Publications by authors named "Jiao Liu"

489 Publications

Metal-organic framework as a mimetic enzyme with excellent adaptability for sensitive chemiluminescence detection of glutathione in cell lysate.

Talanta 2021 Nov 9;238(Pt 2):123041. Epub 2021 Nov 9.

Key Laboratory of Synthetic and Natural Functional Molecule of Ministry of Education, College of Chemistry & Materials Science, Northwest University, Xi'an, 710127, PR China. Electronic address:

A novel [Co(L)(HO)] (1) was obtained by hydrothermal method and it exhibited a 1D chain with exposed carboxyl groups, the unique coordination mode made it have unusual physical and chemical stability. Meanwhile, 1 showed peroxidase-like and weak oxidase-like activity. 1 as a peroxidase mimic enzyme had an excellent affinity for the substrates luminol and HO. Compared with HRP, 1 had catalytic activity in a wide pH range and showed the best catalytic activity at pH 7.4. Meanwhile, the catalysis process of 1 was reversible and recyclable, and the catalytic activity remained stable after different pH and temperatures and long-time storage. Based on the inhibition of glutathione on luminol-HO-MOF 1 chemiluminescence signal, a chemiluminescence method for the determination of glutathione has been proposed with high sensitivity and selectivity and had been applied for detecting glutathione in cell lysate with satisfactory results.
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http://dx.doi.org/10.1016/j.talanta.2021.123041DOI Listing
November 2021

Silencing KLF16 inhibits oral squamous cell carcinoma cell proliferation by arresting the cell cycle and inducing apoptosis.

APMIS 2021 Nov 15. Epub 2021 Nov 15.

Department of Pediatric Stomatology, Dongfeng Stomatological Hospital, Hubei University of Medicine, Shiyan, Hubei Province, China.

Krüppel-like factor 16 (KLF16), a member of the Krüppel-like factor (KLF) family, has been extensively investigated in multiple cancer types. However, the role of KLF16 in oral squamous cell carcinoma (OSCC) remains unknown. Thus, we conducted this study to investigate its related mechanism. KLF16 expression in OSCC cell lines was quantified by western blotting. Then, OECM1 and OC3 cells were divided into Blank, siCtrl, siKLF16#1 and siKLF16#2 groups. Subsequently, cell proliferation was detected using 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assays, cell migration and invasion were detected with wound healing and Transwell assays, and cell cycle distribution and cell apoptosis were detected via flow cytometry. KLF16, p21, CDK4, Cyclin D1 and p-Rb expression was detected by western blotting. Finally, xenograft models were established in nude mice to observe the in vivo effects of KLF16 on OSCC. KLF16 protein expression was upregulated in OSCC cells. Compared to the cells in the Blank group, the OECM1 and OC3 cells in the siKLF16#1 group and siKLF16#2 group exhibited a sharp decrease in proliferation but a remarkable increase in apoptosis. Moreover, the proportion of cells in the G0/G1 phase notably increased and that in the S phase decreased, with evident decreases in cell invasion and migration. Moreover, KLF16, cyclin-dependent kinase 4 (CDK4), Cyclin D1 and p-Rb protein expression was upregulated, but p21 expression was downregulated. The mice in the siKLF16#1 and siKLF16#2 xenograft model groups exhibited slower tumour growth and smaller tumours with evident downregulation of Ki67 expression compared to the mice in the Blank group. KLF16 expression was upregulated in OSCC cells, and interfering with KLF16 led to cell cycle arrest, inhibited OSCC cell growth and promoted cell apoptosis.
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http://dx.doi.org/10.1111/apm.13194DOI Listing
November 2021

HSD10 disease in a female: A case report and review of literature.

JIMD Rep 2021 Nov 15;62(1):35-43. Epub 2021 Sep 15.

Hayward Genetics Center, Department of Pediatrics Tulane University School of Medicine New Orleans Louisiana USA.

HSD10 disease is a rare X-linked mitochondrial disorder caused by pathogenic variants in the gene. The phenotype results from impaired 17β-hydroxysteroid dehydrogenase 10 (17β-HSD10) protein structure and function. HSD10 is a multifunctional protein involved in enzymatic degradation of isoleucine and branched-chain fatty acids, the metabolism of sex hormones and neurosteroids, as well as in regulating mitochondrial RNA maturation. HSD10 disease is characterised by progressive neurologic impairment. Disease onset is varied and includes neonatal-onset, infantile-onset and late-onset in males. Females can also be affected. Our index case is a 45-month-old female, who initially presented at 11 months of age with global developmental delay. She subsequently began to lose previously acquired cognitive and motor skills starting around 29 months of age. Brain MRI showed abnormalities in the basal ganglia indicative of possible mitochondrial disease. Urine organic acid analysis revealed elevations of 2-methyl-3-hydroxybutyric acid and tiglyglycine. gene sequencing revealed a likely pathogenic variant, NM_001037811.2:c.439C>T (p.Arg147Cys) inherited from her mother, expected to be causative of HSD10 disease. Her X-chromosome inactivation study is consistent with a skewed X-inactivation pattern. We report a female patient with HSD10 disease caused by a missense pathogenic variant, Arg147Cys in the gene. The patient is the fifth severely affected female with this disease. This case adds to the small number of known affected families with this highly variable disease in the literature. These findings support the possibility of X-inactivation patterns influencing the penetrance of HSD10 disease in females.
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http://dx.doi.org/10.1002/jmd2.12250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8574182PMC
November 2021

Ordered Vacancies on the Body-Centered Cubic PdCu Nanocatalysts.

Nano Lett 2021 Nov 11;21(22):9580-9586. Epub 2021 Nov 11.

Key Laboratory of Eco-Chemical Engineering, Key Laboratory of Optic-electric Sensing and Analytical Chemistry of Life Science, Taishan Scholar Advantage and Characteristic Discipline Team of Eco-Chemical Process and Technology, College of Chemistry and Molecular Engineering, Qingdao University of Science and Technology, Qingdao 266042, P.R. China.

Defect engineering has become one of the important considerations in today's electrocatalyst design. However, the vacancies in the ordered crystal structure (especially body-centered cubic (bcc) and the effect of ordered vacancies (OVs) on the electronic fabric have not been researched yet. In this work, we report the inaugural time of the generation of OVs in the bcc architecture and discuss the insight of the modulation system of the material and its part in the electrochemical N reduction reaction (NRR). OV-PdCu-2 achieves the highest Faradaic efficiency value of 21.5% at 0.05 V versus RHE. When the potential increases to 0 V versus RHE, the highest ammonia yield is 55.54 μg h mg, which is significantly better than the unetched PdCu nanoparticles (12.83 μg h mg). It is the latest reported catalyst to date in the NRR process at 0 V versus RHE (see Supporting Information).
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http://dx.doi.org/10.1021/acs.nanolett.1c03343DOI Listing
November 2021

Correction to: Hepatitis C virus core protein activates Wnt/β-catenin signaling through multiple regulation of upstream molecules in the SMMC-7721 cell line.

Arch Virol 2021 Nov 4. Epub 2021 Nov 4.

The Second Affiliated Hospital, Chongqing Medical University, Lin Jiang Road, No. 74, Chongqing, 400010, Chongqing, China.

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http://dx.doi.org/10.1007/s00705-021-05275-9DOI Listing
November 2021

Itaconic acid induces ferroptosis by activating ferritinophagy.

Biochem Biophys Res Commun 2021 Oct 25;583:56-62. Epub 2021 Oct 25.

Department of Oncology and Hematology, China-Japan Union Hospital of Jilin University, Changchun, Jilin, 130031, China. Electronic address:

Itaconic acid is an unsaturated dicarbonic acid. It has a wide range of applications in the industrial production of resins and is also a mediator of immunometabolism in macrophages. Here, we show a previously unrecognized role of itaconic acid in triggering ferroptosis, a form of iron-dependent cell death driven by lipid peroxidation. We found that supraphysiological itaconic acid dose-dependently induces ferroptosis, rather than apoptosis, in human cancer cell lines. Mechanistically, we determined that itaconic acid activates NOCA4-mediated ferritinophagy, which leads to ferroptosis through ferritin degradation and subsequent iron overload and oxidative damage. In contrast, itaconic acid-induced expression and activation of NFE2L2 serves as a defense mechanism to limit ferroptosis by producing antioxidant genes. Consequently, impaired NCOA4 expression prevented, whereas a disrupted NFE2L2 pathway enhanced, sensitivity to itaconic acid-induced ferroptosis in vitro and in xenograft models. These findings establish a dynamic model of metabolite-induced ferroptotic cancer cell death, which may contribute to the development of new targeted therapies.
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http://dx.doi.org/10.1016/j.bbrc.2021.10.054DOI Listing
October 2021

Risk factors for poor prognosis in children and adolescents with COVID-19: A systematic review and meta-analysis.

EClinicalMedicine 2021 Nov 19;41:101155. Epub 2021 Oct 19.

Lanzhou University Institute of Health Data Science, Lanzhou 730000, China.

Background: This study provides the first systematic review and meta-analysis to identify the predictors of unfavorable prognosis of COVID-19 in children and adolescents.

Methods: We searched literature databases until July 2021 for studies that investigated risk factors for unfavorable prognosis of children and adolescents with COVID-19. We used random-effects models to estimate the effect size with 95% confidence interval ().

Findings: We identified 56 studies comprising 79,104 individuals. Mortality was higher in patients with multisystem inflammatory syndrome (MIS-C) (odds ratio []=58.00, 95% 6.39-526.79) and who were admitted to intensive care (=12.64, 95% 3.42-46.68). Acute respiratry distress syndrme (ARDS) (=29.54, 95% 12.69-68.78) and acute kidney injury (AKI) (=55.02, 95% 6.26-483.35) increased the odds to be admitted to intensive care; shortness of breath (=16.96, 95% 7.66-37.51) increased the need of respiratory support; and neurological diseases (=5.16, 95% 2.30-11.60), C-reactive protein (CRP) level ≥80 mg/L (=11.70, 95% 4.37-31.37) and D-dimer level ≥0.5ug/mL (=20.40, 95% 1.76-236.44) increased the odds of progression to severe or critical disease.

Interpretation: Congenital heart disease, chronic pulmonary disease, neurological diseases, obesity, MIS-C, shortness of breath, ARDS, AKI, gastrointestinal symptoms, elevated CRP and D-dimer are associated with unfavourable prognosis in children and adolescents with COVID-19.
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http://dx.doi.org/10.1016/j.eclinm.2021.101155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8523335PMC
November 2021

Meta-analysis of the Connection Between Alzheimer Disease and Telomeres.

Alzheimer Dis Assoc Disord 2021 Oct 15. Epub 2021 Oct 15.

Department of Neurology, West China Hospital, Sichuan University, Chengdu Sichuan Department of Neurosurgery, The First Affiliated Hospital of Soochow University, Suzhou, China.

Background: Alzheimer disease (AD) is the most common neurodegenerative disease of the central nervous system. The stability of the telomere-telomerase system is closely related to AD. A previous meta-analysis indicated that AD patients had shorter telomere length (TL) than control subjects. However, there are no consistent telomerase activity findings in AD patients, and the published telomerase studies were not meta-analyzed yet.

Methods: We searched all the related studies that probed into TL and/or telomerase activity in AD patients based on PubMed and Embase database from the establishment to September 2020. The Chinese National Knowledge Infrastructure, Wanfang and China Science and Technology Journal Database were also utilized. The quality of the included studies was evaluated by using Newcastle-Ottawa Scale. All the statistical analyses of this meta-analysis were performed using Stata version 15.0.

Results: Analyzing 30 TL data from 2248 AD patients and 4865 controls, AD patients had a significantly shorter TL than the controls, with a standardized mean difference of -0.70 (confidence interval: -0.95 to -0.46; P<0.05). The meta-analysis included 3 primary studies and did not find a significant difference in the telomerase activity between 233 AD patients and 132 controls, but AD patients had a trend of increased telomerase activity compared with controls (standardized mean difference: 0.47; confidence interval: -0.29 to 1.23; P>0.05).

Conclusion: Our results showed that compared with the control group, the AD group had a shorter TL and may have higher telomerase activity.
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http://dx.doi.org/10.1097/WAD.0000000000000468DOI Listing
October 2021

TREM-2 promotes Th1 responses by interacting with the CD3ζ-ZAP70 complex following Mycobacterium tuberculosis infection.

J Clin Invest 2021 09;131(17)

Center for Infection and Immunity, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong Province, China.

Triggering receptor expressed on myeloid cells 2 (TREM-2) is a modulator of pattern recognition receptors on innate immune cells that regulates the inflammatory response. However, the role of TREM-2 in in vivo models of infection and inflammation remains controversial. Here, we demonstrated that TREM-2 expression on CD4+ T cells was induced by Mycobacterium tuberculosis infection in both humans and mice and positively associated with T cell activation and an effector memory phenotype. Activation of TREM-2 in CD4+ T cells was dependent on interaction with the putative TREM-2 ligand expressed on DCs. Unlike the observation in myeloid cells that TREM-2 signals through DAP12, in CD4+ T cells, TREM-2 interacted with the CD3ζ-ZAP70 complex as well as with the IFN-γ receptor, leading to STAT1/-4 activation and T-bet transcription. In addition, an infection model using reconstituted Rag2-/- mice (with TREM-2-KO vs. WT cells or TREM-2+ vs. TREM-2-CD4+ T cells) or CD4+ T cell-specific TREM-2 conditional KO mice demonstrated that TREM-2 promoted a Th1-mediated host defense against M. tuberculosis infection. Taken together, these findings reveal a critical role of TREM-2 in evoking proinflammatory Th1 responses that may provide potential therapeutic targets for infectious and inflammatory diseases.
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http://dx.doi.org/10.1172/JCI137407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8409584PMC
September 2021

Environmental fate of Bt proteins in soil: Transport, adsorption/desorption and degradation.

Ecotoxicol Environ Saf 2021 Dec 27;226:112805. Epub 2021 Sep 27.

College of Bioscience and Biotechnology, Hunan Agricultural University and Hunan Engineering Laboratory for Pollution Control and Waste Utilization in Swine Production, Changsha 410128, PR China.

During the production and application of Bacillus thuringiensis (Bt) transgenic crops, large doses of insecticidal Bt toxic proteins are expressed continuously. The multi-interfacial behaviors of Bt proteins entering the environment in multi-media affects their states of existence transformation, transport and fate as well as biological and ecological impacts. Because both soil matrix and organisms will be exposed to Bt proteins to a certain extent, knowledge of the multi-interfacial behaviors and affecting factors of Bt proteins are vital not only for understanding the source-sink distribution mechanisms, predicting their bio-availability, but also for exploring the soil safety and environmental problems caused by the interaction between Bt proteins and soil matrix. This review summarized and analyzed various internal and external factors that affect the adsorption/ desorption and degradation of Bt proteins in the environment, so as to understand the multi-interfacial behaviors of Bt proteins. In addition, the reasons of concentration changes of Bt proteins in soil are discussed. This review will also discuss the existing knowledge of the combined effects of Bt proteins and other pollutants in environment. Finally, discussing the factors that should be considered when assessing the environmental risk of Bt proteins, thus to further improve the understanding of the environmental fate of Bt proteins.
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http://dx.doi.org/10.1016/j.ecoenv.2021.112805DOI Listing
December 2021

Effects of Environmental and Pathological Hypoxia on Male Fertility.

Front Cell Dev Biol 2021 13;9:725933. Epub 2021 Sep 13.

Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China.

Male infertility is a widespread health problem affecting approximately 6%-8% of the male population, and hypoxia may be a causative factor. In mammals, two types of hypoxia are known, including environmental and pathological hypoxia. Studies looking at the effects of hypoxia on male infertility have linked both types of hypoxia to poor sperm quality and pregnancy outcomes. Hypoxia damages testicular seminiferous tubule directly, leading to the disorder of seminiferous epithelium and shedding of spermatogenic cells. Hypoxia can also disrupt the balance between oxidative phosphorylation and glycolysis of spermatogenic cells, resulting in impaired self-renewal and differentiation of spermatogonia, and failure of meiosis. In addition, hypoxia disrupts the secretion of reproductive hormones, causing spermatogenic arrest and erectile dysfunction. The possible mechanisms involved in hypoxia on male reproductive toxicity mainly include excessive ROS mediated oxidative stress, HIF-1α mediated germ cell apoptosis and proliferation inhibition, systematic inflammation and epigenetic changes. In this review, we discuss the correlations between hypoxia and male infertility based on epidemiological, clinical and animal studies and enumerate the hypoxic factors causing male infertility in detail. Demonstration of the causal association between hypoxia and male infertility will provide more options for the treatment of male infertility.
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http://dx.doi.org/10.3389/fcell.2021.725933DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8473802PMC
September 2021

Inpatient use of metformin and acarbose is associated with reduced mortality of COVID-19 patients with type 2 diabetes mellitus.

Endocrinol Diabetes Metab 2021 Sep 29:e00301. Epub 2021 Sep 29.

Department of Medicine, University of California, La Jolla, California, USA.

Aims: Type 2 diabetes mellitus (T2DM) is a strong risk factor for complications of coronavirus disease 2019 (COVID-19). The effect of T2DM medications on COVID-19 outcomes remains unclear. In a retrospective analysis of a cohort of 131 patients with T2DM hospitalized for COVID-19 in Wuhan, we have previously found that metformin use prior to hospitalization is associated with reduced mortality. The current study aims to investigate the effects of inpatient use of T2DM medications, including metformin, acarbose, insulin and sulfonylureas, on the mortality of COVID-19 patients with T2DM during hospitalization.

Methods: We continue to carry out a retrospective analysis of a cohort of 131 patients with T2DM hospitalized for COVID-19 and treated with different combinations of diabetes medications.

Results: We found that patients using metformin (p = .02) and acarbose (p = .04), alone or both together (p = .03), after admission were significantly more likely to survive than those who did not use either metformin or acarbose. 37 patients continued to take metformin after admission and 35 (94.6%) survived. Among the 57 patients who used acarbose after admission, 52 survived (91.2%). A total of 20 patients used both metformin and acarbose, while 57 used neither. Of the 20 dual-use patients, 19 (95.0%) survived.

Conclusion: Our analyses suggest that inpatient use of metformin and acarbose together or alone during hospitalization should be studied in randomized trials.
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http://dx.doi.org/10.1002/edm2.301DOI Listing
September 2021

Trypsin-Mediated Sensitization to Ferroptosis Increases the Severity of Pancreatitis in Mice.

Cell Mol Gastroenterol Hepatol 2021 Sep 23. Epub 2021 Sep 23.

Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas. Electronic address:

Background & Aims: Pancreatitis is characterized by acinar cell death and persistent inflammation. Ferroptosis is a type of lipid peroxidation-dependent necrosis, which is negatively regulated by glutathione peroxidase 4. We studied how trypsin, a serine protease secreted by pancreatic acinar cells, affects the contribution of ferroptosis to triggering pancreatitis.

Methods: In vitro, the mouse pancreatic acinar cell line 266-6 and mouse primary pancreatic acinar cells were used to investigate the effect of exogenous trypsin on ferroptosis sensitivity. Short hairpin RNAs were designed to silence gene expression, whereas a library of 1080 approved drugs was used to identify new ferroptosis inhibitors in 266-6 cells. In vivo, a Cre/LoxP system was used to generate mice with a pancreas-specific knockout of Gpx4 (Pdx1-Cre;Gpx4 mice). Acute or chronic pancreatitis was induced in these mice (Gpx4 mice served as controls) by cerulein injections or a Lieber-DeCarli alcoholic liquid diet. Pancreatic tissues, acinar cells, and serum were collected and analyzed by histology, immunoblot, quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, or immunohistochemical analyses.

Results: Supraphysiological doses of trypsin (500 or 1000 ng/mL) alone did not trigger significant cell death in 266-6 cells and mouse primary pancreatic acinar cells, but did increase the sensitivity of these cells to ferroptosis upon treatment with cerulein, L-arginine, alcohol, erastin, or RSL3. Proteasome 26S subunit, non-adenosine triphosphatase 4-dependent lipid peroxidation caused ferroptosis in pancreatic acinar cells by promoting the proteasomal degradation of glutathione peroxidase 4. The drug screening campaign identified the antipsychotic drug olanzapine as an antioxidant inhibiting ferroptosis in pancreatic acinar cells. Mice lacking pancreatic Gpx4 developed more severe pancreatitis after cerulein infection or ethanol feeding than control mice. Conversely, olanzapine administration protected against pancreatic ferroptotic damage and experimental pancreatitis in Gpx4-deficient mice.

Conclusions: Trypsin-mediated sensitization to ferroptotic damage increases the severity of pancreatitis in mice, and this process can be reversed by olanzapine.
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http://dx.doi.org/10.1016/j.jcmgh.2021.09.008DOI Listing
September 2021

Melatonin potentiates the cytotoxic effect of Neratinib in HER2 breast cancer through promoting endocytosis and lysosomal degradation of HER2.

Oncogene 2021 Nov 23;40(44):6273-6283. Epub 2021 Sep 23.

Cancer Institute, The Second Hospital of Dalian Medical University, Dalian, Liaoning, China.

Complete blockade of the HER2 protein itself and HER signaling network is critical to achieving effective HER2-targeted therapies. Despite the success of HER2-targeted therapies, the diseases will relapse in a significant fraction of patients with HER2 breast cancers. How to improve the therapeutic efficacy of existing HER2-targeted agents remains an unmet clinical need. Here, we uncover a role of Melatonin in diminishing HER2-mediated signaling by destruction of HER2 protein. Mechanistically, Melatonin treatment attenuated the protective effect of the HSP90 chaperone complex on its client protein HER2, triggering ubiquitylation and subsequent endocytic lysosomal degradation of HER2. The inhibitory effect of Melatonin on HER2 signaling substantially enhanced the cytotoxic effects of the pan-HER inhibitor Neratinib in HER2 breast cancer cells. Lastly, we demonstrate that dual inhibition of HER2 by combined use of Melatonin and Neratinib effectively blocked the growth of HER2 breast tumor xenografts in vivo. Our findings shed light on the potential use of Melatonin in a novel dual HER2 blockade strategy for HER2 breast cancer treatment.
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http://dx.doi.org/10.1038/s41388-021-02015-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8566236PMC
November 2021

Role of genetics in amyotrophic lateral sclerosis: a large cohort study in Chinese mainland population.

J Med Genet 2021 Sep 20. Epub 2021 Sep 20.

Department of Neurology, Neurological Diseases and Brain Function Laboratory, The Affiliated Hospital of Southwest Medical University, Luzhou, China.

Background: A large number of new causative and risk genes for amyotrophic lateral sclerosis (ALS) have been identified mostly in patients of European ancestry. In contrast, we know relatively little regarding the genetics of ALS in other ethnic populations. This study aims to provide a comprehensive analysis of the genetics of ALS in an unprecedented large cohort of Chinese mainland population and correlate with the clinical features of rare variants carriers.

Methods: A total of 1587 patients, including 64 familial ALS (FALS) and 1523 sporadic ALS (SALS), and 1866 in-house controls were analysed by whole-exome sequencing and/or testing for G4C2 repeats in . Forty-one ALS-associated genes were analysed.

Findings: 155 patients, including 26 (40.6%) FALS and 129 (8.5%) SALS, carrying rare pathogenic/likely pathogenic (P/LP) variants of ALS causative genes were identified. was the most common mutated gene, followed by , , , and . By burden analysis, rare variants in , and contributed to the collective risk for ALS (p<2.5e-6) at the gene level, but at the allelic level p.Gly294Val and p.Arg521Cys and p.Arg521His were the most important single variants causing ALS. Clinically, P/LP variants in and were associated with poor prognosis, in linked with younger age of onset, and repeats tended to affect cognition.

Conclusions: Our data provide essential information for understanding the genetic and clinical features of ALS in China and for optimal design of genetic testing and evaluation of disease prognosis.
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http://dx.doi.org/10.1136/jmedgenet-2021-107965DOI Listing
September 2021

Effect of Nebulized Amphotericin B in Critically ill Patients With Respiratory spp. De-colonization: A Retrospective Analysis.

Front Med (Lausanne) 2021 3;8:723904. Epub 2021 Sep 3.

Department of Intensive Care Medicine, Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China.

The potential relationship among airway spp. de-colonization, nebulized amphotericin B (NAB), and occurrence of ventilator-associated pneumonia (VAP) in patients who are critically ill has not been fully investigated, especially concerning effects on survival. In this observational, retrospective, cohort study in a 22-bed central intensive care unit, we included patients aged >18 years who required mechanical ventilation (MV) for >48 h, with at least two consecutive positive spp. test results. Patients were categorized into NAB and no NAB (control) groups. Propensity matching at 1:1 was performed according to strict standards, and multiple Cox proportional hazard model and multivariate analyses were performed to evaluate the effects of NAB treatment. Throughout an 8-year study period, 526 patients had received MV and had positive respiratory tract spp. cultures. Of these, we included 275 patients and excluded 251 patients. In total, we successfully matched 110 patients from the two groups (each group, = 55; total population median age, 64 years; Acute Physiology and Chronic Health Evaluation II [APACHE II] score, 25.5; sequential organ failure assessment score, 9). The spp. de-colonization rate was 69.1% in patients treated with NAB. VAP incidence did not differ significantly between the NAB (10.91%) and control (16.36%) groups ( = 0.405). related VAP rates differed significantly between the NAB (10.91%) and control (25.45%) groups ( = 0.048). Five (9.1%) patients in the NAB group died during hospitalization compared with 17 (30.9%) controls ( = 0.014). At 28 days, 9 (16.4%) and 16 (29.1%) deaths occurred in the NAB and control groups, respectively, ( = 0.088). The cumulative 90-day mortality rate differed significantly between the two groups (23.6 vs. 43.6%, = 0.015). Multivariate logistic regression analyses indicated a decreased 90-day mortality in the NAB group (adjusted odds ratio 0.413; 95% confidence interval 0.210-0.812; = 0.01). In subgroup analyses, the NAB-associated decreased risk of death at 90 days was consistent across subgroups of patients with a score of 2, younger age (<64 years), a higher APACHE II score (≥25), fewer sites (<2), or MV at admission. NAB treatment contributed to spp. airway de-colonization, was associated with a reduced risk of related VAP, and improved 90-day mortality in patients critically ill with spp. tracheobronchial colonization who had received MV for >2 days. NAB may be an alternative treatment option for critically ill patients with VAP.
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http://dx.doi.org/10.3389/fmed.2021.723904DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8446355PMC
September 2021

CaR: A Cutting and Repulsion-Based Evolutionary Framework for Mixed-Integer Programming Problems.

IEEE Trans Cybern 2021 Sep 14;PP. Epub 2021 Sep 14.

A mixed-integer programming (MIP) problem contains both constraints and integer restrictions. Integer restrictions divide the feasible region defined by constraints into multiple discontinuous feasible parts. In particular, the number of discontinuous feasible parts will drastically increase with the increase of the number of integer decision variables and/or the size of the candidate set of each integer decision variable. Due to the fact that the optimal solution is located in one of the discontinuous feasible parts, it is a challenging task to solve a MIP problem. This article presents a cutting and repulsion-based evolutionary framework (called CaR) to solve MIP problems. CaR includes two main strategies: 1) the cutting strategy and 2) the repulsion strategy. In the cutting strategy, an additional constraint is constructed based on the objective function value of the best individual found so far, the aim of which is to continuously cut unpromising discontinuous feasible parts. As a result, the probability of the population entering a wrong discontinuous feasible part can be decreased. In addition, in the repulsion strategy, once it has been detected that the population has converged to a discontinuous feasible part, the population will be reinitialized. Moreover, a repulsion function is designed to repulse the previously explored discontinuous feasible parts. Overall, the cutting strategy can significantly reduce the number of discontinuous feasible parts and the repulsion strategy can probe the remaining discontinuous feasible parts. Sixteen test problems developed in this article and two real-world cases are used to verify the effectiveness of CaR. The results demonstrate that CaR performs well in solving MIP problems.
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http://dx.doi.org/10.1109/TCYB.2021.3103778DOI Listing
September 2021

Honeycomb-like activated carbon with microporous nanosheets structure prepared from waste biomass cork for highly efficient dye wastewater treatment.

J Hazard Mater 2021 08 20;416:125896. Epub 2021 Apr 20.

Key Laboratory of Wood Material Science and Utilization (Beijing Forestry University), Ministry of Education, Beijing 100083, PR China. Electronic address:

Cork, a porous biomass material, is consist of thin-walled hollow prismatic cells arranged into a compact and orderly honeycomb-like structure and could be applied as an adsorption material. Here, cork-activated carbons (CACs) with a fluffy honeycomb-like structure were synthesized by two-step pyrolysis with solid KOH chemical activation to rapidly and efficiently adsorb methylene blue (MB) (maximum wavelength: 664 nm). The structure, morphology and surface functional groups of the CACs were characterized using BET, SEM, and FTIR analysis. The results show that the CACs have a well-developed hierarchical porous structure and an ultra-high specific surface area of 2864.9 m/g, which would facilitate the efficient diffusion and adsorption of MB molecules onto CACs. MB adsorption performance results show that the CACs have an outstanding maximum MB adsorption capacity (1103.68 mg/g) and fast adsorption kinetics (800 mg/L, 99.8% in 10 min), indicating that CACs possess significant advantages compared with most other adsorbents previously reported. The adsorption mechanism was studied by various kinetic models, isothermal models and thermodynamic models. Langmuir model is the most adapted to describe the adsorption process, indicating that the MB molecules are uniformly adsorbed on CAC's surface in a single layer. Moreover, MB adsorption by the CACs was an endothermic, spontaneous and randomly increasing adsorption. The regeneration test showed that the uptake of MB onto CACs can still reached 580 mg/g after three adsorption-desorption cycles, demonstrating the excellent reusability of CACs. The continuous adsorption performance of MB onto CACs was evaluated by a packed column test, which further confirmed its potential as an adsorbent for dye wastewater purification.
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http://dx.doi.org/10.1016/j.jhazmat.2021.125896DOI Listing
August 2021

PPARG-mediated ferroptosis in dendritic cells limits antitumor immunity.

Biochem Biophys Res Commun 2021 10 29;576:33-39. Epub 2021 Aug 29.

Department of Oncology and Hematology, China-Japan Union Hospital of Jilin University, Changchun, Jilin, 130031, China. Electronic address:

Dendritic cells (DCs) are antigen-presenting cells of the immune system, which play a key role in antitumor immunity by activating cytotoxic T cells. Here, we report that elevated ferroptosis, a lipid peroxidation-mediated cell death, impairs the maturation of DCs and their function in tumor suppression. Ferroptosis is selectively induced in DCs by the GXP4 inhibitor RSL3, but not the SLC7A11 inhibitor erastin. Ferroptotic DCs lose their ability to secrete pro-inflammatory cytokines (TNF and IL6) and express MHC class I in response to the maturation signal of lipopolysaccharide. Moreover, ferroptotic DCs fail to induce CD8 T cells to produce IFNG/IFNγ. Mechanistically, PPARG/PPARγ, a nuclear receptor involved in the regulation of lipid metabolism, is responsible for RSL3-induced ferroptosis in DCs. Consequently, the genetic depletion of PPARG restores the maturation and function of DCs. Using immunogenic cell death-based DC vaccine models, we further demonstrate that PPARG-mediated ferroptosis of DCs limits antitumor immunity in mice. Together, these findings demonstrate a novel role of ferroptotic DCs in driving an immunosuppressive tumor microenvironment.
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http://dx.doi.org/10.1016/j.bbrc.2021.08.082DOI Listing
October 2021

The KRAS-G12C inhibitor: activity and resistance.

Cancer Gene Ther 2021 Sep 1. Epub 2021 Sep 1.

The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.

Although it has long been deemed "undruggable", with the development of drugs specifically binding the KRAS-G12C mutant protein, clinical trials that directly inhibit oncogenic RAS have recently made promising improvements. In particular, the covalent KRAS-G12C inhibitors sotorasib and adagrasib are used to treat patients with advanced non-small cell lung cancer (NSCLC) carrying KRAS-G12C mutations. Unfortunately, the vast majority of patients do not respond to KRAS-G12C inhibitor therapy, mainly due to intrinsic or acquired resistance caused by cellular, molecular, and genetic mechanisms. Improving the understanding of drug response in the tumor microenvironment may continue to promote the design, testing, and clinical application of KRAS-G12C inhibitors.
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http://dx.doi.org/10.1038/s41417-021-00383-9DOI Listing
September 2021

Emergence of IncHI2 Plasmid-Harboring blaNDM-5 from Porcine Isolates in Guangdong, China.

Pathogens 2021 Jul 29;10(8). Epub 2021 Jul 29.

Institute of Quality Standard and Monitoring Technology for Agro-Products, Guangdong Academy of Agricultural Sciences, Guangzhou 510640, China.

Carbapenem resistance has posed potential harmful risks to human and animals. The objectives of this study were to understand the prevalence of in pigs and investigate the molecular characteristics of NDM-5-producing isolates in Guangdong province in China. Carbapenem-resistant isolates were isolated from pigs and obtained using MacConkey plates containing 0.5 mg/L meropenem. Conjugation assay and antimicrobial susceptibility testing were conducted for the isolates and their transconjugants. Whole-genome sequence (WGS) was used to analyze the plasmid genetic feature. A total of five -carrying isolates were obtained in the present investigations. They belonged to five ST types. The genes were found to be in IncX3 and IncHI2 plasmid. The IncX3 plasmid was 46,161 bp in size and identical to other reports. IncHI2 plasmid was 246,593 bp in size and similar to other IncHI2-ST3 plasmids. It consisted of a typical IncHI2 plasmid backbone region and a multiresistance region (MRR). The was closely associated with the unit. We first reported the -carrying IncHI2 in isolates recovered from pigs and revealed the molecular characterization. Continued surveillance for the dissemination of among food-producing animals is required.
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http://dx.doi.org/10.3390/pathogens10080954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8398143PMC
July 2021

Combining electrospinning with hot drawing process to fabricate high performance poly (L-lactic acid) nanofiber yarns for advanced nanostructured bio-textiles.

Biofabrication 2021 09 9;13(4). Epub 2021 Sep 9.

College of Textiles & Clothing, Qingdao University, Qingdao, People's Republic of China.

Fiber constructed yarns are the elementary building blocks for the generation of implantable biotextiles, and there are always needs for designing and developing new types of yarns to improve the properties of biotextile implants. In the present study, we aim to develop novel nanofiber yarns (NYs) by combining nanostructure that more closely mimic the extracellular matrix fibrils of native tissues with biodegradability, strong mechanical properties and great textile processibility. A novel electrospinning system which integrates yarn formation with hot drawing process was developed to fabricate poly(L-lactic acid) (PLLA) NYs. Compared to the PLLA NYs without hot drawing, the thermally drawn PLLA NYs presented superbly-orientated fibrous structure and notably enhanced crystallinity. Importantly, they possessed admirable mechanical performances, which matched and even exceeded the commercial PLLA microfiber yarns (MYs). The thermally drawn PLLA NYs were also demonstrated to notably promote the adhesion, alignment, proliferation, and tenogenic differentiation of human adipose derived mesenchymal stem cells (hADMSCs) compared to the PLLA NYs without hot drawing. The thermally drawn PLLA NYs were further processed into various nanofibrous tissue scaffolds with defined structures and adjustable mechanical and biological properties using textile braiding and weaving technologies, demonstrating the feasibility and versatility of thermally drawn PLLA NYs for textile-forming utilization. The hADMSCs cultured on PLLA NY-based textiles presented enhanced attachment and proliferation capacities than those cultured on PLLA MY-based textiles. This work presents a facile technique to manufacture high performance PLLA NYs, which opens up opportunities to generate advanced nanostructured biotextiles for surgical implant applications.
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http://dx.doi.org/10.1088/1758-5090/ac2209DOI Listing
September 2021

Angiotensin II biphasically regulates cell differentiation in human iPSC-derived kidney organoids.

Am J Physiol Renal Physiol 2021 11 27;321(5):F559-F571. Epub 2021 Aug 27.

Department of Physiology and Hypertension and Renal Center of Excellence, Tulane University School of Medicine, New Orleans, Louisiana.

Human kidney organoid technology holds promise for novel kidney disease treatment strategies and utility in pharmacological and basic science. Given the crucial roles of the intrarenal renin-angiotensin system (RAS) and angiotensin II (ANG II) in the progression of kidney development and injury, we investigated the expression of RAS components and effects of ANG II on cell differentiation in human kidney organoids. Human induced pluripotent stem cell-derived kidney organoids were induced using a modified 18-day Takasato protocol. Gene expression analysis by digital PCR and immunostaining demonstrated the formation of renal compartments and expression of RAS components. The ANG II type 1 receptor (ATR) was strongly expressed in the early phase of organoid development (around ), whereas ANG II type 2 receptor (ATR) expression levels peaked on . Thus, the organoids were treated with 100 nM ANG II in the early phase on (ANG II-E) or during the middle phase on (ANG II-M). ANG II-E was observed to decrease levels of marker genes for renal tubules and proximal tubules, and the downregulation of renal tubules was inhibited by an ATR antagonist. In contrast, ANG II-M increased levels of markers for podocytes, the ureteric tip, and the nephrogenic mesenchyme, and an ATR blocker attenuated the ANG II-M-induced augmentation of podocyte formation. These findings demonstrate RAS expression and ANG II exertion of biphasic effects on cell differentiation through distinct mediatory roles of ATR and ATR, providing a novel strategy to establish and further characterize the developmental potential of human induced pluripotent stem cell-derived kidney organoids. This study demonstrates angiotensin II exertion of biphasic effects on cell differentiation through distinct mediatory roles of angiotensin II type 1 receptor and type 2 receptor in human induced pluripotent stem cell-derived kidney organoids, providing a novel strategy to establish and further characterize the developmental potential of the human kidney organoids.
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http://dx.doi.org/10.1152/ajprenal.00134.2021DOI Listing
November 2021

N-acetyl-L-tryptophan attenuates hepatic ischemia-reperfusion injury via regulating TLR4/NLRP3 signaling pathway in rats.

PeerJ 2021 10;9:e11909. Epub 2021 Aug 10.

Department of Anatomy, Weifang Medical University, Weifang, Shandong, China.

The aim of this study was to investigate the changes of TLR4/NLRP3 signal during hepatic ischemia-reperfusion injury (HIRI) and to verify whether N-acetyl-L-tryptophan (L-NAT) protected hepatocytes by regulating the activation of TLR4/NLRP3 signal. We have established the rat HIRI model and HO-induced cell damage model to simulate ischemia-reperfusion injury and detect the corresponding indicators. Compared with the sham group, Suzuki score and the level of serum ALT increased after HIRI, accompanied by an increased expression of NLRP3, ASC, Caspase-1, IL-1β, TLR4, and NF-κB. While L-NAT pretreatment reversed the above-mentioned changes. Compared with the control group, cells in the HO treated group became smaller in cell volume and round in shape with unclear boundaries. Similar to the phenotypes in vivo, HO treatment also induced significant increase in expression of pyroptosis-related proteins (NLRP3, ASC, Caspase-1 and IL-1β) and inflammatory factors (TLR4 and NF-κB). While L-NAT pretreatment attenuated injuries caused by HO. In conclusion, the present findings demonstrate that L-NAT alleviates HIRI by regulating activation of NLRP3 inflammasome, which may be related to the TLR4/NF-κB signaling pathway.
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http://dx.doi.org/10.7717/peerj.11909DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8362669PMC
August 2021

Case Report: Whole Exome Sequencing Revealed Two Novel Mutations of Implicated in Nonimmune Hydrops Fetalis.

Front Genet 2021 5;12:684555. Epub 2021 Aug 5.

Department of Obstetrics, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Nonimmune hydrops fetalis (NIHF) is a serious and complex fetal condition. Prenatal diagnosis of hydrops fetalis is not difficult by ultrasound. However, determining the underlying etiology of NIHF remains a challenge which is essential to address for prenatal counseling. We extracted DNA from a proband prenatally diagnosed unexplained NIHF. Trio-whole exome sequencing (WES) was performed to filter candidate causative variants. Two gene mutations were identified as a compound heterozygous state in the proband. Both variants located on the gene: c.3895C > T, a missense mutation in exon 27 paternally inherited; c.4030_4032del, a maternally inherited in-frame deletion in exon 28. Both variants were first reported to be related to NIHF. gene mutations, leading to an autosomal recessive congenital lymphatic dysplasia, which can present as NIHF and partial or complete resolution postnatally. In conclusion, WES can aid in the elucidation of the genetic cause of NIHF and has a positive effect on the assessment of prognosis.
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http://dx.doi.org/10.3389/fgene.2021.684555DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8375471PMC
August 2021

Efficacy of Thymosin Alpha 1 in the Treatment of COVID-19: A Multicenter Cohort Study.

Front Immunol 2021 2;12:673693. Epub 2021 Aug 2.

Department of Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Background: Thymosin alpha 1 (Tα1) is widely used to treat patients with COVID-19 in China; however, its efficacy remains unclear. This study aimed to explore the efficacy of Tα1 as a COVID-19 therapy.

Methods: We performed a multicenter cohort study in five tertiary hospitals in the Hubei province of China between December 2019 and March 2020. The patient non-recovery rate was used as the primary outcome.

Results: All crude outcomes, including non-recovery rate (65/306 290/1,976, = 0.003), in-hospital mortality rate (62/306 271/1,976, = 0.003), intubation rate (31/306 106/1,976, = 0.001), acute respiratory distress syndrome (ARDS) incidence (104/306 499/1,976, = 0.001), acute kidney injury (AKI) incidence (26/306 66/1,976, < 0.001), and length of intensive care unit (ICU) stay (14.9 ± 12.7 8.7 ± 8.2 days, < 0.001), were significantly higher in the Tα1 treatment group. After adjusting for confounding factors, Tα1 use was found to be significantly associated with a higher non-recovery rate than non-Tα1 use (OR 1.5, 95% CI 1.1-2.1, = 0.028). An increased risk of non-recovery rate associated with Tα1 use was observed in the patient subgroups with maximum sequential organ failure assessment (SOFA) scores ≥2 (OR 2.0, 95%CI 1.4-2.9, = 0.024), a record of ICU admission (OR 5.4, 95%CI 2.1-14.0, < 0.001), and lower PaO2/FiO2 values (OR 1.9, 95%CI 1.1-3.4, = 0.046). Furthermore, later initiation of Tα1 use was associated with a higher non-recovery rate.

Conclusion: Tα1 use in COVID-19 patients was associated with an increased non-recovery rate, especially in those with greater disease severity.
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http://dx.doi.org/10.3389/fimmu.2021.673693DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8366398PMC
August 2021

Complete Elimination of Peripheral Auditory Input Before Onset of Hearing Causes Long-Lasting Impaired Social Memory in Mice.

Front Neurosci 2021 27;15:723658. Epub 2021 Jul 27.

Department of Otolaryngology Head and Neck Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China.

Hearing is one of the most important senses needed for survival, and its loss is an independent risk factor for dementia. Hearing loss (HL) can lead to communication difficulties, social isolation, and cognitive dysfunction. The hippocampus is a critical brain region being greatly involved in the formation of learning and memory and is critical not only for declarative memory but also for social memory. However, until today, whether HL can affect learning and memory is poorly understood. This study aimed to identify the relationship between HL and hippocampal-associated cognitive function. Mice with complete auditory input elimination before the onset of hearing were used as the animal model. They were first examined via auditory brainstem response (ABR) to confirm hearing elimination, and behavior estimations were applied to detect social memory capacity. We found significant impairment of social memory in mice with HL compared with the controls ( < 0.05); however, no significant differences were seen in the tests of novel object recognition, Morris water maze (MWM), and locomotion in the open field ( > 0.05). Therefore, our study firstly demonstrates that hearing input is required for the formation of social memory, and hearing stimuli play an important role in the development of normal cognitive ability.
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http://dx.doi.org/10.3389/fnins.2021.723658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8353330PMC
July 2021

Gastrokine 2 Regulates the Antitumor Effect of JAK2/STAT3 Pathway in Gastric Cancer.

Evid Based Complement Alternat Med 2021 2;2021:1343808. Epub 2021 Aug 2.

Key Laboratory of Tumor Cellular & Molecular Pathology (University of South China), College of Hunan Province, Cancer Research Institute, Hengyang Medical College, University of South China, Hengyang, Hunan 421001, China.

GKN2 (gastrokine 2) mainly plays a regulatory role in gastric mucosal defense and cell protection mechanisms, and its role in gastric cancer has not been thoroughly elucidated. Immunohistochemistry was used to detect GKN2 and TFF1 expressions in 90 gastric cancer tissues, 48 neoplastic resection margins, and 22 normal gastric mucosa epithelia. It showed that the downregulation of GKN2 and TFF1 expressions in gastric cancer tissues was significantly different from that in adjacent normal gastric tissues and distal gastric mucosal tissues. Nevertheless, correlation analysis showed that GKN2 expression in gastric cancer tissues was independent of TFF1 expression. After overexpression of GKN2 was constructed in human gastric cancer cell line MKN28 with the Ad-GFP-GKN2 transfected, cell viability was measured by CCK-8 assay, and migration and invasion ability were analyzed by transwell migration assay and transwell invasion assay. It indicated that overexpression of GKN2 significantly reduced the viability of MKN28 and SGC7901 cells. Overexpression of GKN2 could also inhibit the migration and invasion ability in MKN28 and SGC7901 cells. In addition, upregulation of GKN2 can inactivate the JAK2/STAT3 pathway. Our data suggest that GKN2 and TFF1 play the antitumor role in gastric carcinoma, and TFF1 may not interact or cooperate with GKN2. GKN2 overexpression can inhibit the growth and metastasis by downregulating the JAK2/STAT3 pathway in gastric cancer cells.
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http://dx.doi.org/10.1155/2021/1343808DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8352702PMC
August 2021

ELK4 promotes the development of gastric cancer by inducing M2 polarization of macrophages through regulation of the KDM5A-PJA2-KSR1 axis.

J Transl Med 2021 08 9;19(1):342. Epub 2021 Aug 9.

Department of Oncology, The First Hospital of Qinhuangdao, No. 258, Wenhua Road, Qinhuangdao, 066000, Hebei Province, People's Republic of China.

Background: We tried to elaborate the molecular mechanism of ETS-like transcription factor 4 (ELK4) affecting gastric cancer (GC) progression through M2 polarization of macrophages mediated by lysine-specific demethylase 5A (KDM5A)-Praja2 (PJA2)-kinase suppressor of ras 1 (KSR1) axis.

Methods: GC expression dataset was obtained from GEO database, and the downstream regulatory mechanism of ELK4 was predicted. Tumor-associated macrophages (TAMs) were isolated from GC tissues. The interaction among ELK4, KDM5A, PJA2 and KSR1 was analyzed by dual luciferase reporter gene, ChIP and Co-IP assays. The stability of KSR1 protein was detected by cycloheximide (CHX) treatment. After TAMs were co-cultured with HGC-27 cells, HGC-27 cell biological processes were assessed through gain- and loss-of function assays. Tumorigenicity was detected by tumorigenicity test in nude mice.

Results: In GC and TAMs, ELK4, KDM5A and KSR1 were highly expressed, while PJA2 was lowly expressed. M2 polarization of macrophages promoted the development of GC. ELK4 activated KDM5A by transcription and promoted macrophage M2 polarization. KDM5A inhibited the expression of PJA2 by removing H3K4me3 of PJA2 promoter, which promoted M2 polarization of macrophages. PJA2 reduced KSR1 by ubiquitination. ELK4 promoted the proliferative, migrative and invasive potentials of GC cells as well as the growth of GC xenografts by regulating KSR1.

Conclusion: ELK4 may reduce the PJA2-dependent inhibition of KSR1 by transcriptional activation of KDM5A to promote M2 polarization of macrophages, thus promoting the development of GC.
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http://dx.doi.org/10.1186/s12967-021-02915-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8353876PMC
August 2021
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