Publications by authors named "Xiang Zhu"

316 Publications

LSD1-Demethylated LINC01134 Confers Oxaliplatin Resistance via SP1-induced p62 Transcription in Hepatocellular Carcinoma.

Hepatology 2021 Jul 29. Epub 2021 Jul 29.

Department of Genetic Engineering, Beijing Institute of Biotechnology, Beijing, China.

Background And Aims: Oxaliplatin (OXA) is one of the most common chemotherapeutics in advanced hepatocellular carcinoma (HCC), the resistance of which poses a big challenge. Long non-coding RNAs (lncRNAs) play vital roles in chemoresistance. Therefore, elucidating the underlying mechanisms and identifying predictive lncRNAs for OXA resistance is needed urgently.

Methods: RNA sequencing and FISH were utilized to investigate the OXA-resistant (OXA-R) lncRNAs. Survival analysis was performed to determine the clinical significance of LINC01134 and p62 expression. Luciferase, RIP, ChIP and ChIRP assays were used to explore the mechanisms by which LINC01134 regulates p62 expression. The effects of LINC01134/SP1/p62 axis on OXA resistance were evaluated using cell viability, apoptosis and mitochondrial function and morphology analysis. Xenografts were used to estimate the in vivo regulation of OXA resistance by LINC01134/SP1/p62 axis. ChIP, cell viability and xenograft assays were used to identify the demethylase for LINC01134 upregulation in OXA resistance.

Results: LINC01134 was identified as one of the most upregulated lncRNAs in OXA-R cells. Higher LINC01134 expression predicted poorer OXA therapeutic effacacy. LINC01134 activates anti-oxidative pathway through p62 by recruiting transcription factor SP1 to the p62 promoter. The LINC01134/SP1/p62 axis regulates OXA resistance by altering cell viability, apoptosis, and mitochondrial homeostasis both in vitro and in vivo. Further, the demethylase, LSD1 was responsible for LINC01134 upregulation in OXA-R cells. In HCC patients, LINC01134 expression was positively correlated with p62 and LSD1 expressions, while SP1 expression positively correlated with p62 expression.

Conclusion: LSD1/LINC01134/SP1/p62 axis is critical for OXA resistance in HCC. Evaluating LINC01134 expression in HCC will be effective in predicting OXA efficacy. In treatment-naive patients, targeting the LINC01134/SP1/p62 axis may be a promising strategy to overcome OXA chemoresistance.
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http://dx.doi.org/10.1002/hep.32079DOI Listing
July 2021

Associations of Genetically Predicted Lipoprotein (a) Levels with Cardiovascular Traits in Individuals of European and African Ancestry.

Circ Genom Precis Med 2021 Jul 20. Epub 2021 Jul 20.

Department of Cardiovascular Medicine & Gonda Vascular Center, Mayo Clinic, Rochester, MN.

- Lipoprotein (a) [Lp(a)] levels are higher in individuals of African ancestry (AA) than in individuals of European ancestry (EA). We examined associations of genetically predicted Lp(a) levels with 1) atherosclerotic cardiovascular disease (ASCVD) subtypes: coronary heart disease (CHD), cerebrovascular disease (CVD), peripheral artery disease (PAD), and abdominal aortic aneurysm (AAA); and 2) non-ASCVD phenotypes, stratified by ancestry. - We performed 1) Mendelian randomization (MR) analyses for previously reported cardiovascular associations, and 2) phenome-wide MR (MR-PheWAS) analyses for novel associations. Analyses were stratified by ancestry in electronic MEdical Records and GEnomics, United Kingdom Biobank, and Million Veteran Program cohorts separately and in a combined cohort of 804,507 EA and 103,580 AA participants. - In MR analyses using the combined cohort, a 1-standard deviation (SD) genetic increase in Lp(a) level was associated with ASCVD subtypes in EA - odds ratio and 95% confidence interval for CHD 1.28(1.16-1.41); CVD 1.14(1.07-1.21); PAD 1.22(1.11-1.34); AAA 1.28(1.17-1.40); in AA the effect estimate was lower than in EA and nonsignificant for CHD 1.11(0.99-1.24) and CVD 1.06(0.99-1.14) but similar for PAD 1.16(1.01-1.33) and AAA 1.34(1.11-1.62). In EA, a 1-SD genetic increase in Lp(a) level was associated with aortic valve disorders 1.34(1.10-1.62), mitral valve disorders 1.18(1.09-1.27), congestive heart failure 1.12(1.05-1.19), and chronic kidney disease 1.07(1.01-1.14). In AA no significant associations were noted for aortic valve disorders 1.08(0.94-1.25), mitral valve disorders 1.02(0.89-1.16), congestive heart failure 1.02(0.95-1.10), or chronic kidney disease 1.05(0.99-1.12). MR-PheWAS identified novel associations in EA with arterial thromboembolic disease, non-aortic aneurysmal disease, atrial fibrillation, cardiac conduction disorders, and hypertension. - Many cardiovascular associations of genetically increased Lp(a) that were significant in EA were not significant in AA. Lp(a) was associated with ASCVD in four major arterial beds in EA but only with PAD and AAA in AA. Additional, novel cardiovascular associations were detected in EA.
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http://dx.doi.org/10.1161/CIRCGEN.120.003354DOI Listing
July 2021

Implementation and data processing of a five-channel microwave interferometer with high temporal resolution and low noise on Sino-UNIted Spherical Tokamak.

Rev Sci Instrum 2021 Apr;92(4):043538

Department of Engineering Physics, Tsinghua University, Beijing 100084, People's Republic of China.

A five-channel microwave interferometer with high temporal resolution and high phase resolution has been developed for measuring electron density profiles and fluctuations on the Sino-UNIted Spherical Tokamak. A correction algorithm, based on the low signal amplitude detection, is proposed to eliminate the fringe jump errors. The correction algorithm achieves an accuracy of 92%. The density profile is reconstructed through the Park-matrix method, with the geometry of magnetic surfaces calculated by the equilibrium fitting. The reconstructed density profiles for discharges with supersonic molecular beam injection are in good agreement with the results of another 94 GHz single-channel horizontal interferometer and the Langmuir probes. The temporal resolution of the system is 0.5 µs and the line-integrated electron density resolution is 1 × 10 m, which benefits from the single sideband modulation technique. Therefore, the multichannel interferometer system is capable of studying the details of the high-frequency (up to 200 kHz) density fluctuation such as that in the minor disruption event.
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http://dx.doi.org/10.1063/5.0043667DOI Listing
April 2021

Efficient synthesis of vinylene-linked conjugated porous networks the Horner-Wadsworth-Emmons reaction for photocatalytic hydrogen evolution.

Chem Commun (Camb) 2021 Jul;57(61):7557-7560

State Key Laboratory for Oxo Synthesis and Selective Oxidation, Suzhou Research Institute of Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Suzhou 215000, China.

A simple, yet efficient synthetic approach for the construction of vinylene-linked conjugated porous networks was developed. Based on the Horner-Wadsworth-Emmons reaction, the condensation polymerization for the formation of an sp2 carbon-linkage can be achieved at room temperature. The resulting vinylene-linked frameworks exhibit a promising porous nature with the best surface area of up to 1373 m2 g-1. Their intrinsic conjugated architectures and semiconducting properties lead to photocatalytic evolution of hydrogen from water under visible light irradiation. This new synthesis method provides a facile means to prepare attractive sp2 carbon linked porous organic frameworks.
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http://dx.doi.org/10.1039/d1cc02280fDOI Listing
July 2021

Integrated Analysis of Omics Data Reveal AP-1 as a Potential Regulation Hub in the Inflammation-Induced Hyperalgesia Rat Model.

Front Immunol 2021 28;12:672498. Epub 2021 May 28.

Department of Anesthesiology, Suzhou Municipal Hospital Affiliated to Nanjing Medical University, Suzhou, China.

Inflammation-associated chronic pain is a global clinical problem, affecting millions of people worldwide. However, the underlying mechanisms that mediate inflammation-associated chronic pain remain unclear. A rat model of cutaneous inflammation induced by Complete Freund's Adjuvant (CFA) has been widely used as an inflammation-induced pain hypersensitivity model. We present the transcriptomics profile of CFA-induced inflammation in the rat dorsal root ganglion (DRG) an approach that targets gene expression, DNA methylation, and post-transcriptional regulation. We identified 418 differentially expressed mRNAs, 120 differentially expressed microRNAs (miRNAs), and 2,670 differentially methylated regions (DMRs), which were all highly associated with multiple inflammation-related pathways, including nuclear factor kappa B (NF-κB) and interferon (IFN) signaling pathways. An integrated analysis further demonstrated that the activator protein 1 (AP-1) network, which may act as a regulator of the inflammatory response, is regulated at both the transcriptomic and epigenetic levels. We believe our data will not only provide drug screening targets for the treatment of chronic pain and inflammation but will also shed light on the molecular network associated with inflammation-induced hyperalgesia.
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http://dx.doi.org/10.3389/fimmu.2021.672498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8194263PMC
May 2021

Carotid Plaques From Symptomatic Patients Are Characterized by Local Increase in Xanthine Oxidase Expression.

Stroke 2021 Jun 10:STROKEAHA120032964. Epub 2021 Jun 10.

Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN. (M.G., V.N., M.P., F.F., M.D.Y., A.L.).

Background And Purpose: XO (xanthine oxidase) is a key enzyme of uric acid metabolism and is thought to contribute to oxidative pathways that promote atherosclerotic plaque progression, yet its role in plaque destabilization is not well elucidated. We hypothesized that XO is expressed in carotid plaque from symptomatic patients in association with cardiovascular risk factors.

Methods: Patients were stratified by symptoms, defined as presentation with an ipsilateral cerebral ischemic event. Carotid atherosclerotic plaques were obtained from 44 patients with symptomatic plaque and 44 patients without ischemic cerebral events. Protein expression of XO was evaluated by immunohistochemical staining and the percentage of cells expressing XO and CD68 (macrophage marker) compared between the groups. Biochemical and demographic cardiometabolic risk factors of study participants also were measured.

Results: Carotid atherosclerotic plaques from symptomatic patients were associated with significantly higher XO expression versus asymptomatic plaque (median [interquartile range]: 1.24 [2.09] versus 0.16 [0.34]; <0.001) and with significantly higher circulating uric acid levels (mean±SD: 7.36±2.10 versus 5.37±1.79 mg/dL; <0.001, respectively). In addition, XO expression in atherosclerotic carotid plaque was inversely associated with serum high-density lipoproteins cholesterol levels (=0.010, =-0.30) and directly with circulating uric acid levels (<0.001, =0.45). The average percentage of macrophages that expressed XO was significantly higher in symptomatic versus asymptomatic plaques (median [interquartile range]: 93.37% [25] versus 46.15% [21], respectively; <0.001).

Conclusions: XO overexpression in macrophages is associated with increased serum uric acid and low high-density lipoproteins cholesterol levels and may potentially have a mechanistic role in carotid plaque destabilization. The current study supports a potential role for uric acid synthesis pathway as a target for management of carotid atherosclerosis in humans.
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http://dx.doi.org/10.1161/STROKEAHA.120.032964DOI Listing
June 2021

Falcarindiol Enhances Cisplatin Chemosensitivity of Hepatocellular Carcinoma Down-Regulating the STAT3-Modulated PTTG1 Pathway.

Front Pharmacol 2021 7;12:656697. Epub 2021 May 7.

Department of Hepato-Pancreato-Biliary Surgery, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China.

Hepatocellular carcinoma (HCC) is the most frequent primary liver malignancy globally and the third leading cause of cancer-related death. Chemotherapy is one of the main methods in treating HCC, while recent studies have found that the resistance of HCC to chemotherapeutic drugs reduces the efficacy of the chemotherapy. Falcarindiol (FAD) is a cytotoxic and anti-inflammatory polyacetylenic oxylipin found in food plants of the carrot family (Apiaceae), while its role in HCC remains to be explored. Here, HCC cells (Huh7 and LM3) were treated with FAD at different doses. Cell proliferation was tested by the cell counting kit-8 (CCK-8) method and colony formation assay, while the apoptosis was monitored by flow cytometry. The profiles of apoptosis-related proteins (Bax, bcl2, and Caspase-3), DNA repair proteins (Rad51, BRCA1, and MDC1), and the signal transducer and activator of transcription 3 (STAT3)/Pituitary Tumor Transforming Gene 1 (PTTG1) were verified by western blot (WB) or quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The interaction between STAT3 and PTTG1 was verified by immunoprecipitation (IP). In addition, a xenograft tumor model was constructed in mice to explore the anti-tumor effects of FAD , and immunohistochemistry (IHC) was performed to count the number of Ki67-stained cells. As a result, FAD inhibited HCC cell proliferation and DNA repair, facilitated their apoptosis, and also enhanced cisplatin (DDP) chemosensitivity. The Combination Index (CI) evaluation showed that FAD and DDP had synergistic effects in repressing HCC cell proliferation. Besides, FAD dampened the STAT3/PTTG1 pathway expression. Further studies revealed that inhibiting STAT3 enhanced the inhibitive effect of FAD on HCC cells, whereas overexpressing PTTG1 attenuated the anti-tumor effect of FAD. Overall, our study illustrated that FAD is a potential anticancer drug and strengthens the chemosensitivity of HCC cells to DDP by inhibiting the STAT3/PTTG1 pathway.
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http://dx.doi.org/10.3389/fphar.2021.656697DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8138572PMC
May 2021

Chaperonin-Containing TCP1 Complex (CCT) Promotes Breast Cancer Growth Through Correlations With Key Cell Cycle Regulators.

Front Oncol 2021 30;11:663877. Epub 2021 Apr 30.

Division of Cancer Research, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, United States.

Uncontrolled proliferation as a result of dysregulated cell cycling is one of the hallmarks of cancer. Therapeutically targeting pathways that control the cell cycle would improve patient outcomes. However, the development of drug resistance and a limited number of inhibitors that target multiple cell cycle modulators are challenges that impede stopping the deregulated growth that leads to malignancy. To advance the discovery of new druggable targets for cell cycle inhibition, we investigated the role of Chaperonin-Containing TCP1 (CCT or TRiC) in breast cancer cells. CCT, a type II chaperonin, is a multi-subunit protein-folding complex that interacts with many oncoproteins and mutant tumor suppressors. CCT subunits are highly expressed in a number of cancers, including breast cancer. We found that expression of one of the CCT subunits, CCT2, inversely correlates with breast cancer patient survival and is subject to copy number alterations through genomic amplification. To investigate a role for CCT2 in the regulation of the cell cycle, we expressed an exogenous CCT2-FLAG construct in T47D and MCF7 luminal A breast cancer cells and examined cell proliferation under conditions of two-dimensional (2D) monolayer and three-dimensional (3D) spheroid cultures. Exogenous CCT2 increased the proliferation of cancer cells, resulting in larger and multiple spheroids as compared to control cells. CCT2-expressing cells were also able to undergo spheroid growth reversal, re-attaching, and resuming growth in 2D cultures. Such cells gained anchorage-independent growth. CCT2 expression in cells correlated with increased expression of MYC, especially in spheroid cultures, and other cell cycle regulators like CCND1 and CDK2, indicative of a novel activity that could contribute to the increase in cell growth. Statistically significant correlations between CCT2, MYC, and CCND1 were shown. Since CCT2 is located on chromosome 12q15, an amplicon frequently found in soft tissue cancers as well as breast cancer, CCT2 may have the basic characteristics of an oncogene. Our findings suggest that CCT2 could be an essential driver of cell division that may be a node through which pathways involving MYC, cyclin D1 and other proliferative factors could converge. Hence the therapeutic inhibition of CCT2 may have the potential to achieve multi-target inhibition, overcoming the limitations associated with single agent inhibitors.
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http://dx.doi.org/10.3389/fonc.2021.663877DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8121004PMC
April 2021

Modeling regulatory network topology improves genome-wide analyses of complex human traits.

Nat Commun 2021 05 14;12(1):2851. Epub 2021 May 14.

Department of Statistics, Stanford University, Stanford, CA, 94305, USA.

Genome-wide association studies (GWAS) have cataloged many significant associations between genetic variants and complex traits. However, most of these findings have unclear biological significance, because they often have small effects and occur in non-coding regions. Integration of GWAS with gene regulatory networks addresses both issues by aggregating weak genetic signals within regulatory programs. Here we develop a Bayesian framework that integrates GWAS summary statistics with regulatory networks to infer genetic enrichments and associations simultaneously. Our method improves upon existing approaches by explicitly modeling network topology to assess enrichments, and by automatically leveraging enrichments to identify associations. Applying this method to 18 human traits and 38 regulatory networks shows that genetic signals of complex traits are often enriched in interconnections specific to trait-relevant cell types or tissues. Prioritizing variants within enriched networks identifies known and previously undescribed trait-associated genes revealing biological and therapeutic insights.
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http://dx.doi.org/10.1038/s41467-021-22588-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8121952PMC
May 2021

FOXO3A-induced LINC00926 suppresses breast tumor growth and metastasis through inhibition of PGK1-mediated Warburg effect.

Mol Ther 2021 May 1. Epub 2021 May 1.

Department of Cellular Engineering Lab, Beijing Institute of Biotechnology, Beijing 100850, China. Electronic address:

Phosphoglycerate kinase 1 (PGK1), a critical component of the glycolytic pathway, relates to the development of various cancers. However, the mechanisms of PGK1 inhibition and physiological significance of PGK1 inhibitors in cancer cells are unclear. Long non-coding RNAs (lncRNAs) play a vital role in tumor growth and progression. Here, we identify a lncRNA LINC00926 that negatively regulates PGK1 expression and predicts good clinical outcome of breast cancer. LINC00926 downregulates PGK1 expression through the enhancement of PGK1 ubiquitination mediated by E3 ligase STUB1. Moreover, hypoxia inhibits LINC00926 expression and activates PGK1 expression largely through FOXO3A. FOXO3A/LINC00926/PGK1 axis regulates breast cancer glycolysis, tumor growth, and lung metastasis both in vitro and in vivo. In breast cancer patients, LINC00926 expression is negatively correlated with PGK1 and positively correlated with FOXO3A expression. Our work established FOXO3A/LINC00926/PGK1 as a critical axis to regulate breast cancer growth and progression. Targeting PGK1 or supplement of LINC00926 or FOXO3A could be potential therapeutic strategies in breast cancer.
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http://dx.doi.org/10.1016/j.ymthe.2021.04.036DOI Listing
May 2021

HsfA1d promotes hypocotyl elongation under chilling via enhancing expression of ribosomal protein genes in Arabidopsis.

New Phytol 2021 07 20;231(2):646-660. Epub 2021 May 20.

The State Key Laboratory of Crop Genetics and Germplasm Enhancement, Nanjing Agricultural University, Nanjing, 210095, China.

How plants maintain growth under nonfreezing low temperatures (chilling) is not well understood. Here we use hypocotyl elongation under dark to investigate the molecular mechanisms for chilling growth in Arabidopsis thaliana. The function of HsfA1d (Heat shock transcription factor A1d) in chilling growth is investigated by physiological and molecular characterization of its mutants. Subcellular localization of HsfA1d under chilling is analyzed. Potential target genes of HsfA1d were identified by transcriptome analysis, chromatin immunoprecipitation, transcriptional activation assay and mutant characterization. HsfA1d is a positive regulator of hypocotyl elongation under chilling. It promotes expression of a large number of ribosome biogenesis genes to a moderate but significant extent under chilling. HsfA1d could bind to the promoter regions of two ribosome protein genes tested and promote their expression. The loss-of-function of one ribosome gene also reduced hypocotyl elongation under chilling. In addition, HsfA1d did not have increased nuclear accumulation under chilling and its basal nuclear accumulation is promoted by a salicylic acid receptor under chilling. This study thus unveils a new HsfA1d-mediated pathway that promotes the expression of cytosolic and plastid cytosolic and plastid ribosomal protein genes which may maintain overall protein translation for plant growth in chilling.
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http://dx.doi.org/10.1111/nph.17413DOI Listing
July 2021

2D conductive MOFs with sufficient redox sites: reduced graphene oxide/Cu-benzenehexathiolate composites as high capacity anode materials for lithium-ion batteries.

Nanoscale 2021 Apr;13(16):7751-7760

School of Environmental and Chemical Engineering, Jiangsu University of Science and Technology, Zhenjiang, Jiangsu 212003, P. R. China.

As a superconductive metal-organic framework (MOF) material, Cu-BHT (BHT: benzenehexathiol) can exhibit outstanding electrochemical properties owing to the potential redox reactions of the cuprous ions, sulfur species and benzene rings of Cu-BHT, but its compact texture limits the specific capacity of Cu-BHT. To improve the dense feature of Cu-BHT, rGO/Cu-BHT (rGO: reduced graphene oxide) composite materials are fabricated via a facile route and they exhibit applicable conductivities, improved lithium ion diffusion kinetics compared to pristine Cu-BHT, and sufficient redox sites. The rGO/Cu-BHT composite materials maximize the potential capacity of Cu-BHT, and the rGO/Cu-BHT 1 : 1 material achieves outstanding reversible specific capacities of 1190.4, 1230.8, 1131.4, and 898.7 mA h g-1, at current densities of 100, 200, 500, and 1000 mA g-1, respectively, superior to those of pristine Cu-BHT and rGO. These results present the promising future of 2D conductive MOFs as functional materials for energy storage, based on the regulation of electronic conductivity, redox sites, and lithium ion diffusion kinetics.
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http://dx.doi.org/10.1039/d0nr08549aDOI Listing
April 2021

Hypoxic preconditioning induces epigenetic changes and modifies swine mesenchymal stem cell angiogenesis and senescence in experimental atherosclerotic renal artery stenosis.

Stem Cell Res Ther 2021 04 14;12(1):240. Epub 2021 Apr 14.

Division of Nephrology and Hypertension, Mayo Clinic, 200, First Street SW, Rochester, MN, 55902, USA.

Background: Atherosclerotic renal artery stenosis (ARAS) is a risk factor for ischemic and hypertensive kidney disease (HKD) for which autologous mesenchymal stem cell (MSC) appears to be a promising therapy. However, MSCs from ARAS patients exhibit impaired function, senescence, and DNA damage, possibly due to epigenetic mechanisms. Hypoxia preconditioning (HPC) exerts beneficial effects on cellular proliferation, differentiation, and gene and protein expression. We hypothesized that HPC could influence MSC function and senescence in ARAS by epigenetic mechanisms and modulating gene expression of chromatin-modifying enzymes.

Methods: Adipose-derived MSC harvested from healthy control (N = 8) and ARAS (N = 8) pigs were cultured under normoxia (20%O) or hypoxia (1%O) conditions. MSC function was assessed by migration, proliferation, and cytokine release in conditioned media. MSC senescence was evaluated by SA-β-gal activity. Specific pro-angiogenic and senescence genes were assessed by reverse transcription polymerase chain reaction (RT-PCR). Dot blotting was used to measure global genome 5-hydroxymethylcytosine (5hmC) levels on DNA and Western blotting of modified histone 3 (H3) proteins to quantify tri-methylated lysine-4 (H3K4me3), lysine-9 (H3K9me3), and lysine-27 (H3K27me3) residues.

Results: Specific pro-angiogenic genes in ARAS assessed by RT-PCR were lower at baseline but increased under HPC, while pro-senescence genes were higher in ARAS at baseline as compared healthy MSCs. ARAS MSCs under basal conditions, displayed higher H3K4me3, H3K27me3, and 5hmC levels compared to healthy MSCs. During HPC, global 5hmC levels were decreased while no appreciable changes occurred in histone H3 tri-methylation. ARAS MSCs cultured under HPC had higher migratory and proliferative capacity as well as increased vascular endothelial growth factor and epidermal growth factor expression compared to normoxia, and SA-β-gal activity decreased in both animal groups.

Conclusions: These data demonstrate that swine ARAS MSCs have decreased angiogenesis and increased senescence compared to healthy MSCs and that HPC mitigates MSC dysfunction, senescence, and DNA hydroxymethylation in ARAS MSC. Thus, HPC for MSCs may be considered for their optimization to improve autologous cell therapy in patients with nephropathies.
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http://dx.doi.org/10.1186/s13287-021-02310-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048283PMC
April 2021

The corticospinal tract structure of collagen/silk fibroin scaffold implants using 3D printing promotes functional recovery after complete spinal cord transection in rats.

J Mater Sci Mater Med 2021 Mar 22;32(4):31. Epub 2021 Mar 22.

Tianjin Key Laboratory of Neurotrauma Repair, Pingjin Hospital Brain Center, Characteristic Medical Center of PAPF, Tianjin, 300162, China.

No effective treatment has been established for nerve dysfunction caused by spinal cord injury (SCI). Orderly axonal growth at the site of spinal cord transection and creation of an appropriate biological microenvironment are important for functional recovery. To axially guiding axonal growth, designing a collagen/silk fibroin scaffold fabricated with 3D printing technology (3D-C/SF) emulated the corticospinal tract. The normal collagen/silk fibroin scaffold with freeze-drying technology (C/SF) or 3D-C/SF scaffold were implanted into rats with completely transected SCI to evaluate its effect on nerve repair during an 8-week observation period. Electrophysiological analysis and locomotor performance showed that the 3D-C/SF implants contributed to significant improvements in the neurogolical function of rats compared to C/SF group. By magnetic resonance imaging, 3D-C/SF implants promoted a striking degree of axonal regeneration and connection between the proximal and distal SCI sites. Compared with C/SF group, rats with 3D-C/SF scaffold exhibited fewer lesions and disordered structures in histological analysis and more GAP43-positive profiles at the lesion site. The above results indicated that the corticospinal tract structure of 3D printing collagen/silk fibroin scaffold improved axonal regeneration and promoted orderly connections within the neural network, which could provided a promising and innovative approach for tissue repair after SCI.
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http://dx.doi.org/10.1007/s10856-021-06500-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985105PMC
March 2021

Quercetin Reverses Cardiac Systolic Dysfunction in Mice Fed with a High-Fat Diet: Role of Angiogenesis.

Oxid Med Cell Longev 2021 19;2021:8875729. Epub 2021 Feb 19.

Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA.

Global consumption of high-fat diets (HFD) is associated with an increased incidence of cardiometabolic syndrome and cardiac injury, warranting identification of cardioprotective strategies. Cardioprotective effects of quercetin (Q) have mostly been evaluated in ischemic heart disease models and attributed to senolysis. We hypothesized that Q could alleviate murine cardiac damage caused by HFD by restoring the myocardial microcirculation. C57BL/6J mice were fed standard chow or HFD for 6 months and then treated with Q (50 mg/kg) or vehicle 5-day biweekly for 10 additional weeks. Left ventricular (LV) cardiac function was studied in vivo using magnetic resonance imaging, and intramyocardial fat deposition, microvascular density, oxidative stress, and senescence were analyzed ex vivo. Additionally, direct angiogenic effects of Q were studied in vitro in HUVECs. HFD increased body weight, heart weight, total cholesterol, and triglyceride levels, whereas Q normalized heart weight and triglycerides. LV ejection fraction was lower in HFD vs. control mice (56.20 ± 15.8% vs. 73.38 ± 5.04%, respectively, < 0.05), but improved in HFD + Q mice (67.42 ± 7.50%, < 0.05, vs. HFD). Q also prevented cardiac fat accumulation and reduced HFD-induced cardiac fibrosis, cardiomyocyte hypertrophy, oxidative stress, and vascular rarefaction. Cardiac senescence was not observed in any group. In vitro, ox-LDL reduced HUVEC tube formation activity, which Q effectively improved. Quercetin may directly induce angiogenesis and decrease myocardial oxidative stress, which might account for its cardioprotective effects in the murine HFD-fed murine heart independently from senolytic activity. Furthermore, its beneficial effects might be partly attributed to a decrease in plasma triglycerides and intramyocardial fat deposition.
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http://dx.doi.org/10.1155/2021/8875729DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914089PMC
May 2021

Multiomics-based dissection of citrus flavonoid metabolism using a Citrus reticulata × Poncirus trifoliata population.

Hortic Res 2021 Mar 1;8(1):56. Epub 2021 Mar 1.

Key Laboratory of Horticultural Plant Biology, College of Horticulture and Forestry Sciences, Huazhong Agricultural University, Wuhan, 430070, China.

Deciphering the genetic basis of plant secondary metabolism will provide useful insights for genetic improvement and enhance our fundamental understanding of plant biological processes. Although citrus plants are among the most important fruit crops worldwide, the genetic basis of secondary metabolism in these plants is largely unknown. Here, we use a high-density linkage map to dissect large-scale flavonoid metabolic traits measured in different tissues (young leaf, old leaf, mature pericarp, and mature pulp) of an F pseudo-testcross citrus population. We detected 80 flavonoids in this population and identified 138 quantitative trait loci (QTLs) for 57 flavonoids in these four tissues. Based on transcriptional profiling and functional annotation, twenty-one candidate genes were identified, and one gene encoding flavanone 3-hydroxylase (F3H) was functionally verified to result in naturally occurring variation in dihydrokaempferol content through genetic variations in its promoter and coding regions. The abundant data resources collected for diverse citrus germplasms here lay the foundation for complete characterization of the citrus flavonoid biosynthetic pathway and will thereby promote efficient utilization of metabolites in citrus quality improvement.
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http://dx.doi.org/10.1038/s41438-021-00472-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917093PMC
March 2021

Determining structural and chemical heterogeneities of surface species at the single-bond limit.

Science 2021 02;371(6531):818-822

Hefei National Laboratory for Physical Sciences at the Microscale and Synergetic Innovation Center of Quantum Information and Quantum Physics, University of Science and Technology of China, Hefei, Anhui 230026, China.

The structure determination of surface species has long been a challenge because of their rich chemical heterogeneities. Modern tip-based microscopic techniques can resolve heterogeneities from their distinct electronic, geometric, and vibrational properties at the single-molecule level but with limited interpretation from each. Here, we combined scanning tunneling microscopy (STM), noncontact atomic force microscopy (AFM), and tip-enhanced Raman scattering (TERS) to characterize an assumed inactive system, pentacene on the Ag(110) surface. This enabled us to unambiguously correlate the structural and chemical heterogeneities of three pentacene-derivative species through specific carbon-hydrogen bond breaking. The joint STM-AFM-TERS strategy provides a comprehensive solution for determining chemical structures that are widely present in surface catalysis, on-surface synthesis, and two-dimensional materials.
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http://dx.doi.org/10.1126/science.abd1827DOI Listing
February 2021

Piperazine-Derived α Antagonist 1- Benzyl-N- (3-(4- (2-Methoxyphenyl) Piperazine-1-yl) Propyl) -1H- Indole-2- Carboxamide Induces Apoptosis in Benign Prostatic Hyperplasia Independently of α1-Adrenoceptor Blocking.

Front Pharmacol 2020 27;11:594038. Epub 2021 Jan 27.

The Fifth Affiliated Hospital, Key Laboratory of Molecular Target & Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, China.

Previous studies have indicated that α antagonist naftopidil (NAF) suppresses prostate growth by decreasing cell proliferation without affecting apoptosis and prostate volume in benign prostatic hyperplasia (BPH). A NAF-derived α1D/1A antagonist 1- benzyl-N-(3-(4-(2-methoxyphenyl) piperazine-1-yl) propyl)-1H-indole-2- carboxamide (HJZ-12) has been reported from our laboratory, which exhibits high subtype-selectivity to both α- and α- AR (47.9- and 19.1- fold, respectively) with respect to a1B-AR . However, no further study was conducted. In the present study, a pharmacological evaluation of HJZ-12 in BPH was performed on an estrogen/androgen-induced rat BPH model and human BPH-1 cell line. , HJZ-12 exhibited better performance than NAF in preventing the progression of rat prostatic hyperplasia by not only decreasing prostate weight and proliferation (similar to NAF) but also, shrinking prostate volume and inducing prostate apoptosis (different from NAF). , HJZ-12 exhibited significant cell viability inhibition and apoptotic induction in BPH-1 cell line, without presenting cell anti-proliferation properties. Intriguingly, the role of HJZ-12 on cell viability and apoptosis was an α1-independent action. Furthermore, RNA-Seq analysis was applied to screen out six anti-apoptotic genes (Bcl-3, B-lymphoma Mo-MLV insertion region 1 [Bmi-1], ITGA2, FGFR3, RRS1, and SGK1). Amongst them, Bmi-1 was involved in the apoptotic induction of HJZ-12 in BPH-1. Overall, HJZ-12 played a remarkable role in preventing the progression of prostatic hyperplasia through α1-independent apoptotic induction, indicating that it will be a multi-target effective candidate for BPH treatment.
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http://dx.doi.org/10.3389/fphar.2020.594038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873900PMC
January 2021

TMEM2 binds to CSNK2A3 to inhibit HBV infection via activation of the JAK/STAT pathway.

Exp Cell Res 2021 Mar 12;400(1):112517. Epub 2021 Feb 12.

Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, Guangdong, China; Guangdong Provincial Key Laboratory of Liver Diseases, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, Guangdong, China; Key Laboratory of Tropical Disease Control, Ministry of Education, Sun Yat-Sen University, Guangzhou, 510080, Guangdong, China. Electronic address:

To investigate mechanisms that TMEM2 activation inhibits hepatitis B virus (HBV) infection in hepatocarcinoma (HCC) cells, co-immunoprecipitation (Co-IP) and mass spectrometry were used in screening interacting proteins for TMEM2. Levels of casein kinase 2 subunit α3 (CSNK2A3) in HCC cells were found to be inhibited or overexpressed using siRNAs and pcDNA3.1-CSNK2A3, respectively. Effect of CSNK2A3 expression on cell proliferation was analyzed using MTS, while its effect on HBV infection was measured using ddPCR and IHC. Western blotting and JAK inhibitor ruxolitinib were also used to determine whether TMEM2-regulated CSNK2A3 expression and HBV infection were affected by JAK-STAT signaling. Co-IP and mass spectrometry results showed that CSNK2A3 interacts with TMEM2. Moreover, overexpression of CSNK2A3 significantly inhibited cell proliferation, while inhibition of CSNK2A3 promoted proliferation of HCC cells. In addition, overexpression of CSNK2A3 was observed to significantly enhance HBV infection, while siRNA knockdown of CSNK2A3 inhibited HBV infection. Notably, effect of CSNK2A3 overexpression on HBV infection was suppressed by TMEM2 overexpression. Further mechanistic analyses have revealed that TMEM2 could antagonize the effects of CSNK2A3 on cell proliferation and HBV infection via JAK-STAT pathway activation. In conclusion, TMEM2 has been determined to bind to CSNK2A3 to inhibit HBV infection via activation of the JAK-STAT pathway.
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http://dx.doi.org/10.1016/j.yexcr.2021.112517DOI Listing
March 2021

Sacrificial Synthesis of Supported Ru Single Atoms and Clusters on N-doped Carbon Derived from Covalent Triazine Frameworks: A Charge Modulation Approach.

Adv Sci (Weinh) 2021 Feb 20;8(3):2001493. Epub 2020 Dec 20.

Chemical Sciences Division Oak Ridge National Laboratory Oak Ridge TN 37831 USA.

High-temperature pyrolysis of nitrogen (N)-rich, crystalline porous organic architectures in the presence of a metal precursor is an important chemical process in heterogeneous catalysis for the fabrication of highly porous N-carbon-supported metal catalysts. Herein, covalent triazine framework (CTF) and CTF-I (that is, CTF after charge modulation with iodomethane) are presented as sacrificial templates, for the synthesis of carbon-supported Ru catalysts-Ru-CTF-900 and Ru-CTF-I-900 respectively, following high-temperature pyrolysis at 900 °C under N atmosphere. Predictably, the dispersed Ru on pristine CTF carrier suffered severe sintering of the Ru nanoparticles (NPs) during heat treatment at 900 °C. However, the Ru-CTF-I-900 catalyst is composed of ultra-small Ru NPs and abundant Ru single atoms which may have resulted from much stronger Ru-N interactions. Through modification of the micro-environment within the CTF architecture, Ru precursor interacted on charged-modulated CTF framework shows electrostatic repulsion and steric hindrance, thus contributing toward the high density of single Ru atoms and even smaller Ru NPs after pyrolysis. A Ru-Ru coordination number of only 1.3 is observed in the novel Ru-CTF-I-900 catalyst, which exhibits significantly higher catalytic activity than Ru-CTF-900 for transfer hydrogenation of acetophenone.
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http://dx.doi.org/10.1002/advs.202001493DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856886PMC
February 2021

Meta-Analysis Reveals the Prognostic Relevance of Nuclear and Membrane-Associated Bile Acid Receptors in Gastric Cancer.

Clin Transl Gastroenterol 2021 01 12;12(1):e00295. Epub 2021 Jan 12.

Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, Florida, USA.

Introduction: Bile acids (BAs) arising from duodenogastric reflux are known to facilitate gastric cancer (GC) development. Although BAs traditionally contribute to carcinogenesis through direct cellular cytotoxicity, increasing evidence implicates nuclear and membrane BA receptors (BARs) as additional factors influencing cancer risk. Indeed, some BARs are already linked with GC, but conflicting evidence and lack of information regarding other endogenous BARs warrant further investigation. In this study, we meta-analyzed multiple data sets to identify clinically relevant relationships between BAR expression and prognosis, clinicopathology, and activity in GC.

Methods: We collected transcriptomic data from the Gene Expression Omnibus and The Cancer Genome Atlas to analyze associations between BAR expression and GC prognosis, subtype, and clinicopathology. We also used Ingenuity Pathway Analysis to assess and predict functions, upstream regulators, and downstream mediators of membrane and nuclear BARs in GC.

Results: BARs showed differential distribution in GC; membrane BARs (G protein-coupled BAR 1, sphingosine-1-phosphate receptor 2, and cholinergic receptor muscarinic 2) were enriched in diffuse-, genome-stable, and mesenchymal-type tumors, whereas nuclear BARs (pregnane-X-receptor, constitutive androstane receptor, and farnesoid-X-receptor) were enriched in chromosome instability and metabolic subtypes. High expression of all membrane but not nuclear BARs was associated with poor prognosis and unfavorable GC clinicopathologic features. Similarly, expression patterns of membrane but not nuclear BARs varied geographically, aligning with Helicobacter pylori infection and GC mortality rates. Finally, GC-related oncogenes, namely transforming growth factor β1, were associated with membrane BARs, whereas many metabolic-associated genes were associated with nuclear BARs.

Discussion: Through transcriptomic meta-analysis, we identified distinct expression profiles between nuclear and membrane BARs that demonstrate prognostic relevance and warrant further investigation.
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http://dx.doi.org/10.14309/ctg.0000000000000295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806235PMC
January 2021

The 48-week safety and therapeutic effects of tenofovir alafenamide in hbv-related acute-on-chronic liver failure: A prospective cohort study.

J Viral Hepat 2021 04 19;28(4):592-600. Epub 2021 Jan 19.

Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China.

Tenofovir alafenamide (TAF) has been available in China for a short time, little is known about its safety and efficacy in patients with hepatitis B virus (HBV)-related acute-on-chronic liver failure (HBV-ACLF). We conducted this study to further verify the safety and efficacy of TAF in these patients. Eighty-eight eligible subjects were included and divided into three groups: TAF group, TDF group and ETV group. Clinical and laboratory test results were collected and the survival status, virus suppression status and liver and renal function improvement were observed during follow-up. No drug-related adverse events were observed within a 48-week observation period. At week 48, the survival rates of the three groups were 56.5%, 78.3% and 59.5% (p = 0.262). HBV DNA undetectable rates were similar (80.0% vs.75.0% vs.84.6%, respectively, p = 0.863). Liver function improved in all the three groups over time. Compared with the other two groups, patients in the TAF group had a greater decrease in serum creatinine (CR) and an increase in estimated glomerular filtration rate (eGFR), especially at week 12. At week 48, the median changes of CR were -0.7 (IQR -3.0, 13.0) vs. 15.0 (IQR -3.0, 21.0) vs. 5.0 (IQR -9.0, 14.0), respectively (p = 0.334), while the median changes of eGFR were -2.12 (IQR -13.87, 1.44) vs. -10.43 (IQR -20.21, 3.18) vs. -5.31 (IQR -14.72, 5.44) ml/min/1.73 m , respectively (p = 0.592). In this real-world clinical study, TAF is as effective as TDF and ETV, and may be more beneficial in protecting renal function in the early stages of antiviral therapy.
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http://dx.doi.org/10.1111/jvh.13468DOI Listing
April 2021

Endovascular reversal of renovascular hypertension blunts cardiac dysfunction and deformation in swine.

J Hypertens 2021 Mar;39(3):556-562

Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA.

Objective: Renovascular hypertension (RVH) induces hemodynamic and humoral aberrations that may impair cardiac function, structure and mechanics, including cardiac twist and deformation. Revascularization of a stenotic renal artery can decrease blood pressure (BP), but its ability to restore cardiac mechanics in RVH remains unclear. We hypothesized that percutaneous transluminal renal angioplasty (PTRA) would improve cardiac function and left ventricular (LV) deformation in swine RVH.

Methods: Seventeen domestic pigs were studied for 16 weeks: RVH, RVH + PTRA and normal controls (n = 5-6 each). Global LV function was estimated by multidetector computed-tomography, and LV deformation by electrocardiographically triggered MRI tagging at the apical, mid, and basal LV levels. Cardiomyocyte hypertrophy, myocardial capillary density, and fibrosis were evaluated ex vivo.

Results: BP and wall thickness were elevated in RVH and decreased by PTRA, yet remained higher than in controls. LV myocardial muscle mass increased in RVH pigs, which also developed diastolic dysfunction, whereas cardiac output increased. Furthermore, both apical rotation and peak torsion angle increased in RVH compared with controls. Ex vivo, RVH induced myocardial fibrosis and vascular rarefaction. PTRA restored cardiac function and alleviated hypertrophy, vascular rarefaction, and fibrosis. PTRA also normalized apical rotation and peak torsion angle, and elevated basal peak radial strain and apical peak radial strain compared with RVH.

Conclusion: In addition to cardiac LV adaptive hypertrophy and diastolic dysfunction, short-term RVH causes cardiac deformation. Despite only partial improvement in BP, PTRA effectively restored cardiac function and reversed abnormal mechanics. Hence, renal revascularization may be a useful strategy to preserve cardiac function in RVH.
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http://dx.doi.org/10.1097/HJH.0000000000002654DOI Listing
March 2021

MFAP2 Promotes the Proliferation of Cancer Cells and Is Associated With a Poor Prognosis in Hepatocellular Carcinoma.

Technol Cancer Res Treat 2020 Jan-Dec;19:1533033820977524

Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China.

Backgrounds: Microfibril-associated protein 2 (MFAP2) is an extracellular matrix protein that regulates the function of microfibrils by interacting with fibrillin. MFAP2 has been reported to play an important role in metabolic diseases and has been shown to be significantly overexpressed in head and neck squamous cell carcinoma and Hepatocellular carcinoma (HCC). However, the molecular function and prognostic value of MFAP2 have never been reported in HCC or other tumors.

Methods: In the present study, expression characteristics of MFAP2 in HCC, its influence on the development of HCC, as well as its function and potential mechanism in HCC were verified by Quantitative reverse transcription-polymerase chain reaction, bioinformatics data mining and in vitro cell experiments.

Results: MFAP2 was prominently high-expressed in HCC and associated with cancer stages. HCC patients with higher MFAP2 expression displayed lower overall survival (OS) and disease-specific survival(DSS), while there was no significant difference in recurrence-free survival (RFS). In vitro experiments showed that downregulation of MFAP2 inhibited proliferation, migration level of HCC cells. Transcription factors, DNA methyltransferases, immune factors may interact with MFAP2 mRNA to promote tumor progression in HCC.

Conclusion: These findings suggest that MFAP2 may play a key role in the development of HCC. Therefore, MFAP2 may be a valuable prognostic marker and an effective anticancer target in HCC.
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http://dx.doi.org/10.1177/1533033820977524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724263PMC
December 2020

A novel circular RNA hsa_circRNA_103809/miR-377-3p/GOT1 pathway regulates cisplatin-resistance in non-small cell lung cancer (NSCLC).

BMC Cancer 2020 Dec 4;20(1):1190. Epub 2020 Dec 4.

The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, 310022, Zhejiang, China.

Background: Cisplatin is the first-line chemotherapeutic drug for non-small cell lung cancer (NSCLC), and emerging evidences suggests that targeting circular RNAs (circRNAs) is an effective strategy to increase cisplatin-sensitivity in NSCLC, but the detailed mechanisms are still not fully delineated.

Methods: Cell proliferation, viability and apoptosis were examined by using the cell counting kit-8 (CCK-8) assay, trypan blue staining assay and Annexin V-FITC/PI double staining assay, respectively. The expression levels of cancer associated genes were measured by using the Real-Time qPCR and Western Blot analysis at transcriptional and translated levels. Dual-luciferase reporter gene system assay was conducted to validated the targeting sites among hsa_circRNA_103809, miR-377-3p and 3' untranslated region (3'UTR) of GOT1 mRNA. The expression status, including expression levels and localization, were determined by immunohistochemistry (IHC) assay in mice tumor tissues.

Results: Here we identified a novel hsa_circRNA_103809/miR-377-3p/GOT1 signaling cascade which contributes to cisplatin-resistance in NSCLC in vitro and in vivo. Mechanistically, parental cisplatin-sensitive NSCLC (CS-NSCLC) cells were subjected to continuous low-dose cisplatin treatment to generate cisplatin-resistant NSCLC (CR-NSCLC) cells, and we found that hsa_circRNA_103809 and GOT1 were upregulated, while miR-377-3p was downregulated in CR-NSCLC cells but not in CS-NSCLC cells. In addition, hsa_circRNA_103809 sponged miR-337-3p to upregulate GOT1 in CS-NSCLC cells, and knock-down of hsa_circRNA_103809 enhanced the inhibiting effects of cisplatin on cell proliferation and viability, and induced cell apoptosis in CR-NSCLC cells, which were reversed by downregulating miR-377-3p and overexpressing GOT1. Consistently, overexpression of hsa_circRNA_103809 increased cisplatin-resistance in CS-NSCLC cells by regulating the miR-377-3p/GOT1 axis. Finally, silencing of hsa_circRNA_103809 aggravated the inhibiting effects of cisplatin treatment on NSCLC cell growth in vivo.

Conclusions: Analysis of data suggested that targeting the hsa_circRNA_103809/miR-377-3p/GOT1 pathway increased susceptibility of CR-NSCLC cells to cisplatin, and this study provided novel targets to improve the therapeutic efficacy of cisplatin for NSCLC treatment in clinic.
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http://dx.doi.org/10.1186/s12885-020-07680-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7716498PMC
December 2020

F-FHBG PET-CT Reporter Gene Imaging of Adoptive CIK Cell Transfer Immunotherapy for Breast Cancer in a Mouse Model.

Onco Targets Ther 2020 13;13:11659-11668. Epub 2020 Nov 13.

Department of Molecular Imaging and Nuclear Medicine, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin 300060, People's Republic of China.

Background: To further improve the efficiency of adoptively transferred cytokine-induced killer (CIK) cell immunotherapy in breast cancer (BC), a reliable imaging method is required to visualize and monitor these transferred cells in vivo.

Methods: Herpes simplex virus 1-thymidine kinase () and 9-(4-[F]fluoro-3-(hydroxymethyl)butyl)guanine (F-FHBG) were used as a pair of reporter gene/reporter probe for positron emission tomography (PET) imaging in this study. Following the establishment of subcutaneous BC xenograft-bearing nude mice models, induced human CIK cells expressing reporter gene through lentiviral transduction were intravenously injected to nude mice. γ-radioimmunoassay was used to determine the specific uptake of F-FHBG by these genetically engineered CIK cells expressing in vitro, and F-FHBG micro positron emission tomography-computed tomography (PET-CT) imaging was performed to visualize these adoptively transferred CIK cells in tumor-bearing nude mice.

Results: Specific uptake of F-FHBG by CIK cells expressing was clearly observed in vitro. Consistently, the localization of adoptively transferred CIK cells in tumor target could be effectively visualized by F-FHBG micro PET-CT reporter gene imaging.

Conclusion: PET-CT reporter gene imaging using F-FHBG as a reporter probe enables the visualization and monitoring of adoptively transferred CIK cells in vivo.
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http://dx.doi.org/10.2147/OTT.S271657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7671474PMC
November 2020

Virus-specific T-cell therapy to treat BK polyomavirus infection in bone marrow and solid organ transplant recipients.

Blood Adv 2020 11;4(22):5745-5754

Division of Bone Marrow Transplant and Immune Deficiency, Cincinnati Children's Hospital, Cincinnati, OH.

BK polyomavirus (BKPyV) infection is a major complication of hematopoietic stem cell transplant (HSCT) and solid organ transplant (SOT). Treatment options are limited, poorly effective, and have significant toxicities. Cellular therapy using T cells directed against BKPyV is an emerging therapy, and we report efficacy in controlling BKPyV-associated disease in highly immunocompromised patients. Virus-specific T cells (VSTs) against BKPyV were manufactured using either blood from the patient's stem cell donor (donor-derived VSTs) or from unrelated donors (third-party VSTs). VSTs were used to treat BKPyV in 38 HSCT recipients and 3 SOT recipients between June 2017 and December 2019. Overall response rate was 86% in patients treated for BK viremia, 100% in patients treated for hemorrhagic cystitis, and 87% in patients treated for both BK viremia and hemorrhagic cystitis. No infusional toxicity, de novo graft-versus-host disease, or rejection of the organ occurred attributable to the VST infusion. BKPyV-specific immune responses were demonstrated by interferon-γ production by peripheral blood mononuclear cells postinfusion in response to BKPyV antigens. VSTs are a safe and potentially effective strategy to treat BKPyV and associated symptoms in recipients of HSCT and SOT. Cellular therapy should be considered for all patients with BKPyV and underlying immune suppression at risk of complications. This trial was registered at www.clinicaltrials.gov as #NCT02532452.
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http://dx.doi.org/10.1182/bloodadvances.2020003073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686882PMC
November 2020

Evaluation of Early Retinal Nerve Injury in Type 2 Diabetes Patients Without Diabetic Retinopathy.

Front Endocrinol (Lausanne) 2020 29;11:475672. Epub 2020 Sep 29.

Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.

To investigate the damage to the retinal nerve fiber layer (RNFL) and ganglion cell complex layer (GCL+) in diabetic patients without retinal microangioma and to determine the kind of nerve damage more likely to indicate early injury. We included 360 patients (360 eyes) with type 2 diabetes mellitus and 168 healthy volunteers (168 eyes). Patients with retinal microangioma were excluded by fundus fluorescein angiography (FFA). The parameters around the optic disc and macular area were measured by optical coherence tomography (OCT). The peripapillary RNFL thickness was thinner in the temporal (72.98 ± 13.76 μm, < 0.0001) and inferior (120.71 ± 21.43 μm, = 0.0103) sectors in patients with no diabetic retinopathy (NDR) compared to healthy controls. The reduction of retinal thickness in the macular region was prominent in the inferior sector in patients (34.74 ± 4.92 μm, < 0.0001) compared to normal controls. Thinning of GCL+ in the second region of the macular area was significant in patients with NDR compared to normal controls ( < 0.05). However, no difference in the GCL+ and retinal thicknesses of the central macular region was observed between the patients with NDR and healthy controls. Using the 5th percentile (P5) of normal controls as the reference value, we found that the parameters with the highest indices in patients with NDR were the inferior and temporal peripapillary RNFL thickness (13.0%), the inferior RNFL thickness in the macular area (20%), the inferior retinal thickness in the outer ring of the macular area (10.8%), and the inferior GCL+ thickness in the macular area (10.6%). The GCL+ and RNFL thicknesses in the central macular area accounted for the smallest proportion in P5 of normal controls (3%). Retinal nerve injury can occur in patients without retinal microangioma. The inferior RNFL in the macular area and the inferior and temporal peripapillary RNFL were most sensitive to glucose damage. These areas might be associated with early detection of diabetic retinopathy (DR) as they are more likely to indicate early damage.
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http://dx.doi.org/10.3389/fendo.2020.475672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7552190PMC
May 2021

ITPKA1 Promotes Growth, Migration and Invasion of Renal Cell Carcinoma via Activation of mTOR Signaling Pathway.

Onco Targets Ther 2020 15;13:10515-10523. Epub 2020 Oct 15.

Department of Cellular Engineering Lab, Beijing Institute of Biotechnology, Beijing, People's Republic of China.

Background: Renal cell cancer (RCC) is one of the most lethal malignancies of the kidney in adults. mTOR (mammalian target of rapamycin) signaling pathway plays a pivotal role in RCC tumorigenesis and progression and inhibitors targeting the mTOR pathway have been widely used in advanced RCC treatment. Therefore, it is of great significance to explore the potential regulators of the mTOR pathway as RCC therapeutic targets.

Materials And Methods: Bioinformatics analysis was used to screen out the most significant differentially expressed genes in the RCC dataset of The Cancer Genome Atlas (TCGA). Real-time PCR and Western-blot analysis were utilized to examine the expression of inositol-1,4,5-trisphosphate-3-kinase-A (ITPKA) in four RCC cell lines and one human embryonic kidney cell line. Cell counting Kit-8 and colony formation assay were performed to estimate the effect of ITPKA on the proliferation ability of RCC cells. Wound healing and Transwell assays were used to test the effect of ITPKA on RCC cell migration and invasion. Xenograft formation assay was performed in nude mice to investigate the effect of ITPKA in vivo. mTORC1 pathway inhibitor was added to explore the mechanisms by which ITPKA regulates RCC cell growth and progression.

Results: Based on bioinformatics analysis, ITPKA is screened out as one of the most significant differentially expressed genes in RCC. ITPKA is upregulated and positively correlated with RCC malignancy and poorer prognosis. ITPKA promotes RCC growth, migration and invasion in cultured cells, and accelerates tumor growth in nude mice. Mechanistically, ITPKA stimulates the mTORC1 signaling pathway which is a requirement for ITPKA modulation of RCC cell proliferation, migration and invasion.

Conclusion: Our data demonstrate a critical regulatory role of the ITPKA in RCC and suggest that ITPKA/mTORC1 axis may be a promising target for diagnosis and treatment of RCC.
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http://dx.doi.org/10.2147/OTT.S266095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7573328PMC
October 2020

Ubc9 Attenuates Myocardial Ischemic Injury Through Accelerating Autophagic Flux.

Front Pharmacol 2020 15;11:561306. Epub 2020 Sep 15.

The Fifth Affiliated Hospital, Key Laboratory of Molecular Target & Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, China.

Aims: SUMOylation is a post-translational modification that plays a crucial role in the cellular stress response. We aimed to demonstrate whether and how the SUMO E2 conjugation enzyme Ubc9 affects acute myocardial ischemic (MI) injury.

Methods And Results: Adenovirus expressing Ubc9 was administrated by multipoint injection in the border zone of heart immediately after MI in C57BL/6 mice. Neonatal rat cardiomyocytes (NRCMs) were also infected, followed by oxygen and glucose deprivation (OGD). , Ubc9 adenovirus-injected mice showed decreased cardiomyocyte apoptosis, reduced myocardial fibrosis, and improved cardiac function post-MI. , overexpression of Ubc9 decreased cardiomyocyte apoptosis, whereas silence of Ubc9 showed the opposite results during OGD. We next found that Ubc9 significantly decreased the accumulation of autophagy marker p62/SQSTM, while the LC3 II level hardly changed. When in the presence of bafilomycin A1 (BAF), the Ubc9 adenovirus plus OGD group presented a higher level of LC3 II and GFP-LC3 puncta than the OGD group. Moreover, the Ubc9 adenovirus group displayed increased numbers of yellow plus red puncta and a rising ratio of red to yellow puncta on the mRFP-GFP-LC3 fluorescence assay, indicating that Ubc9 induces an acceleration of autophagic flux from activation to degradation. Mechanistically, Ubc9 upregulated SUMOylation of the core proteins Vps34 and Beclin1 in the class III phosphatidylinositol 3-kinase (PI3K-III) complexes and boosted the protein assembly of PI3K-III complex I and II under OGD. Moreover, the colocalization of Vps34 with autophagosome marker LC3 or lysosome marker Lamp1 was augmented after Ubc9 overexpression, indicating a positive effect of Ubc9-boosted protein assembly of the PI3K-III complexes on autophagic flux enhancement.

Conclusions: We uncovered a novel role of Ubc9 in protecting cardiomyocytes from ischemic stress Ubc9-induced SUMOylation, leading to increased PI3K-III complex assembly and autophagy-positioning. These findings may indicate a potential therapeutic target, Ubc9, for treatment of myocardial ischemia.
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http://dx.doi.org/10.3389/fphar.2020.561306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7522513PMC
September 2020
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