Publications by authors named "Yu Zhang"

8,690 Publications

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Gut microbial involvement in Alzheimer's disease pathogenesis.

Aging (Albany NY) 2021 May 10;13. Epub 2021 May 10.

Department of Geriatrics, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai 519000, China.

Alzheimer's disease (AD) is a chronic, progressive neurodegenerative disease characterized by memory loss, inability to carry out everyday daily life, and noticeable behavioral changes. The essential neuropathologic criteria for an AD diagnosis are extracellular β-amyloid deposition and intracellular accumulation of hyperphosphorylated tau. However, the exact pathogenic mechanisms underlying AD remain elusive, and current treatment options show only limited success. New research indicates that the gut microbiota contributes to AD development and progression by accelerating neuroinflammation, promoting senile plaque formation, and modifying neurotransmitter production. This review highlights laboratory and clinical evidence for the pathogenic role of gut dysbiosis on AD and provides potential cues for improved AD diagnostic criteria and therapeutic interventions based on the gut microbiota.
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http://dx.doi.org/10.18632/aging.202994DOI Listing
May 2021

Soil type shapes the antibiotic resistome profiles of long-term manured soil.

Sci Total Environ 2021 Apr 27;786:147361. Epub 2021 Apr 27.

College of Resources and Environment, Southwest University, Chongqing 400716, China. Electronic address:

Animal manure fertilization facilitates the proliferation and dissemination of antibiotic resistance genes (ARGs) in soil, posing high risks to humans and ecosystem health. Although studies suggest that soil types could shape the ARG profiles in greenhouse soil, there is still a lack of comparative studies on the fate of ARGs in different types of manured soils under field trials. Thus, a metagenomic approach was used to decipher the fate of ARGs in 12-year long-term fertilized (inorganic fertilizer, compost manure and a mix of them) acidic, near-neutral and alkaline soils. A total of 408 unique ARG subtypes with multidrug, glycopeptide, beta-lactam and aminoglycoside resistance genes were identified as the most universal ARG types in all soil samples. Genes conferred to beta-lactam was the predominant ARG type in all the manure-amended soils. Genomic and statistical analyses showed that manure application caused the enrichment of 98 and 91 ARG subtypes in acidic and near-neutral soils, respectively, and 8 ARG subtypes in alkaline soil. The abundances of Proteobacteria (acidic and near-neutral soils) and Actinobacteria (alkaline soil), which are the potential hosts of ARGs, were clearly increased in manured soils. Random forest modelling and Pearson correlation analysis revealed that the soil properties (pH and bio-available Zn) and mobile genetic elements had considerable impacts on the transmission of ARGs. A structural equation model further indicated that soil types shaped the ARG profiles by significantly (P < 0.01) influencing the soil properties, bacterial abundance and bacterial diversity, where bacterial abundance was the major factor influencing the ARG profiles. This study systematically explored the mechanisms shaping the ARG profiles of long-term manured soils, and this information could support strategies to manage the dissemination of ARGs in different soil types.
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http://dx.doi.org/10.1016/j.scitotenv.2021.147361DOI Listing
April 2021

Copper-Catalyzed Diamination of Unactivated Alkenes With Electron-Rich Amino Sources.

Org Lett 2021 May 10. Epub 2021 May 10.

Jilin Province Key Laboratory of Organic Functional Molecular Design & Synthesis, Department of Chemistry, Northeast Normal University, Changchun 130024, China.

The catalytic intermolecular diamination of unactivated alkenes with electron-rich amino sources is a challenge. Herein, by employing a directing-group strategy, a copper-catalyzed diamination of unactivated alkenes was realized. Symmetrical diamines were efficiently produced in a highly diastereoselective manner with readily available dialkylamines as amino sources, while a one-pot and two-step operation was necessary to produce the unsymmetrical diamines. These reactions were proposed to proceed through aziridinium intermediates.
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http://dx.doi.org/10.1021/acs.orglett.1c01313DOI Listing
May 2021

Mobile Media Promotes Orientation of 2D/3D Hybrid Lead Halide Perovskite for Efficient Solar Cells.

ACS Nano 2021 May 10. Epub 2021 May 10.

Beijing Key Laboratory for Theory and Technology of Advanced Battery Materials, Key Laboratory of Polymer Chemistry and Physics of Ministry of Education, BIC-ESAT, School of Materials Science and Engineering, Peking University, Beijing 100871, P.R. China.

2D/3D hybrid perovskites have shown great environmental stability for use as solar cells. Yet insulating organic cation spacers affect the formation of vertically oriented crystalline grains to hamper carrier transport. To date, the selection of cation spacers is limited because crystal growth kinetics should be strictly obeyed. Here, we adopted a mobile-media-assisted method to fabricate highly oriented 2D/3D hybrid perovskite films, wherein bulky molecules of (C(CH)NH, TBA) are used as cation spacers. We found the compositional volatile salt promote the orientation of perovskite polycrystalline films with various compositions universally. And we obtained efficient solar cells with a photoelectric conversion efficiency (PCE) of 17.38% and a certified PCE of 19.30% based on 2D/3D hybrid perovskites an overall stoichiometry matching = 10 and 20, respectively, which are one of the highest efficiencies among all 2D/3D hybrid perovskite based solar cells so far. These findings largely broaden the selection category of bulky cations and promote further exploration of more functional organic cations.
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http://dx.doi.org/10.1021/acsnano.0c09822DOI Listing
May 2021

Microarray analysis of the time-dependent expression profiles of long non-coding RNAs in the progression of vein graft stenotic disease.

Exp Ther Med 2021 Jun 15;21(6):635. Epub 2021 Apr 15.

Department of Cardiovascular Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China.

Long non-coding RNAs (lncRNAs) have been reported to be involved in various biological processes, including cell proliferation and apoptosis. However, the expression profiles of lncRNAs in patients with vein graft restenosis remain unknown. In the present study, the time-dependent expression profiles of genes in vein bypass grafting models were examined by microarray analysis. A total of 2,572 lncRNAs and 1,652 mRNAs were identified to be persistently significantly differentially expressed. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis was performed to investigate the functions of these lncRNAs. A total of 360 lncRNAs and 135 protein-coding genes were predicted to be involved in the vascular remodeling process. Co-expression network analysis revealed the association between 194 lncRNAs and seven associated protein-coding genes, including transforming growth factor-β1, Fes, Yes1 associated transcriptional regulator, sphingosine-1-phosphate receptor 1, Src, insulin receptor and melanoma cell adhesion molecule. Moreover, reverse transcription-quantitative PCR results supported those of the microarray data, and overexpression of AF062402, which regulates the transcription of Src, stimulated the proliferation of primary vascular smooth muscle cells. The findings of the present study may facilitate the development of novel therapeutic targets for vein graft restenosis and may help to improve the prognosis of patients following coronary artery bypass grafting.
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http://dx.doi.org/10.3892/etm.2021.10067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8097238PMC
June 2021

[Research Progress on Role and Mechanism of Elabela in Organ Fibrosis].

Zhongguo Yi Xue Ke Xue Yuan Xue Bao 2021 Apr;43(2):278-282

Department of Nephrology,The Second Hospital of Jilin University,Changchun 130041,China.

Elabela is a newly discovered peptide in recent years.It is the endogenous ligand of Apelin receptor(APJ)and plays an important role in embryonic development and adult organs.Elabela-APJ axis is closely related to organ fibrosis.Elabela can protect the functions of heart and kidney by antagonizing renin-angiotensin system and regulating blood pressure.In addition,it can prevent kidney and heart fibrosis by down-regulating the expression of fibrosis and inflammatory factors.However,there is a positive correlation between the level of Elabela and the degree of liver fibrosis,suggesting that Elabela may play a role in promoting liver fibrosis.This review aims to explore the role of Elabela-APJ axis in renal fibrosis,cardiac fibrosis,and liver fibrosis,and to provide a new therapeutic target for organ fibrosis.
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http://dx.doi.org/10.3881/j.issn.1000-503X.13014DOI Listing
April 2021

XRCC2 repairs mitochondrial DNA damage and fuels malignant behavior in hepatocellular carcinoma.

Cancer Lett 2021 May 5;512:1-14. Epub 2021 May 5.

Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. Electronic address:

The effects of DNA damage repair (DDR) and mitochondrial dysfunction associated with HCC have been investigated, but the functional role of mitochondrial DDR in HCC remains elusive. We studied the DDR genes and identified XRCC2 as a potential prognostic marker for HCC. XRCC2 overexpression was detected in HCC cells and shown to promote the malignant behavior of cancer cells. XRCC2 depletion in HCC cells led to DNA damage accumulation at the replication site in the nucleus. Additionally, XRCC2-depleted HCC cells exhibited impaired mitochondrial respiration and reduced complex I (CI) activity as XRCC2 was responsible for elimination of mitochondrial DNA (mtDNA) damage and maintenance of mtDNA-encoded CI-related genes' transcription in a RAD51-dependent manner. We showed that tunicamycin (Tm)-activated sXBP1 bound to the TGTCAT domain and suppressed XRCC2 expression. In HCC patients, we observed a negative correlation between XBP1 and XRCC2 expression. Moreover, XRCC2 inhibition by Tm led to genomic and mtDNA damage, which impaired the transcription of mtDNA-encoded CI-related genes and prevented tumor proliferation in vivo. We described the role of XRCC2 in mtDNA damage repair and HCC progression while unveiling the potential anti-tumor effect of Tm.
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http://dx.doi.org/10.1016/j.canlet.2021.04.026DOI Listing
May 2021

Circular RNA circitga7 accelerates glioma progression via miR-34a-5p/VEGFA axis.

Aging (Albany NY) 2021 May 7;13. Epub 2021 May 7.

Department of Oncological Neurosurgery, First Hospital of Jilin University, Changchun 130021, China.

Circular RNAs (circRNAs) are a group of noncoding RNAs derived from back-splicing events. CircRNA is reported to be involved in various tumor progressions, including glioma. Although there are a few reports of circular RNAs participating in gliomas, it is still unclear whether circular RNAs regulate the occurrence of gliomas. In our research, we found that the expression of circITGA7 in glioma tissues and glioma cells increased significantly. Knocking down circITGA7 can significantly inhibit the proliferation of glioma cells and reduce cell metastasis. Through analysis and dual-luciferase report assay, we found that circITGA7 acts as a sponge for miR-34a-5p targeting VEGFA in glioma. Our study showed that circITGA7 regulates the proliferation and metastasis of glioma cell lines (SW1783&U373) by regulating the miR-34a-5p/VEGFA pathway. In conclusion, our study revealed a regulatory loop for the circITGA7/miR-34a-5p/VEGFA axis to regulate glioma development.
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http://dx.doi.org/10.18632/aging.202996DOI Listing
May 2021

Transcriptome analysis provides insights into long noncoding RNAs in medaka gonads.

Comp Biochem Physiol Part D Genomics Proteomics 2021 Apr 29;39:100842. Epub 2021 Apr 29.

International Research Center for Marine Biosciences, Ministry of Science and Technology, Shanghai Ocean University, Shanghai 201306, China; Key Laboratory of Freshwater Aquatic Genetic Resources, Ministry of Agriculture and Rural Affairs, Shanghai Ocean University, Shanghai 201306, China. Electronic address:

Long non-coding RNAs (lncRNAs) are gradually regarded as regulators in sex determination and gonad development of various animals. Medaka (Oryzias latipes) is an excellent reproductive research model with sex-determining genes. However, the regulation of gonadal lncRNAs on medaka reproductive development remains unknown. Here, 5317 lncRNAs were obtained from medaka ovary and testis by Illumina HiSeq4000, among which 177 lncRNAs were up-regulated and 120 lncRNAs were down-regulated in the testis compared to the ovary. In addition, 6904 cis-regulated target genes were predicted from 3099 lncRNAs. GO and KEGG enrichment analysis showed that these target genes were mainly involved in phosphorylation, metabolic, metabolism of xenobiotics by cytochrome P450, insulin secretion, and GnRH signaling pathways. Furthermore, six highly expressed lncRNAs were randomly selected to verify the sequencing data by quantitative real time PCR (qRT-PCR). Next, in situ hybridization revealed that one of the sex-biased lncRNA MSTRG.14827.1 was highly expressed in immature germ cells, indicating MSTRG.14827.1 may play a key role in gametogenesis. Taken together, this study provides emerging lncRNA libraries and opens new avenues for future investigation of lncRNAs in medaka.
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http://dx.doi.org/10.1016/j.cbd.2021.100842DOI Listing
April 2021

Periconceptional iron supplementation and risk of gestational diabetes mellitus: a prospective cohort study.

Diabetes Res Clin Pract 2021 May 4:108853. Epub 2021 May 4.

Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Ministry of Education Key Laboratory of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. Electronic address:

Aims: Iron supplementation has been recommended for healthy pregnancy, but concerns have been raised regarding the potential adverse effects. We sought to examine the impact of periconceptional iron supplement use on subsequent gestational diabetes mellitus (GDM) risk.

Methods: Participants (N=5101) with information on periconceptional micronutrient supplementation and diagnosis of GDM were involved. Information on iron supplementation and general characteristics were collected at enrollment and follow-up visits. GDM was diagnosed by oral glucose tolerance tests (OGTT) conducted at 24-28 weeks of gestation. Robust Poisson regression model was used to estimate the relative risks (RRs) and 95% confidence intervals (CI) for the effect of iron supplement use on GDM.

Results: 10.5% of the participants were diagnosed with GDM and the incidence was significantly higher in users with iron >30 mg/d for more than 3 months (Iron>30-L) than in nonusers. Adjusted RRs (95% CI) were 1.53 (1.21, 1.93) in Iron>30-L group, 1.14 (0.80, 1.61) in users with iron >30 mg/d for less than 3 months (Iron>30-S) and 1.15 (0.86, 1.54) in users with iron ≤30 mg/d for any duration (Iron≤30) respectively, compared to nonusers. This link in Iron>30-L group was even stronger (adjusted RR: 1.70, 95% CI: 1.25, 2.31) when restricting the analysis among primiparous and iron-replete participants without family history of diabetes. There were no significant differences in birth outcomes among groups.

Conclusions: Periconceptional iron supplementation>30 mg/d for long-term was associated with increased GDM risk. The need and safety of prophylactic iron supplement in iron-replete pregnant women should be reconsidered.
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http://dx.doi.org/10.1016/j.diabres.2021.108853DOI Listing
May 2021

Ruthenabenzene: A Robust Precatalyst.

J Am Chem Soc 2021 May 7. Epub 2021 May 7.

Department of Chemistry, University of Illinois at Chicago, 845 W. Taylor St., Chicago, Illinois 60607, United States.

Metallaaromatics constitute a unique class of aromatic compounds where one or more transition metal elements are incorporated into the aromatic system, the parent of which is metallabenzene. One of the main concerns about metallabenzenes generally deals with the structural characterization related to their relative aromaticity compared to the carbon archetype. Transition metal-containing metallabenzenes are also implicated in certain catalytic processes such as alkyne metathesis polymerization; however, these transition metal-based metallaaromatic compounds have not been developed as a catalyst. Herein, we describe an effective strategy to generate diverse arrays of ruthenabenzenes and demonstrated them as an aromatic equivalent of the Grubbs-type ruthenium alkylidene catalysts. These ruthenabenzenes can be prepared via an enyne metathesis and metallotropic [1,3]-shift cascade process to form alkyne-chelated ruthenium alkylidene intermediates followed by spontaneous cycloaromatization. The aromatic nature of these complexes was confirmed by spectroscopic and X-ray crystallographic data, and the mechanistic pathways for the cycloaromatization process were studied by DFT calculations. These ruthenabenzenes display robust catalytic activity for metathesis and other transformations, which illustrates that metallabenzenes are not only compounds of structural and theoretical interests but also are a novel platform for new catalyst development.
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http://dx.doi.org/10.1021/jacs.1c02237DOI Listing
May 2021

RAS-association domain family 1A regulates the abnormal cell proliferation in psoriasis via inhibition of Yes-associated protein.

J Cell Mol Med 2021 May 7. Epub 2021 May 7.

State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.

Psoriasis is a chronic, inflammatory skin disease with a high incidence and recurrence; however, its exact pathogenesis and aetiology remain unclear. This study aimed to analyse the effect of the upstream negative regulator RAS-association domain family 1A (RASSF1A) on Yes-associated protein (YAP) in psoriasis. Skin lesions of 22 patients with psoriasis and 19 healthy controls were used. Human epidermal keratinocytes stimulated by M5 (IL-1α, IL-17, IL-22, TNF-α and oncostatin M) were used to establish a psoriatic cell model. BALB/c mice treated with topical imiquimod were used to establish a psoriatic mouse model. As the methylation level of RASSF1A increased, its expression in psoriatic patients and mice model decreased. Addition of the methylation inhibitor 5-Aza-CdR or RASSF1A-overexpressing lentivirus vector increased RASSF1A and reduced YAP expression; meanwhile improved skin lesions, reduced cell proliferation, induced cell cycle arrest in the G0/G1 phase, increased apoptosis, reduced inflammatory cytokines and activities of ERK, STAT3 and NF-κB signalling pathways. The results indicated that RASSF1A could play a role in the treatment of psoriasis by inhibiting YAP expression. Based on these findings, targeted drugs that can inhibit the methylation or increase the expression of RASSF1A may be useful for treating psoriasis.
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http://dx.doi.org/10.1111/jcmm.16489DOI Listing
May 2021

Ultrasound-Targeted Microbubble Destruction Enhances Inhibitory Effect of Apatinib on Angiogenesis in Triple Negative Breast Carcinoma Xenografts.

Anal Cell Pathol (Amst) 2021 17;2021:8837950. Epub 2021 Apr 17.

Department of Ultrasound, Fujian Medical University Union Hospital, Fuzhou, Fujian, China.

Ultrasound-targeted microbubble destruction (UTMD) has been proven as an effective technique to assist drugs to cross the vascular wall and cell membrane. This study was aimed at evaluating the synergistic antiangiogenic and growth-inhibiting effects of apatinib (APA) and UTMD on the triple negative breast cancer (TNBC). The TNBC xenograft model was established in nude mice ( = 40) which were then randomly divided into the APA plus UTMD (APA-U) group, UTMD group, APA group, and model control (M) group ( = 10 per group). Corresponding treatment was done once daily for 14 consecutive days. The general condition and body weight of tumor-bearing nude mice were monitored. Routine blood test and detection of liver and kidney function were done after treatments. The tumor size and microcirculation were examined by two-dimensional ultrasonography (2DUS) and contrast-enhanced ultrasonography (CEUS), respectively. Then, the tumor tissues were harvested for the detection of vascular endothelial growth factor (VEGF) by immunohistochemistry and for CD31-PAS double staining to assess microvessel density (MVD) and heterogeneous vascular positivity rate. After treatments, the tumor growth and angiogenesis were significantly inhibited in the APA group and the APA-U group, and these effects were more obvious in the APA-U group. The tumor volume, CEUS parameters, VEGF expression, and MVD in the APA-U group were significantly lower than those in the APA group ( < 0.05), while there were no marked differences in the heterogeneous vascular positivity rate, body weight, and blood parameters between the two groups ( > 0.05). In the UTMD group, the tumor growth and angiogenesis were not significantly inhibited, and all the parameters were similar to those in the M group ( > 0.05). During the experiment, all mice survived and generally had good condition. In conclusion, APA combined with UTMD may exert synergistic antiangiogenic and growth-inhibiting effects on the TNBC and not increase the heterogeneous vasculature and the severity of APA-related systemic side effects.
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http://dx.doi.org/10.1155/2021/8837950DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8075700PMC
April 2021

Relationships Between Annual and Perennial Seagrass () Populations and Their Sediment Geochemical Characteristics in the Yellow River Delta.

Front Plant Sci 2021 20;12:634199. Epub 2021 Apr 20.

CAS Key Laboratory of Marine Ecology and Environmental Sciences, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, China.

Annual and perennial populations commonly occur for the same submerged aquatic angiosperm species, yet relationships between population types and sediment characteristics are poorly understood. In the current study two habitats with annual and perennial populations were surveyed in the Yellow River Delta (YRD). Biomass and seasonal seed bank size were used to evaluate population status and potential recruitment capacity. Sediment geochemical parameters including moisture, sulfide, Chl , carbohydrate, OM, TOC, TN, and TP were measured to compare sediment nutrient composition and variability. The results revealed a higher biomass and larger seed bank in the annual population compared with the perennial population. The P levels in sediments between the two populations were similar; while the N level in the sediment of the annual population was significantly higher than the perennial population, which might support the recruitment of vegetative shoots when a large amount of seeds germinated during wet periods. The annual population exhibited greater resilience after habitat desiccation, with the population recovering rapidly once water appeared. The results of this study add to the knowledge of populations and their sediment geochemical characteristics, and can be used as a reference for population conservation and management.
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http://dx.doi.org/10.3389/fpls.2021.634199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8095395PMC
April 2021

Potential Fluid Biomarkers and a Prediction Model for Better Recognition Between Multiple System Atrophy-Cerebellar Type and Spinocerebellar Ataxia.

Front Aging Neurosci 2021 20;13:644699. Epub 2021 Apr 20.

Department of Laboratory Medicine, West China Hospital of Sichuan University, Chengdu, China.

Objective: This study screened potential fluid biomarkers and developed a prediction model based on the easily obtained information at initial inspection to identify ataxia patients more likely to have multiple system atrophy-cerebellar type (MSA-C).

Methods: We established a retrospective cohort with 125 ataxia patients from southwest China between April 2018 and June 2020. Demographic and laboratory variables obtained at the time of hospital admission were screened using Least Absolute Shrinkage and Selection Operator (LASSO) regression and logistic regression to construct a diagnosis score. The receiver operating characteristic (ROC) and decision curve analyses were performed to assess the accuracy and net benefit of the model. Also, independent validation using 25 additional ataxia patients was carried out to verify the model efficiency. Then the model was translated into a visual and operable web application using the R studio and Shiny package.

Results: From 47 indicators, five variables were selected and integrated into the prediction model, including the age of onset (AO), direct bilirubin (DBIL), aspartate aminotransferase (AST), eGFR, and synuclein-alpha. The prediction model exhibited an area under the curve (AUC) of 0.929 for the training cohort and an AUC of 0.917 for the testing cohort. The decision curve analysis (DCA) plot displayed a good net benefit for this model, and external validation confirmed its reliability. The model also was translated into a web application that is freely available to the public.

Conclusion: The prediction model that was developed based on laboratory and demographic variables obtained from ataxia patients at admission to the hospital might help improve the ability to differentiate MSA-C from spinocerebellar ataxia clinically.
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http://dx.doi.org/10.3389/fnagi.2021.644699DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8093568PMC
April 2021

Abelson interactor 1 splice isoform-L plays an anti-oncogenic role in colorectal carcinoma through interactions with WAVE2 and full-length Abelson interactor 1.

World J Gastroenterol 2021 Apr;27(15):1595-1615

Department of Central Laboratory and Institute of Clinical Molecular Biology, Peking University People's Hospital, Beijing 100044, China.

Background: Expression of the full-length isoform of Abelson interactor 1 (ABI1), ABI1-p65, is increased in colorectal carcinoma (CRC) and is thought to be involved in one or more steps leading to tumor progression or metastasis. The ABI1 splice isoform-L (ABI1-SiL) has conserved WAVE2-binding and SH3 domains, lacks the homeo-domain homologous region, and is missing the majority of PxxP- and Pro-rich domains found in full-length ABI1-p65. Thus, ABI1-SiL domain structure suggests that the protein may regulate CRC cell morphology, adhesion, migration, and metastasis interactions with the WAVE2 complex pathway.

Aim: To investigate the potential role and underlying mechanisms associated with ABI1-SiL-mediated regulation of CRC.

Methods: ABI1-SiL mRNA expression in CC tissue and cell lines was measured using both qualitative reverse transcriptase-polymerase chain reaction (RT-PCR) and real-time quantitative RT-PCR. A stably ABI1-SiL overexpressing SW480 cell model was constructed using Lipofectamine 2000, and cells selected with G418. Image J software, CCK8, and transwell assays were used to investigate SW480 cell surface area, proliferation, migration, and invasion. Immunoprecipitation, Western blot, and co-localization assays were performed to explore intermolecular interactions between ABI1-SiL, WAVE2, and ABI1-p65 proteins.

Results: ABI1-SiL was expressed in normal colon tissue and was significantly decreased in CRC cell lines and tissues. Overexpression of ABI1-SiL in SW480 cells significantly increased the cell surface area and inhibited the adhesive and migration properties of the cells, but did not alter their invasive capacity. Similar to ABI1-p65, ABI1-SiL still binds WAVE2, and the ABI1-p65 isoform in SW480 cells. Furthermore, co-localization assays confirmed these intermolecular interactions.

Conclusion: These results support a model in which ABI1-SiL plays an anti-oncogenic role by competitively binding to WAVE2 and directly interacting with phosphorylated and non-phosphorylated ABI1-p65, functioning as a dominant-negative form of ABI1-p65.
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http://dx.doi.org/10.3748/wjg.v27.i15.1595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8058658PMC
April 2021

A population-based analysis of malignant gastric tumor in children.

J Pediatr Surg 2021 Apr 3. Epub 2021 Apr 3.

Department of Gastrointestinal Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Huansha Road 261, Hangzhou 31006, China. Electronic address:

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http://dx.doi.org/10.1016/j.jpedsurg.2021.03.056DOI Listing
April 2021

circ_NRIP1 is oncogenic in malignant development of esophageal squamous cell carcinoma (ESCC) via miR-595/SEMA4D axis and PI3K/AKT pathway.

Cancer Cell Int 2021 May 6;21(1):250. Epub 2021 May 6.

Department of Oncology, The Second Affiliated Hospital of Henan University of Chinese Medicine, No.6 Dongfeng Road, Jinshui District, Zhengzhou, 450002, Henan, China.

Background: The hsa_circ_0004771 derived from NRIP1 (called circ_NRIP1) is a recently identified oncogenic circRNA. Here, we intended to investigate the role and mechanism of circ_NRIP1 in esophageal squamous cell carcinoma (ESCC), a prevalent and aggressive type of esophageal cancer.

Methods: Expression of circ_NRIP1, miRNA-595-5p (miR-595) and semaphorin 4D (SEMA4D) was detected by RT-qPCR and western blotting. Cell growth was assessed by colony formation assay, MTS assay, flow cytometry, and xenograft experiment; migration and invasion were evaluated by transwell assay and western blotting. Dual-luciferase reporter assay identified the relationship among circ_NRIP1, miR-595 and SEMA4D. Western blotting measured phosphatidylinositol-3-hydroxykinase (PI3K)/AKT pathway-related proteins.

Results: Expression of circ_NRIP1 was upregulated in ESCC tissues and cells. Knockdown of circ_NRIP1 could enhance apoptosis rate and E-cadherin expression, but suppress colony formation, cell viability, migration, invasion, and snail expression in KYSE30 and KYSE450 cells, as well as retarded tumor growth in mice. The suppressive role of circ_NRIP1 knockdown in cell growth, migration and invasion in vitro was abated by blocking miR-595; meanwhile, miR-595 overexpression elicited similar anti-tumor role in KYSE30 and KYSE450 cells, which was abrogated by restoring SEMA4D. Notably, circ_NRIP1 was a sponge for miR-595, and SEMA4D was a target of miR-595. Besides, PI3K/AKT signal was inhibited by circ_NRIP1 knockdown and/or miR-595 overexpression via indirectly or directly regulating SEMA4D.

Conclusion: circ_NRIP1 functioned as an oncogene in ESCC, and modulated ESCC cell growth, migration and invasion both in vitro and in vivo via targeting miR-595/SEMA4D axis and inhibiting PI3K/AKT signaling pathway.
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http://dx.doi.org/10.1186/s12935-021-01907-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8101145PMC
May 2021

Glyphosate exposure attenuates testosterone synthesis via NR1D1 inhibition of StAR expression in mouse Leydig cells.

Sci Total Environ 2021 Apr 25;785:147323. Epub 2021 Apr 25.

Northwest A&F University, Yangling 712100, Shaanxi, China; Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling 712100, Shaanxi, China; Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, Northwest A&F University, Yangling 712100, Shaanxi, China. Electronic address:

Glyphosate is a broad-spectrum herbicide that impairs testosterone synthesis in mammals. Leydig cells (LCs), the primary producers of testosterone, demonstrate rhythmic expression of circadian clock genes both in vivo and in vitro. The nuclear receptor NR1D1 is an important clock component that constitutes the subsidiary transcriptional/translational loop in the circadian clock system. Nr1d1 deficiency resulted in diminished fertility in both male and female mice. However, whether NR1D1 is involved in the glyphosate-mediated inhibition of testosterone synthesis in LCs remains unclear. Here, the involvement of NR1D1 in glyphosate-mediated inhibition of testosterone synthesis was investigated both in vitro and in vivo. Glyphosate exposure of TM3 cells significantly increased Nr1d1 mRNA levels, but decreased Bmal1, Per2, StAR, Cyp11a1, and Cyp17a1 mRNA levels. Western blotting confirmed elevated NR1D1 and reduced StAR protein levels following glyphosate exposure. Glyphosate exposure also reduced testosterone production in TM3 cells. In primary LCs, glyphosate exposure also upregulated Nr1d1 mRNA levels and downregulated the mRNA levels of other clock genes (Bmal1 and Per2) and steroidogenic genes (StAR, Cyp17a1, Cyp11a1, and Hsd3b2), and inhibited testosterone synthesis. Moreover, glyphosate exposure significantly reduced the amplitude and shortened the period of PER2::LUCIFERASE oscillations in primary LCs isolated from mPer2 knock-in mice. Four weeks of oral glyphosate upregulated NR1D1 at both the mRNA and protein levels in mouse testes, and this was accompanied by a reduction in StAR expression. Notably, serum testosterone levels were also drastically reduced in mice treated with glyphosate. Moreover, dual-luciferase reporter and EMSA assays revealed that in TM3 cells NR1D1 inhibits the expression of StAR by binding to a canonical RORE element present within its promoter. Together, these data demonstrate that glyphosate perturbs testosterone synthesis via NR1D1 mediated inhibition of StAR expression in mouse LCs. These findings extend our understanding of how glyphosate impairs male fertility.
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http://dx.doi.org/10.1016/j.scitotenv.2021.147323DOI Listing
April 2021

Screening and Identification of LMNB1 and DLGAP5, Two Key Biomarkers in Gliomas.

Biosci Rep 2021 May 6. Epub 2021 May 6.

Insititute of Nervous System Diseases, Xuzhou Medical University, Xuzhou, China.

Glioma is the most common primary cancer in the central nervous system.  Despite advances in surgery, radiotherapy, and chemotherapy over the past decades, the prognosis of glioblastoma patients remains poor.  We aim to identify robust gene signatures to better understand the complex molecular mechanisms and to discover potential novel molecular biomarkers for glioma.  By exploring GSE16011, GSE4290 and GSE50161 data in Gene Expression Omnibus (GEO) database, we screened out 380 differentially expressed genes between non-tumor and glioma tissues, and further selected 30 hub genes through the Molecular Complex Detection (MCODE) plug-in in Cytoscape.  In addition, LMNB1 and DLGAP5 were selected for further analyses due to their high expression in gliomas and were verified by using our cohort.  Our study confirmed that LMNB1 and DLGAP5 were upregulated in gliomas and patients with high expression of LMNB1 or DLGAP5 had poor survival rate.  Furthermore, silence of LMNB1 and DLGAP5 inhibited the proliferation of glioma cells.  Together, LMNB1 and DLGAP5 were two potentially novel molecular biomarkers for diagnosis and prognosis of glioma.
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http://dx.doi.org/10.1042/BSR20210231DOI Listing
May 2021

Identification of Circulating Biomarkers and Construction of a Prognostic Signature for Survival Prediction in Locally Advanced Pancreatic Cancer After Irreversible Electroporation.

J Inflamm Res 2021 28;14:1689-1699. Epub 2021 Apr 28.

Department of Pancreatobiliary Surgery, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, People's Republic of China.

Background: Irreversible electroporation (IRE) is a novel treatment for locally advanced pancreatic cancer (LAPC), but the predictive factors, based on cytokines and immunocytes of survival, are still lacking. This study aimed to establish a risk model based on cytokines and immunocytes for LAPC patients undergoing IRE treatment.

Patients And Methods: Peripheral blood samples were obtained from 31 LAPC patients and 8 healthy control subjects before IRE. The phenotypes of lymphocytes were analyzed by flow cytometry, and the cytokines were evaluated with Luminex microarray assay. Least absolute shrinkage and selection operator (LASSO) and Cox regression were applied to assess the prognostic factors for overall survival (OS) and progression-free survival (PFS). A receiver operating characteristic (ROC) curve and a concordance index (C-index) were used to compare the abilities to predict survival rates.

Results: The relationship between multiple cytokines and clinical factors was evaluated and their prognostic value was compared. The five best predictors for OS and PFS, including CA19-9, CD3CD4 T cells, CD3CD8 T cells, IL-17A, and TNF-α were selected and incorporated into a new immune panel. A risk model based on this immune panel was established and exhibited significantly higher values of C-indexes and AUC for OS and PFS prediction as compared with tumor marker score and TNM stage system.

Conclusion: We presented a risk model based on a microarray assay of cytokines and lymphocytes for LAPC patients after receiving IRE treatment for the first time. The established risk model showed relatively good performance in survival prediction and was able to facilitate tailed patient management in clinical practice.
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http://dx.doi.org/10.2147/JIR.S307884DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8091593PMC
April 2021

Effects of integrated rice-duck farming system on duck carcass traits, meat quality, amino acid, and fatty acid composition.

Poult Sci 2021 Mar 12;100(6):101107. Epub 2021 Mar 12.

Key Laboratory of Animal Genetics and Breeding and Molecular Design of Jiangsu Province, College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China; Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Jiangsu Yangzhou 225009, China. Electronic address:

Integrated rice-duck farming (RD) system, which aims to improve the welfare of ducks, has gained popularity in Asian countries. However, the effects of RD system on the carcass and quality traits of duck meat have not been evaluated. Here, a paddy field experiment was conducted to examine the effects of RD system on the carcass and quality traits of duck meat. A total of 180 Jinding ducklings (7 days old) were randomly divided into 2 rearing systems of floor pen rearing (FPR) system and RD system. After 11 weeks, 12 ducks from each rearing system (6 males and females each) were used for carcass traits, meat quality, amino acid, and fatty acid analyses. The results showed that ducks reared in the RD system had higher carcass yield and intramuscular fat content (P < 0.05) than those reared in the FPR system; however, ducks reared in the RD system had lower protein and moisture content (P < 0.05). Additionally, the concentration of essential amino acids, including Tyr, Val, Met, Phe, His, Ala, Arg, and Pro, was higher in the breast muscle of ducks reared in the RD system than those reared in the FPR system. Furthermore, higher saturated fatty acid (C12:0, C14:0, C16:0, C18:0, and C21:0), monounsaturated fatty acid (C16:1, C18:1, and C18:1T), and polyunsaturated fatty acid (C22:2, C18:2n-6, and C22:6n3) content was recorded in the breast muscle of ducks reared in the RD system than those reared in the FPR system (P < 0.05). Taken together, our results indicated that the RD system improved the carcass traits, intramuscular fat, essential amino acids, and polyunsaturated fatty acids profiles of the ducks. These findings suggest that the RD system is an effective strategy to improve the welfare and meat quality of ducks.
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http://dx.doi.org/10.1016/j.psj.2021.101107DOI Listing
March 2021

Confirming the contribution and genetic spectrum of de novo mutation in infantile spasms: Evidence from a Chinese cohort.

Mol Genet Genomic Med 2021 May 5:e1689. Epub 2021 May 5.

Department of Medical Genetics, Capital Institute of Pediatrics, Beijing, China.

Objective: We determined the yield, genetic spectrum, and actual origin of de novo mutations (DNMs) for infantile spasms (ISs) in a Chinese cohort. The efficacy of levetiracetam (LEV) for STXBP1-related ISs was explored also.

Methods: Targeted sequencing of 153 epilepsy-related candidate genes was applied to 289 Chinese patients with undiagnosed ISs. Trio-based amplicon deep sequencing was used for all DNMs to distinguish somatic/mosaic mutations from germline ones.

Results: Total of 26 DNMs were identified from 289 recruited Chinese patients with undiagnosed ISs. Among them, 24 DNMs were interpreted as pathogenic mutations based on American College of Medical Genetics and Genomics guidelines, contributing to 8.3% (24/289) of diagnosis yield in the Chinese IS cohort. CDKL5 and STXBP1 are the top genes with recurrent DNMs, accounting for 3.1% (9/289) of yield. Further deep resequencing for the trio members showed that 22.7% (5/22) of DNMs are actually somatic in the proband or a parent. These somatic carriers presented milder seizure attacks than those with true germline DNMs. After treatment with LEV for half a year, three patients with DNM in STXBP1 showed improved clinical symptoms, including seizure-free and normal electroencephalogram, except for a patient with a second DNM in DIAPH3.

Significance: Our study confirmed the contribution and genetic spectrum of DNMs in Chinese IS patients. Somatic mutation account for a quarter of DNMs in IS cases. Treatment with LEV improved the prognosis of STXBP1-related ISs.
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http://dx.doi.org/10.1002/mgg3.1689DOI Listing
May 2021

Allogeneic hematopoietic stem cell transplantation overcomes the poor prognosis in MLL-rearranged solid tumor therapy related-acute myeloid leukemia.

Am J Cancer Res 2021 15;11(4):1683-1696. Epub 2021 Apr 15.

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

MLL rearrangement is very common in solid tumor therapy-related acute myeloid leukemia (t-AML). To investigated the prognosis of solid tumor MLL t-AML, 157 patients were divided into 3 groups: non-MLL t-AML (n=41), MLL t-AML (n=18) and MLL de novo AML (n=98). Of the 150 patients underwent anti-leukemia therapy, the complete remission (CR) was similar in MLL t-AML, non-MLL t-AML and MLL de novo AML (P=0.251). 3-years overall survival (OS) was 37.5%, 21.5% and 20.4% (P=0.046), and leukemia-free survival (LFS) was 28.0%, 32.2% and 22.7% (P=0.031), and the incidence of relapse was 30.0%, 50.4% and 53.5% (P=0.382), respectively, in the three groups. Multivariate analysis revealed that MLL t-AML was a risk factor while allo-HSCT was a protective factor for OS, LFS, and relapse (P<0.001, P<0.001 and P=0.005) (P=0.002, P<0.001 and P<0.001, respectively). The 3-years OS was 0%, 17.9% and 2.3% (P=0.038), and LFS was 0%, 23.1% and 3.3% (P=0.017), and relapse was 100%, 53.1% and 74.4% (P=0.001), respectively, among three groups in patients undergoing chemotherapy alone, while OS was 64.3%, 52.7% and 40.7% (P=0.713), LFS was 60.0%, 48.8% and 37.0% (P=0.934), and relapse was 25.0%, 47.4% and 47.5% (P=0.872), respectively, among these groups in patients undergoing allo-HSCT. Intriguingly, MLL t-AML was no longer risk factor for relapse and LFS (P=0.882 and P=0.484, respectively), and it became a favorable factor for OS (P=0.011) in patients undergoing allo-HSCT. In conclusion, MLL t-AML had poor prognosis compared with non-MLL t-AML and MLL de novo AML, but allo-HSCT might overcome the poor prognosis of MLL t-AML.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085874PMC
April 2021

Low miR-16 expression induces regulatory CD4NKG2D T cells involved in colorectal cancer progression.

Am J Cancer Res 2021 15;11(4):1540-1556. Epub 2021 Apr 15.

Department of Immunology, School of Medicine, Yangzhou University Yangzhou 225001, Jiangsu Province, P. R. China.

MiR-15a/16 is a member of the miRNA cluster that exhibits tumor suppression and immune modulation via targeting multiple genes. Decreased miR-15a/16 expression is involved in many cancer cells. Here, miR-16 had decreased expression in NK1.1CD4NKG2D T cells and bound with the 3'-UTR of gene. MiR-15a/16-deficient mice had many CD4NKG2D T cells, which produced TGF-β1 and IL-10 and inhibited the IFN-γ production of CD8 T cells. Adoptive transfer of NK1.1CD4NKG2D T cells from miR-15a/16-deficient mice promoted tumor growth . However, no changes for NK1.1CD4NKG2D T cells were found in the miR-15a/16-transgenic mice. Although the miR-15a/16 transgenic mice transplanted with B16BL6 or MC38 cells exhibited rapid growth, these tumor-bearing mice did not show changes in NK1.1CD4NKG2D T cell distributions in either spleens or tumors. When NK1.1CD4 T cells were stimulated by α-CD3/sRAE-1 , the NKG2D expression was difficult to induce in the T cells of miR-15a/16-transgenic mice. Finally, increased frequencies of regulatory CD4NKG2D T cells with low miR-16 levels were observed in patients with late-stage colorectal cancer (Duke's C, D). Thus, miR-16 modulates NK1.1CD4NKG2D T cell functions via targeting NKG2D. Low miR-16 expression in CD4 T cells induces the regulatory CD4NKG2D T subpopulation, which promotes tumor evasion via the secretion of immune-suppressive molecules.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085839PMC
April 2021

Circular RNA hsa_circ_0006401 promotes proliferation and metastasis in colorectal carcinoma.

Cell Death Dis 2021 May 4;12(5):443. Epub 2021 May 4.

Department of Gastroenterology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, No. 158 Shangtang Road, Hangzhou, Zhejiang, China.

Dysregulation of circular RNA (circRNA) expression is involved in the progression of cancer. Here, we aimed to study the potential function of hsa_circ_0006401 in colorectal cancer (CRC). CircRNA hsa_circ_0006401 expression levels in CRC and adjacent nontumor tissues were analyzed by real-time quantitative PCR (qRT-PCR) and circRNA in situ hybridization (RNA-ISH). Then, CRC cell proliferation was assessed by cell counting. Wound-healing and transwell assays were utilized to detect the effect of hsa_circ_0006401 on CRC migration. A circRNA-ORF construct was created, and a specific antibody against the splice junction of hsa_circ_0006401 was prepared. Finally, the proteins directly binding to hsa_circ_0006401 peptides were identified by immunoprecipitation combined with mass spectrometry. In our study, we found hsa_circ_0006401 was closely related to CRC metastasis and exhibited upregulated expression in metastatic CRC tissue samples. Proliferation and migration were inhibited in vitro when hsa_circ_0006401 expression was silenced. Downregulation of hsa_circ_0006401 expression decreased CRC proliferation and liver metastasis in vivo. A 198-aa peptide was encoded by sequences of the splice junction absent from col6a3. Hsa_circ_0006401 promoted CRC proliferation and migration by encoding the hsa_circ_0006401 peptide. Hsa_circ_0006401 peptides decreased the mRNA and protein level of the host gene col6a3 by promoting col6a3 mRNA stabilation. In conclusion, our study revealed that circRNAs generated from col6a3 that contain an open-reading frame (ORF) encode a novel 198-aa functional peptide and hsa_circ_0006401 peptides promote stability of the host gene col6a3 mRNA to promote CRC proliferation and metastasis.
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http://dx.doi.org/10.1038/s41419-021-03714-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8097074PMC
May 2021

Reversed-engineered human alveolar lung-on-a-chip model.

Proc Natl Acad Sci U S A 2021 05;118(19)

Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA 02139;

Here, we present a physiologically relevant model of the human pulmonary alveoli. This alveolar lung-on-a-chip platform is composed of a three-dimensional porous hydrogel made of gelatin methacryloyl with an inverse opal structure, bonded to a compartmentalized polydimethylsiloxane chip. The inverse opal hydrogel structure features well-defined, interconnected pores with high similarity to human alveolar sacs. By populating the sacs with primary human alveolar epithelial cells, functional epithelial monolayers are readily formed. Cyclic strain is integrated into the device to allow biomimetic breathing events of the alveolar lung, which, in addition, makes it possible to investigate pathological effects such as those incurred by cigarette smoking and severe acute respiratory syndrome coronavirus 2 pseudoviral infection. Our study demonstrates a unique method for reconstitution of the functional human pulmonary alveoli in vitro, which is anticipated to pave the way for investigating relevant physiological and pathological events in the human distal lung.
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http://dx.doi.org/10.1073/pnas.2016146118DOI Listing
May 2021

Acteoside exerts neuroprotection effects in the model of Parkinson's disease via inducing autophagy: Network pharmacology and experimental study.

Eur J Pharmacol 2021 Apr 30;903:174136. Epub 2021 Apr 30.

State Key Laboratory of Pathogenesis, Prevention and Treatment of Central Asian High Incidence Diseases, Clinical Medical Research Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054, Xinjiang, China. Electronic address:

Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease. At present, the incidence rate of PD is increasing worldwide, there is no effective cure available so far, and currently using drugs are still limited in efficacy due to serious side effects. Acteoside (ACT) is an active ingredient of many valuable medicinal plants, possesses potential therapeutic effects on many pathological conditions. In this study, we dissected the neuroprotection effects of ACT on PD and its potential molecular mechanism in our PD model pathology based on network pharmacology prediction and experimental assays. Network pharmacology and bioinformatics analysis demonstrated that ACT has 381 potential targets; among them 78 putative targets associated with PD were closely related to cellular autophagy and apoptotic processes. Our experimental results showed that ACT exerted significant neuroprotection effects on Rotenone (ROT) -induced injury of neuronal cells and Drosophila melanogaster (D. melanogaster). Meanwhile, ACT treatment induced autophagy in both neuronal cell lines and fat bodies of D. melanogaster. Furthermore, ACT treatment decreased ROT induced apoptotic rate and reactive oxygen species production, increased mitochondrial membrane potentials in neuronal cells, and promoted clearance of α-synuclein (SNCA) aggregations in SNCA overexpressed cell model through the autophagy-lysosome pathway. Interestingly, ACT treatment significantly enhanced mitophagy and protected cell injury in neuronal cells. Taken together, ACT may represent a potent stimulator of mitophagy pathway, thereby exerts preventive and therapeutic effects against neurodegenerative diseases such as PD by clearing pathogenic proteins and impaired cellular organelles like damaged mitochondria in neurons.
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http://dx.doi.org/10.1016/j.ejphar.2021.174136DOI Listing
April 2021

Mycobacterium tuberculosis protein kinase G acts as an unusual ubiquitinating enzyme to impair host immunity.

EMBO Rep 2021 May 2:e52175. Epub 2021 May 2.

CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Beijing, China.

Upon Mycobacterium tuberculosis (Mtb) infection, protein kinase G (PknG), a eukaryotic-type serine-threonine protein kinase (STPK), is secreted into host macrophages to promote intracellular survival of the pathogen. However, the mechanisms underlying this PknG-host interaction remain unclear. Here, we demonstrate that PknG serves both as a ubiquitin-activating enzyme (E1) and a ubiquitin ligase (E3) to trigger the ubiquitination and degradation of tumor necrosis factor receptor-associated factor 2 (TRAF2) and TGF-β-activated kinase 1 (TAK1), thereby inhibiting the activation of NF-κB signaling and host innate responses. PknG promotes the attachment of ubiquitin (Ub) to the ubiquitin-conjugating enzyme (E2) UbcH7 via an isopeptide bond (UbcH7 K82-Ub), rather than the usual C86-Ub thiol-ester bond. PknG induces the discharge of Ub from UbcH7 by acting as an isopeptidase, before attaching Ub to its substrates. These results demonstrate that PknG acts as an unusual ubiquitinating enzyme to remove key components of the innate immunity system, thus providing a potential target for tuberculosis treatment.
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http://dx.doi.org/10.15252/embr.202052175DOI Listing
May 2021

A Novel Immune-Related Prognostic Biomarker and Target Associated With Malignant Progression of Glioma.

Front Oncol 2021 16;11:643159. Epub 2021 Apr 16.

Department of Neurosurgery, First Hospital of Shanxi Medical University, Taiyuan, China.

Background: Glioma is one of the most common malignancies in the central nervous system and has limited effective therapeutic options. Therefore, we sought to identify a suitable target for immunotherapy.

Materials And Methods: We screened prognostic genes for glioma in the CGGA database and GSE43378 dataset using survival analysis, receiver operating characteristic (ROC) curves, independent prognostic analysis, and clinical correlation analysis. The results were intersected with immune genes from the ImmPort database through Venn diagrams to obtain likely target genes. The target genes were validated as prognostically relevant immune genes for glioma using survival, ROC curve, independent prognostic, and clinical correlation analyses in samples from the CGGA database and GSE43378 dataset, respectively. We also constructed a nomogram using statistically significant glioma prognostic factors in the CGGA samples and verified their sensitivity and specificity with ROC curves. The functions, pathways, and co-expression-related genes for the glioma target genes were assessed using PPI networks, enrichment analysis, and correlation analysis. The correlation between target gene expression and immune cell infiltration in glioma and the relationship with the survival of glioma patients were investigated using the TIMER database. Finally, target gene expression in normal brain, low-grade glioma, and high-grade glioma tissues was detected using immunohistochemical staining.

Results: We identified TNFRSF12A as the target gene. Satisfactory results from survival, ROC curve, independent prognosis, and clinical correlation analyses in the CGGA and GSE43378 samples verified that TNFRSF12A was significantly associated with the prognosis of glioma patients. A nomogram was constructed using glioma prognostic correlates, including TNFRSF12A expression, primary-recurrent-secondary (PRS) type, grade, age, chemotherapy, IDH mutation, and 1p19q co-deletion in CGGA samples with an AUC value of 0.860, which illustrated the accuracy of the prognosis prediction. The results of the TIMER analysis validated the significant correlation of TNFRSF12A with immune cell infiltration and glioma survival. The immunohistochemical staining results verified the progressive up-regulation of TNFRSF12A expression in normal brain, low-grade glioma, and high-grade glioma tissues.

Conclusion: We concluded that TNFRSF12A was a viable prognostic biomarker and a potential immunotherapeutic target for glioma.
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http://dx.doi.org/10.3389/fonc.2021.643159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085360PMC
April 2021