing
October 2021

Preparative separation of six compounds from Salvia yunnanensis Radix using pH-zone-refining counter-current chromatography.

Biomed Chromatogr 2021 Jun 16:e5182. Epub 2021 Jun 16.

Key Laboratory for Applied Technology of Sophisticated Analytic Instrument of Shandong Province, Shandong Analysis and Test Center, Qilu University of Technology, Jinan, China.

Phenolic acids are the main active components in Salvia yunnanensis Radix, which have significant effects such as cardiovascular protection, anti-thrombosis, anti-oxidant, and anti-inflammation. In this study, pH-zone-refining counter-current chromatography (pH-ZRCCC) was successfully applied to the preparative separation of phenolic acids from S. yunnanensis Radix. First, a two-phase solvent system composed of Pet-EtOAc-ACN-H O (1.5:2.5:1:5, v/v) [TFA (10 mM) was added in the upper phase and NH ·H O (30 mM) was added in the lower phase] was used for the separation of 4.0 g of the crude sample to obtain 55.6 mg of rosmarinic acid (1), 69.0 mg of caffeic acid (2), 18.9 mg of protocatechualdehyde (3), 14.6 mg of 8-epiblechnic acid 9-methyl ester (4), and a mixture containing two compounds. After the recovery, 1.3 g of the mixture was obtained and separated using the MtBE-H O (1:1, v/v) solvent system containing TFA (5 mM) and NH ·H O (60 mM) to obtain 259.9 mg of salvianolic acid B (5) and 28.75 mg of lithospermic acid (6). Moreover, a systematic separation pattern for separating the relatively low-polarity phenolic acids from natural products by pH-ZRCCC was summarized for the first time. This study provided technical support for the pharmacological activity and quality control research of S. yunnanensis Radix.
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http://dx.doi.org/10.1002/bmc.5182DOI Listing
June 2021

Leveraging breeding programs and genomic data in Norway spruce (Picea abies L. Karst) for GWAS analysis.

Genome Biol 2021 06 13;22(1):179. Epub 2021 Jun 13.

Umeå Plant Science Centre, Department Forest Genetics and Plant Physiology, Swedish University of Agricultural Sciences, SE-90183, Umeå, Sweden.

Background: Genome-wide association studies (GWAS) identify loci underlying the variation of complex traits. One of the main limitations of GWAS is the availability of reliable phenotypic data, particularly for long-lived tree species. Although an extensive amount of phenotypic data already exists in breeding programs, accounting for its high heterogeneity is a great challenge. We combine spatial and factor-analytics analyses to standardize the heterogeneous data from 120 field experiments of 483,424 progenies of Norway spruce to implement the largest reported GWAS for trees using 134 605 SNPs from exome sequencing of 5056 parental trees.

Results: We identify 55 novel quantitative trait loci (QTLs) that are associated with phenotypic variation. The largest number of QTLs is associated with the budburst stage, followed by diameter at breast height, wood quality, and frost damage. Two QTLs with the largest effect have a pleiotropic effect for budburst stage, frost damage, and diameter and are associated with MAP3K genes. Genotype data called from exome capture, recently developed SNP array and gene expression data indirectly support this discovery.

Conclusion: Several important QTLs associated with growth and frost damage have been verified in several southern and northern progeny plantations, indicating that these loci can be used in QTL-assisted genomic selection. Our study also demonstrates that existing heterogeneous phenotypic data from breeding programs, collected over several decades, is an important source for GWAS and that such integration into GWAS should be a major area of inquiry in the future.
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http://dx.doi.org/10.1186/s13059-021-02392-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8201819PMC
June 2021

Construction of C-C bonds via photoreductive coupling of ketones and aldehydes in the metal-organic-framework MFM-300(Cr).

Nat Commun 2021 Jun 11;12(1):3583. Epub 2021 Jun 11.

Department of Chemistry, University of Manchester, Manchester, UK.

Construction of C-C bonds via reductive coupling of aldehydes and ketones is hindered by the highly negative reduction potential of these carbonyl substrates, particularly ketones, and this renders the formation of ketyl radicals extremely endergonic. Here, we report the efficient activation of carbonyl compounds by the formation of specific host-guest interactions in a hydroxyl-decorated porous photocatalyst. MFM-300(Cr) exhibits a band gap of 1.75 eV and shows excellent catalytic activity and stability towards the photoreductive coupling of 30 different aldehydes and ketones to the corresponding 1,2-diols at room temperature. Synchrotron X-ray diffraction and electron paramagnetic resonance spectroscopy confirm the generation of ketyl radicals via confinement within MFM-300(Cr). This protocol removes simultaneously the need for a precious metal-based photocatalyst or for amine-based sacrificial agents for the photochemical synthesis.
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http://dx.doi.org/10.1038/s41467-021-23302-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196067PMC
June 2021

Supramolecular Catalysis of Acyl Transfer within Zinc Porphyrin-Based Metal-Organic Cages.

Inorg Chem 2021 Jun 4;60(12):8802-8810. Epub 2021 Jun 4.

State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116012, P. R. China.

To illustrate the supramolecular catalysis process in molecular containers, two porphyrinatozinc(II)-faced cubic cages with different sizes were synthesized and used to catalyze acyl-transfer reactions between -acetylimidazole (NAI) and various pyridylcarbinol (PC) regioisomers (2-PC, 3-PC, and 4-PC). A systemic investigation of the supramolecular catalysis occurring within these two hosts was performed, in combination with a host-guest binding study and density functional theory calculations. Compared to the reaction in a bulk solvent, the results that the reaction of 2-PC was found to be highly efficient with high rate enhancements (/ = 283 for and 442 for ), as well as the different efficiencies of the reactions with various ortho-substituted 2-PC substrates and NAI derivates should be attributed to the cages having preconcentrated and preoriented substrates. The same cage displayed different catalytic activities toward different PC regioisomers, which should be mainly attributed to different binding affinities between the respective reactant and product with the cages. Furthermore, control experiments were carried out to learn the effect of varying reactant concentrations and product inhibition. The results all suggested that, besides the confinement effect caused by the inner microenvironment, substrate transfer, including the encapsulation of the reactant and the release of products, should be considered to be a quite important factor in supramolecular catalysis within a molecular container.
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http://dx.doi.org/10.1021/acs.inorgchem.1c00745DOI Listing
June 2021

Online extraction based on ionic covalent organic framework for sensitive determination of trace per- and polyfluorinated alkyl substances in seafoods by UHPLC-MS/MS.

Food Chem 2021 Nov 27;362:130214. Epub 2021 May 27.

Key Laboratory for Applied Technology of Sophisticated Analytical Instruments of Shandong Province, Shandong Analysis and Test Center, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250014, China; School of Pharmaceutical Sciences, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250014, China. Electronic address:

The ionic covalent organic framework (TPB-BFBIm-iCOF) was facilely synthetized by the size-controllable confinement method and chosen as the online solid phase extraction (SPE) adsorbent. This adsorbent showed fast adsorption equilibrium (5 min) and high adsorption capacity (87.7-140.8 mg g) for the per- and polyfluorinated alkyl substances (PFASs). The TPB-BFBIm-iCOF microsphere revealed the satisfactory enrichment performance for PFASs by means of the electrostatic interaction, hydrophobic effect and ordered channel structure. After extraction, the loaded TPB-BFBIm-iCOF-online SPE column was eluted and applied to the ultrahigh performance liquid chromatography tandem mass spectrometry analysis. Under the optimum conditions, the method displayed satisfactory linearity (R ≥ 0.9910) and low limits of detection (≤0.0017 ng g) for five seafoods. The relative recoveries of PFASs were 85.3%-109.4% with the relative standard deviation ≤ 9.9%. The method exhibited potential value in monitoring the toxicokinetics and environmental behaviors of PFASs.
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http://dx.doi.org/10.1016/j.foodchem.2021.130214DOI Listing
November 2021

Comprehensive Lipidome and Metabolome Profiling Investigations of and Application in Different Growing Regions Using Liquid Chromatography Coupled with Mass Spectrometry.

J Agric Food Chem 2021 Jun 3;69(23):6710-6719. Epub 2021 Jun 3.

Key Laboratory for Applied Technology of Sophisticated Analytical Instruments of Shandong Province, Shandong Analysis and Test Center, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250014, China.

is one of the most recognized ginseng species. In this study, lipidome and metabolome extraction methods for were optimized with methanol/methyl--butyl ether/water (0.3 mg/1 μL/6 μL/8 μL). A total of 497 metabolites were identified, including 365 lipids and 76 ginsenosides. Comprehensive lipidome profiling was first performed for , in which 32.6% glycerophospholipids, 39.5% glycerolipids, 9.3% sphingolipids, 3.3% sterol lipids, and 15.3% fatty acyls were identified. Orthogonal partial least squares discrimination analysis (OPLS-DA) showed obvious metabolomic differences in two growing regions of China. In the northern growing region, the ratio of bilayer- to nonbilayer-forming membrane lipids (PCs/PEs, DGDGs/MGDGs), the degree of unsaturation of acyl chains in galactolipids, and the content of membrane glycerophospholipids were increased. In the eastern growing region, the synthesis of storage lipids, ceramides, and fatty acyls was increased, and secondary metabolism was enhanced with 24 differential ginsenosides found. The investigation deepens the understanding of metabolic regulation mechanisms of .
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http://dx.doi.org/10.1021/acs.jafc.1c02241DOI Listing
June 2021

Mechanical Properties and Toxicity Risks of Lead-Zinc Sulfide Tailing-Based Construction Materials.

Materials (Basel) 2021 May 29;14(11). Epub 2021 May 29.

College of Environmental Science and Engineering, Zhongkai University of Agriculture and Engineering, Guangzhou 510408, China.

The leaching residue of the lead-zinc sulfide tailing (LRT) is the only residue generated from the tailing leaching recovery process; it is a typical hazardous material for its high heavy-metal contents and high acidity. Due to the large output of LRT, and because its main components are Ca, Si, and Al, the preparation of building construction materials with LRT was studied. The results showed that when the LRT addition is less than 47%, with the ordinary Portland cement (OPC) and fly ash (FA) added and the curing conditions appropriate, the strength values of the tested specimens meet the M15 Class of the autoclaved lime sand brick standard (GB/T 16753-1997). The carbonization coefficient and drying shrinkage of the specimen were 0.79 and smaller than 0.42, respectively. As the SEM, TG, and XRD analysis have shown, the LRT can chemically react with additives to form stable minerals. The heavy metal contents that were leached out well met the limits in GB5085.3-2007. Based on the high addition of the LRT, the good strength and lower heavy metals were leached out of the prepared test specimen, and the tailing could be reused completely with the leaching recovery and the LRT reuse process. LRT can be used to replace OPC, allowing more sustainable concrete production and improved ecological properties of LRT.
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http://dx.doi.org/10.3390/ma14112940DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8198401PMC
May 2021

Identification of m6A methyltransferase-related lncRNA signature for predicting immunotherapy and prognosis in patients with hepatocellular carcinoma.

Biosci Rep 2021 Jun;41(6)

Department of Gastroenterology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, People's Republic of China.

N6-methyladenosine (m6A) methyltransferase has been shown to be an oncogene in a variety of cancers. Nevertheless, the relationship between the long non-coding RNAs (lncRNAs) and hepatocellular carcinoma (HCC) remains elusive. We integrated the gene expression data of 371 HCC and 50 normal tissues from The Cancer Genome Atlas (TCGA) database. Differentially expressed protein-coding genes (DE-PCGs)/lncRNAs (DE-lncRs) analysis and univariate regression and Kaplan-Meier (K-M) analysis were performed to identify m6A methyltransferase-related lncRNAs. Three prognostic lncRNAs were selected by univariate and LASSO Cox regression analyses to construct the m6A methyltransferase-related lncRNA signature. Multivariate Cox regression analyses illustrated that this signature was an independent prognostic factor for overall survival (OS) prediction. The Gene Set Enrichment Analysis (GSEA) suggested that the m6A methyltransferase-related lncRNAs were involved in the immune-related biological processes (BPs) and pathways. Besides, we discovered that the lncRNAs signature was correlated with the tumor microenvironment (TME) and the expression of critical immune checkpoints. Tumor Immune Dysfunction and Exclusion (TIDE) analysis revealed that the lncRNAs could predict the clinical response to immunotherapy. Our study had originated a prognostic signature for HCC based on the potential prognostic m6A methyltransferase-related lncRNAs. The present study had deepened the understanding of the TME status of HCC patients and laid a theoretical foundation for the choice of immunotherapy.
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http://dx.doi.org/10.1042/BSR20210760DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8188173PMC
June 2021

Selective intra-arterial brain cooling induces cerebral protection against ischemia/reperfusion injury through SENP1-Sirt3 signaling.

Free Radic Biol Med 2021 08 18;171:272-283. Epub 2021 May 18.

Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, 110004, China; Liaoning Clinical Medical Research Center in Nervous System Disease, Shenyang, 110004, China; Key Laboratory of Neuro-oncology in Liaoning Province, Shenyang, 110004, China. Electronic address:

Background: Although it is well known that selective intra-arterial cooling (SI-AC) elicits cerebral protection against ischemia/reperfusion (I/R) injury, the underlying mechanism remains unclear. This study aimed to determine whether SI-AC can protect against cerebral I/R injury by inhibiting oxidative stress and mitochondrial dysfunction through regulation of Sirt3 deSUMOylation via SENP1.

Methods: All mice were subjected to 2 h of cerebral ischemia followed by 24 h of reperfusion. SI-AC treatment was performed by infusion with cold saline (10 °C, 20 mL/kg) for 15 min through a microcatheter placed in the internal carotid artery immediately before reperfusion. The infarct volume, survival rate, neurological deficit scores, behavioral parameters, histopathology findings, and apoptosis were assessed. HT22 cells were subjected to 2 h of oxygen and sugar deprivation (OGD) and 22 h of reoxygenation. HA-SUMO1, Flag-Sirt3, a Sirt3 mutation plasmid (Flag-Sirt3 K288R), His-SENP1, and SENP1 small interfering RNA were transfected into HT22 cells 48 h before OGD. Apoptosis-related proteins were analyzed by western blotting. SUMOylation of Sirt3, acetylation of cyclooxygenase 1 (COX1), superoxide dismutase 2 (SOD2), and isocitrate dehydrogenase 2 (IDH2), the activities of COX1, SOD2, and IDH2, oxidative stress, and mitochondrial dysfunction were evaluated.

Results: Compared with the I/R group, SI-AC decreased cerebral infarct volume and neurological deficit scores and increased motor coordination, exploratory behavior, and memory. Hematoxylin and eosin and Nissl staining showed that SI-CA decreased karyopyknosis, nuclear fragmentation, and nucleolysis, increased neuron density, and decreased the cell apoptosis rate. In addition, Sirt3 was revealed as a target protein of SUMO1. SI-AC attenuated cerebral I/R injury through Sirt3 deSUMOylation via SENP1.

Conclusions: SENP1-mediated deSUMOylation of Sirt3 plays an essential role in SI-AC-induced cerebral protection against I/R injury. Our findings provide a promising therapeutic approach for treatment of acute cerebral I/R injury.
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http://dx.doi.org/10.1016/j.freeradbiomed.2021.05.026DOI Listing
August 2021

Efficacy and Safety of Veverimer in the Treatment of Metabolic Acidosis Caused by Chronic Kidney Disease: A Meta-analysis.

Front Pharmacol 2021 29;12:643128. Epub 2021 Apr 29.

Department of Nephrology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China.

Metabolic acidosis is a common complication of chronic kidney disease (CKD). Veverimer is an orally administrated, free amine polymer with high capacity and binding selectivity to hydrochloric acid from the gastrointestinal tract. This study pooled the current evidence of the efficacy and safety of veverimer for the treatment of metabolic acidosis associated with CKD. We conducted a systematic literature search on PubMed, Embase, and Cochrane Central for relevant randomized controlled trials (RCTs) in June 2020. In this study, three RCTs with 548 patients were included in our analysis. The analysis revealed that veverimer was associated with increased bicarbonate level of patients (weight mean difference [WMD] 3.08, 95% confidence interval [CI] [2.40, 3.77], < 0.001) and improved physical function compared with placebo measured by Kidney Disease and Quality of Life Short Form 36, question 3 (physical functioning domain) (KDQoL-PFD) score (WMD 5.25, 95% CI [1.58, 8.92], = 0.005). For safety outcomes, both groups exhibited similar risks for developing headache, diarrhea, flatulence, and hyperkalemia. In conclusion, current clinical evidence indicates that veverimer is efficacious and safe against metabolic acidosis related to CKD compared with placebo. Further research comparing long-term veverimer use with traditional alkali therapy is needed.
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http://dx.doi.org/10.3389/fphar.2021.643128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8117340PMC
April 2021
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