Publications by authors named "Gui Fu"

55 Publications

Nc886 promotes renal cancer cell drug-resistance by enhancing EMT through Rock2 phosphorylation-mediated β-catenin nuclear translocation.

Cell Cycle 2022 Jan 2:1-12. Epub 2022 Jan 2.

Department of Urology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China.

Drug resistance is a significant challenge in the present treatment regimens of renal cell carcinoma (RCC). Our previous study confirmed that nc886 functions as an oncogene in RCC. Nevertheless, the role and underlying mechanism of nc886 in RCC drug resistance are unclear. In the present study, Sunitinib and Everolimus treatment, respectively, downregulated nc886 expression in a dose-dependent manner in all four renal cancer cell lines. Nc886 overexpression in 786-O cells and ACHN cells significantly reduced the sensitivity of cancer cells to both Sunitinib and Everolimus treatment, respectively, by promoting cell viability and inhibiting cell apoptosis, whereas nc886 silencing increased cancer cell sensitivity. In renal cancer cell line with the highest drug-resistance, 786-O cells, Sunitinib, or Everolimus treatment enhanced the cellular EMT and was further enhanced by nc886 overexpression while attenuated by nc886 silencing. In 786-O cells, nc886 overexpression significantly promoted EMT, ROCK2 phosphorylation, and β-catenin nucleus translocation under Sunitinib or Everolimus treatment. Moreover, ROCK2 silencing significantly reversed the effects of nc886 overexpression on EMT, ROCK2 phosphorylation, and β-catenin nucleus translocation, as well as drug-resistant renal cancer cell viability and apoptosis. In conclusion, it was demonstrated that nc886 promotes renal cancer cell proliferation, migration, and invasion, as demonstrated previously. nc886 also promotes renal cancer cell drug-resistance to Sunitinib or Everolimus by promoting EMT through Rock2 phosphorylation-mediated nuclear translocation of β-catenin.
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http://dx.doi.org/10.1080/15384101.2021.2020431DOI Listing
January 2022

A new ALK inhibitor overcomes resistance to first- and second-generation inhibitors in NSCLC.

EMBO Mol Med 2022 Jan 30;14(1):e14296. Epub 2021 Nov 30.

State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, China.

More than 60% of nonsmall cell lung cancer (NSCLC) patients show a positive response to the first ALK inhibitor, crizotinib, which has been used as the standard treatment for newly diagnosed patients with ALK rearrangement. However, most patients inevitably develop crizotinib resistance due to acquired secondary mutations in the ALK kinase domain, such as the gatekeeper mutation L1196M and the most refractory mutation, G1202R. Here, we develop XMU-MP-5 as a new-generation ALK inhibitor to overcome crizotinib resistance mutations, including L1196M and G1202R. XMU-MP-5 blocks ALK signaling pathways and inhibits the proliferation of cells harboring either wild-type or mutant EML4-ALK in vitro and suppresses tumor growth in xenograft mouse models in vivo. Structural analysis provides insights into the mode of action of XMU-MP-5. In addition, XMU-MP-5 induces significant regression of lung tumors in two genetically engineered mouse (GEM) models, further demonstrating its pharmacological efficacy and potential for clinical application. These preclinical data support XMU-MP-5 as a novel selective ALK inhibitor with high potency and selectivity. XMU-MP-5 holds great promise as a new therapeutic against clinically relevant secondary ALK mutations.
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http://dx.doi.org/10.15252/emmm.202114296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8749467PMC
January 2022

Establishment of reference (housekeeping) genes via quantitative real-time PCR for investigation of the genomic basis of abiotic stress resistance in Psammochloa villosa (Poaceae).

J Plant Physiol 2022 Jan 20;268:153575. Epub 2021 Nov 20.

School of Life Sciences, Qinghai Normal University, Xining, 810008, China.

Psammochloa villosa is a desert plant growing in Northwest China with considerable resistance to abiotic stress, including drought, cold, and salt. To facilitate future studies of stress resistance in Psammochloa villosa, we sought to establish a suite of reference (or housekeeping) genes for utilization within future gene expression studies. Specifically, we selected nine candidate genes based on prior studies and new transcriptomic data for P. villosa, and we evaluated their expression stability in three different tissues of P. villosa under different treatments simulating abiotic stress conditions using four different bioinformatics assessments. Our results showed that TIP41 (TIP41-like family protein) was the most stable reference gene in drought- and salt-stressed leaves and salt-stressed stems, ELF-1α (elongation factor 1-α) was the most stable in cold-stressed leaves and drought- and salt-stressed roots, ACT (actin) was the most stable in drought-stressed stems, TUA (α-tubulin) was the most stable in cold-stressed stems, and 18S rRNA (18S ribosomal RNA) was the most stable in cold-stressed roots. Additionally, we tested the utility of these candidate reference genes to detect the expression pattern of P5CS (Δ-pyrroline-5-carboxylate synthetase), which is a drought-related gene. This study is the first report on selecting and validating reference genes of P. villosa under various stress conditions and will benefit future investigations of the genomic mechanisms of stress resistance in this ecologically important species.
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http://dx.doi.org/10.1016/j.jplph.2021.153575DOI Listing
January 2022

Pancreas-specific CHRM3 activation causes pancreatitis in mice.

JCI Insight 2021 09 8;6(17). Epub 2021 Sep 8.

Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida, USA.

Hyperstimulation of the cholecystokinin 1 receptor (CCK1R), a G protein-coupled receptor (GPCR), in pancreatic acinar cells is commonly used to induce pancreatitis in rodents. Human pancreatic acinar cells lack CCK1R but express cholinergic receptor muscarinic 3 (M3R), another GPCR. To test whether M3R activation is involved in pancreatitis, a mutant M3R was conditionally expressed in pancreatic acinar cells in mice. This mutant receptor loses responsiveness to its native ligand, acetylcholine, but can be activated by an inert small molecule, clozapine-N-oxide (CNO). Intracellular calcium and amylase were elicited by CNO in pancreatic acinar cells isolated from mutant M3R mice but not WT mice. Similarly, acute pancreatitis (AP) could be induced by a single injection of CNO in the transgenic mice but not WT mice. Compared with the cerulein-induced AP, CNO caused more widespread acinar cell death and inflammation. Furthermore, chronic pancreatitis developed at 4 weeks after 3 episodes of CNO-induced AP. In contrast, in mice with 3 recurrent episodes of cerulein-included AP, pancreas histology was restored in 4 weeks. Furthermore, the M3R antagonist ameliorated the severity of cerulein-induced AP in WT mice. We conclude that M3R activation can cause the pathogenesis of pancreatitis. This model may provide an alternative approach for pancreatitis research.
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http://dx.doi.org/10.1172/jci.insight.132585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8492327PMC
September 2021

MiR-195 inhibits the ubiquitination and degradation of YY1 by Smurf2, and induces EMT and cell permeability of retinal pigment epithelial cells.

Cell Death Dis 2021 07 15;12(7):708. Epub 2021 Jul 15.

Department of Ophthalmology, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi Province, P. R. China.

The dysregulated microRNAs (miRNAs) are involved in diabetic retinopathy progression. Epithelial mesenchymal transition (EMT) and cell permeability are important events in diabetic retinopathy. However, the function and mechanism of miR-195 in EMT and cell permeability in diabetic retinopathy remain largely unclear. Diabetic retinopathy models were established using streptozotocin (STZ)-induced diabetic mice and high glucose (HG)-stimulated ARPE-19 cells. Retina injury was investigated by hematoxylin-eosin (HE) staining. EMT and cell permeability were analyzed by western blotting, immunofluorescence, wound healing, and FITC-dextran assays. MiR-195 expression was detected via qRT-PCR. YY1, VEGFA, Snail1, and Smurf2 levels were detected via western blotting. The interaction relationship was analyzed via ChIP, Co-IP, or dual-luciferase reporter assay. The retina injury, EMT, and cell permeability were induced in STZ-induced diabetic mice. HG induced EMT and cell permeability in ARPE-19 cells. MiR-195, YY1, VEGFA, and Snail1 levels were enhanced, but Smurf2 abundance was reduced in STZ-induced diabetic mice and HG-stimulated ARPE-19 cells. VEGFA knockdown decreased Snail1 expression and attenuated HG-induced EMT and cell permeability. YY1 silence reduced VEGFA and Snail1 expression, and mitigated HG-induced EMT and cell permeability. YY1 could bind with VEGFA and Snail1, and it was degraded via Smurf2-mediated ubiquitination. MiR-195 knockdown upregulated Smurf2 to decrease YY1 expression and inhibited HG-induced EMT and cell permeability. MiR-195 targeted Smurf2, increased expression of YY1, VEGFA, and Snail1, and promoted HG-induced EMT and cell permeability. MiR-195 promotes EMT and cell permeability of HG-stimulated ARPE-19 cells by increasing VEGFA/Snail1 via inhibiting the Smurf2-mediated ubiquitination of YY1.
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http://dx.doi.org/10.1038/s41419-021-03956-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8282777PMC
July 2021

Role of Prealbumin in Predicting the Prognosis of Severely and Critically Ill COVID-19 Patients.

Am J Trop Med Hyg 2021 08 9;105(3):718-726. Epub 2021 Aug 9.

2Department of Paediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, P.R. China.

Most critically ill patients experience malnutrition, resulting in a poor prognosis. This study aimed to evaluate the association of prealbumin (PAB) with the prognosis for severely and critically ill coronavirus disease 2019 (COVID-19) patients and explore factors related to this association. Patients with laboratory-confirmed COVID-19 from West Campus of Union Hospital in Wuhan from January 29, 2020 to March 31, 2020 were enrolled in this study. Patients were classified into the PAB1 (150-400 mg/L; N = 183) and PAB2 (< 150 mg/L; N = 225) groups. Data collection was performed using the hospital's electronic medical records system. The predictive value of PAB was evaluated by measuring the area under the receiver-operating characteristic (AUROC) curve. Patients were defined as severely or critically ill based on the Guidance for COVID-19 (7th edition) by the National Health Commission of China. During this analysis, 316 patients had severe cases and 65 had critical cases. A reduced PAB level was associated with a higher risk of mortality and a longer hospital stay. The AUROC curve for the prognosis based on the PAB level was 0.93, with sensitivity of 97.2% and specificity of 77.6%. For severe cases, a lower level of PAB was associated with a higher risk of malnutrition, higher NK cell counts, and lower B lymphocyte counts; these factors were not significant in critical cases. C-reactive protein and nutritional status mediated the association between PAB and prognosis. This retrospective analysis suggests that the PAB level on admission is an indicator of the prognosis for COVID-19.
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http://dx.doi.org/10.4269/ajtmh.21-0234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8592333PMC
August 2021

An Optimized Integrin α6-Targeted Magnetic Resonance Probe for Molecular Imaging of Hepatocellular Carcinoma in Mice.

J Hepatocell Carcinoma 2021 24;8:645-656. Epub 2021 Jun 24.

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.

Introduction: Integrin α6 is an attractive diagnostic biomarker for molecular imaging of hepatocellular carcinoma (HCC) as it has an extremely high positive rate (approximately 94%) in clinical early-stage HCC. In this study, based on our previously identified integrin α6-targeted peptide, we developed an optimized integrin α6-targeted magnetic resonance (MR) probe dubbed DOTA(Gd)-ANADYWR for MR imaging of HCC in mice.

Materials And Methods: The longitudinal (R) relaxivity of DOTA(Gd)-ANADYWR was measured on a 3.0 T MR system . The specific tumor enhancement of the agent was investigated in four distinct mouse models, including subcutaneous, orthotopic, genetically engineered and chemically induced HCC mice.

Results: The R relaxivity value of DOTA(Gd)-ANADYWR is 5.11 mMs at 3.0 T, which is similar to that of the nonspecific clinical agent Gadoteridol. DOTA(Gd)-ANADYWR generated superior enhanced MR signal in HCC lesions and provided complementary enhancement MR signals to the clinically available hepatobiliary MR contrast agent gadoxetate disodium (Gd-EOB-DTPA). Importantly, DOTA(Gd)-ANADYWR could efficiently visualize small HCC lesion (approximately 1 mm) which was hardly detected by the clinical Gd-EOB-DTPA.

Conclusion: These findings suggest the potential application of this integrin α6-targeted MR probe for the detection of HCC, particularly for small HCC.
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http://dx.doi.org/10.2147/JHC.S312921DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8244641PMC
June 2021

A diastolic dysfunction model in non-human primates with transverse aortic constriction.

Exp Anim 2021 Nov 15;70(4):498-507. Epub 2021 Jun 15.

National Heart Research Institute Singapore, National Heart Centre Singapore, 5 Hospital Drive, 169609, Singapore.

Transverse aortic constriction (TAC) has been widely used to study cardiac hypertrophy, fibrosis, diastolic dysfunction, and heart failure in rodents. Few studies have been reported in preclinical animal models. The similar physiology and anatomy between non-human primates (NHPs) and humans make NHPs valuable models for disease modeling and testing of drugs and devices. In the current study, we aimed to establish a TAC model in NHPs and characterize the structural and functional profiles of the heart after TAC. A non-absorbable suture was placed around the aorta between the brachiocephalic artery and left common carotid artery to create TAC. NHPs were divided into 2 groups according to pressure gradient (PG): the Mild Group (PG=31.01 ± 12.40 mmHg, n=3) and the Moderate Group (PG=53.00 ± 9.37 mmHg, n=4). At 4 weeks after TAC, animals in both TAC groups developed cardiac hypertrophy: enlarged myocytes and increased wall thickness of the left ventricular (LV) anterior wall. Although both TAC groups had normal systolic function that was similar to a Sham Group, the Moderate Group showed diastolic dysfunction that was associated with more severe cardiac fibrosis, as evidenced by a reduced A wave velocity, large E wave velocity/A wave velocity ratio, and short isovolumic relaxation time corrected by heart rate. Furthermore, no LV arrhythmia was observed in either animal group after TAC. A diastolic dysfunction model with cardiac hypertrophy and fibrosis was successfully developed in NHPs.
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http://dx.doi.org/10.1538/expanim.21-0050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8614021PMC
November 2021

LACTB and LC3 could serve as potential biomarkers of gastric cancer to neoadjuvant chemotherapy with oxaliplatin plus S-1.

Oncol Lett 2021 Jun 13;21(6):470. Epub 2021 Apr 13.

Department of Pathology, Guizhou Medical University, Guiyang, Guizhou 550004, P.R. China.

The present study investigated and evaluated the correlation between the expression of LACTB and LC3 and the clinical outcomes of patients with advanced gastric cancer treated with oxaliplatin plus S-1 neoadjuvant chemotherapy (NACT). A total of 51 patients with advanced gastric cancer underwent NACT treatment between June 2015 and June 2017. Pathomorphological changes in gastric cancer were analyzed by H&E staining. The expression level and subcellular localization of LACTB and LC3 in paraffin-embedded biopsies were detected by immunohistochemistry and immunofluorescence. The mRNA and protein expression of LACTB were investigated by reverse transcription quantitative polymerase chain reaction and Western blotting, respectively. Statistical analysis was performed to determine the association between the expression of LACTB and LC3 and clinical chemotherapy efficacy of NACT for gastric cancer. Among the 51 patients, 3 (5.88%), 27 (52.94%), 13 (25.49%) and 8 (15.69%) displayed complete remission, partial remission, stable disease and progressive disease, respectively. The rate of decreased LACTB expression was 68.6%, while the rate of increased LC3 expression was 60.8%. Furthermore, there was a significant negative correlation between the expression of LACTB and that of LC3 following NACT (P<0.001). High expression of LC3 (P<0.01) and low expression of LACTB (P<0.01) were associated with a poor response of patients with advanced gastric cancer to NACT. In conclusion, the expression of LACTB and LC3 may serve as a promising novel biomarker for determining the prognosis of patients with advanced gastric cancer receiving NACT, while its potential clinical significance requires further elucidation.
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http://dx.doi.org/10.3892/ol.2021.12731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8063359PMC
June 2021

Suppressing long noncoding RNA OGRU ameliorates diabetic retinopathy by inhibition of oxidative stress and inflammation via miR-320/USP14 axis.

Free Radic Biol Med 2021 06 21;169:361-381. Epub 2021 Mar 21.

Department of Ophthalmology, The Second Affiliated Hospital of Nanchang University, Minde Road, Nanchang, 330006, PR China.

Long noncoding RNAs (lncRNAs) are important regulators in various diseases including diabetic retinopathy (DR). In this study, DR patients exhibited significantly increased expression of serum LncRNA-OGRU compared with normal individuals. Streptozotocin (STZ)-challenged rats with DR also had higher OGRU expression in retinas than that of the control group, which was confirmed in Müller cells upon high glucose (HG) stimulation. OGRU knockdown remarkably decreased vascular endothelial growth factor (VEGF) and transforming growth factor-β1 (TGF-β1) expression in HG-incubated Müller cells. HG-induced inflammatory response and oxidative stress in vitro were markedly mitigated by OGRU knockdown through restraining IκBɑ/nuclear factor kappa beta (NF-κB) and improving nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathways, respectively. Further studies indicated that OGRU suppression greatly restored miR-320 expression, and a negative correlation between them was detected in DR patients. We also found that miR-320 over-expression considerably restrained TGF-β1 signaling, and hindered inflammation and reactive oxygen species (ROS) production in HG-stimulated Müller cells. Additionally, OGRU knockdown or miR-320 over-expression could dramatically down-regulate ubiquitin-specific peptidase 14 (USP14) expression levels in HG-incubated Müller cells, and miR-320 could directly target USP14. Notably, OGRU/miR-320 axis-mediated TGF-β1 signaling, inflammation and ROS were largely dependent on USP14. Intriguingly, our results showed that USP14 directly interacted with transforming growth factor-beta type 1 receptor (TβR1), and impeded TβR1 ubiquitination and degradation. Furthermore, USP14 could also facilitate IκBɑ deubiquitination and degradation, exacerbating IκBɑ phosphorylation and NF-κB activation. Finally, our in vivo studies confirmed that OGRU knockdown considerably ameliorated DR progression in STZ-challenged rats through mediating the mechanisms observed in vitro. Collectively, these findings implicated that LncRNA-OGRU mediated DR progression through competing for miR-320 to regulate USP14 expression, and thus LncRNA-OGRU/miR-320/USP14 axis may be considered as a therapeutic target for DR treatment.
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http://dx.doi.org/10.1016/j.freeradbiomed.2021.03.016DOI Listing
June 2021

LACTB induced apoptosis of oxaliplatin-resistant gastric cancer through regulating autophagy-mediated mitochondrial apoptosis pathway.

Am J Transl Res 2021 15;13(2):601-616. Epub 2021 Feb 15.

Department of Pathology, Guizhou Medical University Guiyang, Guizhou, China.

Oxaliplatin (OXA), as a third-generation platinum anticancer drug, is a treatment drug for gastric cancer (GC). However, OXA resistance has become the main reason for OXA treatment failure. Serine beta-lactamase-like protein (LACTB), acts as a mitochondrial protein, can affect multiple cancer processes. Here, we aimed to investigate the function and mechanism of LACTB in OXA-resistant GC. After LACTB overexpression or autophagy activator (RAPA) treatment, cell proliferation, reactive oxygen species (ROS), apoptosis, mitochondrial dysfunction were evaluated through CCK-8 assay, Edu staining, flow cytometry and immunofluorescence assay. Moreover, DNA double-stranded damage and autophagy-related proteins were examined via western blot. We revealed that LACTB was downregulated in OXA-resistant MGC-803 cells, and overexpression of LACTB reduced the resistance of GC cells to OXA. Besides, our results uncovered that overexpression of LACTB induced apoptosis, reduced the mitochondrial membrane potential (MMP) and accelerated ROS accumulation in OXA-resistant MGC-803 (MGC-803/OXA) cells. Meanwhile, we verified that overexpression of LACTB decreased glucose uptake and ATP synthesis, induced mitochondria and DNA damages, and inhibited autophagy of MGC-803/OXA cells. Furthermore, our results certified that RAPA could weaken the function of LACTB on apoptosis and mitochondrial morphology and function in OXA-resistant MGC-803 cells with OXA treatment. Therefore, we demonstrated that LACTB could attenuate the resistance of MGC-803/OXA cells to OXA through autophagy-mediated mitochondrial morphological changes, mitochondrial dysfunction, and apoptosis, suggesting that LACTB, functions as a suppressor, is conducive to the therapy of OXA-resistant GC.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868839PMC
February 2021

Pretreatment abnormalities in white matter integrity predict one-year clinical outcome in first episode schizophrenia.

Schizophr Res 2021 02 22;228:241-248. Epub 2021 Jan 22.

Huaxi MR Research Center (HMRRC), Department of Radiology, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China; Psychoradiology Research Unit of Chinese Academy of Medical Sciences, Functional and Molecular Imaging Key Laboratory of Sichuan Province, West China Hospital of Sichuan University, Chengdu 610041, China.

Schizophrenia is a serious mental illness for which the mainstay of treatment is antipsychotics. Up to 30% of schizophrenia patients show limited response to antipsychotics. Identifying these patients before treatment could guide individualized treatment for improving outcomes in those not likely to show robust benefit from antipsychotics. Diffusion tensor imaging was performed with 56 drug-naïve first-episode schizophrenia patients and 69 matched healthy controls. Patients were followed clinically after one-year of antipsychotic treatment and classified at that point into groups of 17 poor outcome and 39 good outcome patients based on whether they showed at least a 50% reduction of Positive and Negative Syndrome Scale (PANSS) scores from baseline. Tract-based spatial statistics were applied to assess white matter microstructure in the two patient subgroups and healthy controls. Poor outcome patients showed reduced pretreatment fractional anisotropy (FA) in left cingulum and anterior thalamic radiation and increased FA in right superior and inferior longitudinal fasciculus compared with good outcome patients. FA in each of these four tracts was decreased in both patient subgroups relative to healthy controls. Considered together, the four altered tracts showed promising ability to differentiate poor from good outcome patients (sensitivity = 74.4%, specificity = 95.2%, AUC = 0.90, p < 0.001), and superior prediction of clinical outcome to baseline PANSS scores (p < 0.015). Prediction of outcomes using DTI features was not related to duration of untreated psychosis. Baseline alterations in white matter integrity may identify schizophrenia patients less likely to respond to treatment, which could be useful information for stratification in clinical trials and for individualized treatment planning.
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http://dx.doi.org/10.1016/j.schres.2020.12.011DOI Listing
February 2021

The complete chloroplast genome sequence of , a herb with volatile aroma component.

Mitochondrial DNA B Resour 2020 Jan 14;5(1):595-596. Epub 2020 Jan 14.

The College of Ecological Environmental and Resources, Qinghai Nationalities University, Xining, China.

The complete chloroplast genome sequence of was analysed. The results indicated that the size of the chloroplast genome was 149,095 bp in length with a large single-copy region (LSC) of 81,497 bp, a small single-copy region (SSC) of 17,364 bp, and a pair of inverted repeat (IR) regions of 25,117bp. The overall GC content of the cpDNA genome was 37.86%, while the corresponding values of the LSC, SSC, and IR regions were 35.96%, 31.92%, and 43.16%, respectively. A total of 132 functional genes were identified, including 84 protein-coding genes, 37 tRNA genes, and 8 rRNA genes. The maximum likelihood phylogenetic tree suggested that was closely related to the species in the family Labiatae.
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http://dx.doi.org/10.1080/23802359.2019.1710597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7748739PMC
January 2020

Endothelial Dysfunction in Diabetic Retinopathy.

Front Endocrinol (Lausanne) 2020 4;11:591. Epub 2020 Sep 4.

Department of Ophthalmology, The Second Affiliated Hospital of Nanchang University, Nanchang, China.

Diabetic retinopathy (DR) is a diabetic complication which affects retinal function and results in severe loss of vision and relevant retinal diseases. Retinal vascular dysfunction caused by multifactors, such as advanced glycosylation end products and receptors, pro-inflammatory cytokines and chemokines, proliferator-activated receptor-γ disruption, growth factors, oxidative stress, and microRNA. These factors promote retinal endothelial dysfunction, which results in the development of DR. In this review, we summarize the contributors in the pathophysiology of DR for a better understanding of the molecular and cellular mechanism in the development of DR with a special emphasis on retinal endothelial dysfunction.
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http://dx.doi.org/10.3389/fendo.2020.00591DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499433PMC
May 2021

MiR-1224-5p acts as a tumor suppressor via inhibiting the malignancy of rectal cancer through targeting SLC29A3.

IUBMB Life 2020 10 1;72(10):2204-2213. Epub 2020 Aug 1.

Department of Thoracic Surgery, Luoyang Central Affiliated to Zhengzhou university, Luoyang, P. R. China.

The emphasis of our study was to determine the physiological function of miR-1224-5p in rectal cancer (RC) and its in-depth mechanism. First, the expression of miR-1224-5p in RC tissues was analyzed using public data from the TCGA database. Then, miR-1224-5p expression in RC cell lines SW480 and SW837 was measured using the qRT-PCR assay. The subsequent CCK-8 assay was executed to assess the function of miR-1224-5p in the viability of the RC cell. Bioinformatics prediction prompted that SLC29A3 may be a potential target gene for miR-1224-5p. Western blotting and dual-luciferase reporter assays were performed to affirm the above forecasting. Kaplan-Meier analysis and Cox multivariate analysis were carried out to assess the relationship between SLC29A3 and prognosis. Finally, CCK-8, colony formation assay, and transwell assay were used for functional analysis of miR-1224-5p/ SLC29A3 axis in vitro. MiR-1224-5p was expressed at low levels in RC tissues and cell lines. Up-regulation of miR-1224-5p inhibited SW480 cell viability, while inhibition of miR-1224-5p enhanced the viability of SW837 cells. What is more, we affirmed that miR-1224-5p could direct target SLC29A3, which was expressed at high levels in RC tissues. In addition, SLC29A3 could be used as an independent predictive factor of prognosis in patients with RC, and the higher SLC29A3 expression, the lower survival rate. Finally, cellular functional experiments evidenced that miR-1224-5p mimic can reduce the cell viability, invasion, and migration, while overexpression of SLC29A3 presented an opposite effect. Importantly, co-transfection experiments indicated that SLC29A3 can reverse miR-1224-5p-mediated inhibition in the malignant progression of RC cells. Our work raised the possibility that miR-1224-5p functioned as a tumor suppressor in RC, which achieved its function via targeting SLC29A3.
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http://dx.doi.org/10.1002/iub.2352DOI Listing
October 2020

Oncogenic microRNA-301b regulates tumor repressor dystrobrevin alpha to facilitate cell growth, invasion and migration in esophageal cancer.

Esophagus 2021 Apr 31;18(2):315-325. Epub 2020 Jul 31.

Department of Thoracic Surgery, Luoyang Central Hospital Affiliated to Zhengzhou University, No. 288 Zhong Zhou Zhong Road, Luoyang, 471000, Henan, People's Republic of China.

Background: Esophageal cancer (EC) ranks the eighth in morbidity and the sixth in mortality around the whole world, which is an aggressive malignancy. To authenticate potential therapeutic targets for EC is therefore imperative. Although miR-301b might display changed expression in esophageal adenocarcinoma by utilizing Taqman miRNA profiling analysis, much less is known about the impact of miR-301b in EC.

Methods And Results: By analyzing the data of 187 cancer tissues and 13 normal samples from TCGA database, we discovered that miR-301b was highly expressed in EC tissues. Then, RT-qPCR determined that miR-301b was up-regulated in EC cell lines (ECA109, JAR, TE-1 and OE33). Besides, miR-301b expression level was higher in ESCC cell line-TE-1 cells and lower in ESCC cell line-ECA109 cells compared to other EC cell lines. Hence, ECA109 cell line was used to up-regulate miR-301b expression while TE-1 cell line was applied to down-regulate miR-301b expression in the subsequent experiments. Additionally, OE33, as an ECA cell line, was applied to upregulate miR-301b expression to reflect the influence of miR-301b overexpression on EC progression. More interestingly, miR-301b appeared to act as a promoting effect on the proliferation of EC cells, which was tested by CCK8. Dystrobrevin alpha (DTNA) was a targeting gene of miR-301b, which was predicted by the websites of miRanda, miRWalk and TargetScan. Additionally, DTNA was low expressed in EC tissues and was an independent predictor of EC. Meanwhile, the low expression of DTNA was related to worse overall survival in EC patients. The Pearson correlation coefficient analyzed that DTNA expression was negatively correlated with miR-301b. Furthermore, RT-qPCR and western blotting assays ulteriorly indicated that DTNA was negatively modulated by miR-301b. The facilitating impact of miR-301b re-expression on ECA109 and OE33 cell growth, invasion and migration was receded by DTNA over-expression, whilst the repressive effect of miR-301b ablation on TE-1 cell growth, invasion and migration was inversed by DTNA silencing. Overexpression of miR-301b accelerated EC cell growth, migration and invasion through targeting DTNA.

Conclusions: Above all, we concluded that miR-301b was concerned with the progression of EC via regulating DTNA, suggesting that miR-301b and its target gene, DTNA, might serve as predictive biomarkers for EC therapy.
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http://dx.doi.org/10.1007/s10388-020-00764-3DOI Listing
April 2021

Evaluation of Nutrition Risk and Its Association With Mortality Risk in Severely and Critically Ill COVID-19 Patients.

JPEN J Parenter Enteral Nutr 2021 01 20;45(1):32-42. Epub 2020 Jul 20.

Department of Paediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, P. R. China.

Background: The nutrition status of coronavirus disease 2019 patients is unknown. This study evaluates clinical and nutrition characteristics of severely and critically ill patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and investigates the relationship between nutrition risk and clinical outcomes.

Methods: A retrospective, observational study was conducted at West Campus of Union Hospital in Wuhan. Patients confirmed with SARS-CoV-2 infection by a nucleic acid-positive test and identified as severely or critically ill were enrolled in this study. Clinical data and outcomes information were collected and nutrition risk was assessed using Nutritional Risk Screening 2002 (NRS).

Results: In total, 413 patients were enrolled in this study, including 346 severely and 67 critically ill patients. Most patients, especially critically ill patients, had significant changes in nutrition-related parameters and inflammatory markers. As for nutrition risk, the critically ill patients had significantly higher proportion of high NRS scores (P < .001), which were correlated with inflammatory and nutrition-related markers. Among 342 patients with NRS score ≥3, only 84 (of 342, 25%) received nutrition support. Critically ill patients and those with higher NRS score had a higher risk of mortality and longer stay in hospital. In logistic regression models, 1-unit increase in NRS score was associated with the risk of mortality increasing by 1.23 times (adjusted odds ratio, 2.23; 95% CI, 1.10-4.51; P = .026).

Conclusions: Most severely and critically ill patients infected with SARS-CoV-2 are at nutrition risk. The patients with higher nutrition risk have worse outcome and require nutrition therapy.
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http://dx.doi.org/10.1002/jpen.1953DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7361906PMC
January 2021

[A preliminary study on schizophrenia of distinct antipsychotic response based on diffusion tensor imaging].

Sheng Wu Yi Xue Gong Cheng Xue Za Zhi 2020 Jun;37(3):480-486

Huaxi MR Research Center (HMRRC), Department of Radiology, West China Hospital of Sichuan University, Chengdu 610041, P.R.China.

The study aims to investigate whether there is difference in pre-treatment white matter parameters in treatment-resistant and treatment-responsive schizophrenia. Diffusion tensor imaging (DTI) was acquired from 60 first-episode drug-naïve schizophrenia (39 treatment-responsive and 21 treatment-resistant schizophrenia patients) and 69 age- and gender-matched healthy controls. Imaging data was preprocessed via FSL software, then diffusion parameters including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) were extracted. Besides, structural network matrix was constructed based on deterministic fiber tracking. The differences of diffusion parameters and topology attributes between three groups were analyzed using analysis of variance (ANOVA). Compared with healthy controls, treatment-responsive schizophrenia showed altered white matter mainly in anterior thalamus radiation, splenium of corpus callosum, cingulum bundle as well as superior longitudinal fasciculus. While treatment-resistant schizophrenia patients showed white matter abnormalities in anterior thalamus radiation, cingulum bundle, fornix and pontine crossing tract relative to healthy controls. Treatment-resistant schizophrenia showed more severe white matter abnormalities in anterior thalamus radiation compared with treatment-responsive patients. There was no significant difference in white matter network topological attributes among the three groups. The performance of support vector machine (SVM) showed accuracy of 63.37% in separating the two patient subgroups ( = 0.04). In this study, we showed different patterns of white matter alterations in treatment-responsive and treatment-resistant schizophrenia compared with healthy controls before treatment, which may help guiding patient identification, targeted treatment and prognosis improvement at baseline drug-naïve state.
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http://dx.doi.org/10.7507/1001-5515.201905062DOI Listing
June 2020

Study on the influence of an underground low-light environment on human safety behavior.

Int J Occup Saf Ergon 2020 Jul 21:1-10. Epub 2020 Jul 21.

School of Emergency Management and Safety Engineering, China University of Mining and Technology (Beijing), Beijing, China.

This study aimed to research the impact that a coal mine lighting environment has on human safety behavior in an underground coal mine. We built a coal mine lighting simulation experiment system including both general lighting and local lighting divided into six different illumination gradients (0, 10, 30, 50, 75 and 100 lx) to test and analyze the effects of general illumination gradients on human fatigue, attention, reaction and eye-hand coordination with SPSS version 22.0. . Illuminance has a significant effect on human fatigue, attention, reaction ability and eye-hand coordination ability. Specifically, human fatigue is negatively correlated and the other indicators are positively correlated with the increase of illuminance. Notably, attention distribution ability seems to be most significantly influenced by illuminance according to this study, followed by human fatigue, reaction and eye-hand coordination ability. The results of the study indicate that illumination of the general lighting environment is expected to be controlled at a gradient of at least 50-75 lx or above in the coal mine environment where there is both general lighting and local lighting to reduce the incidence of accidents.
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http://dx.doi.org/10.1080/10803548.2020.1784586DOI Listing
July 2020

Targeting RIPK3 oligomerization blocks necroptosis without inducing apoptosis.

FEBS Lett 2020 07 1;594(14):2294-2302. Epub 2020 Jun 1.

School of Life Sciences, Xiamen University, Xiamen, China.

Receptor-interacting serine/threonine-protein kinase 3 (RIPK3) is a central protein in necroptosis with great potential as a target for treating necroptosis-associated diseases, such as Crohn's disease. However, blockade of RIPK3 kinase activity leads to unexpected RIPK3-initiated apoptosis. Herein, we found that PP2, a known SRC inhibitor, inhibits TNF-α-induced necroptosis without initiating apoptosis. Further investigation showed that PP2 acts as an inhibitor of not only SRC but also RIPK3. PP2 does not disturb the integrity of the RIPK1-RIPK3-mixed lineage kinase domain-like pseudokinase (MLKL) necroptosome or the autophosphorylation of RIPK3 at T231/S232 but disrupts RIPK3 oligomerization, thereby impairing the phosphorylation and oligomerization of MLKL. These results demonstrate the essential role of RIPK3 oligomerization in necroptosis and suggest a potential RIPK3 oligomerization-targeting strategy for therapeutic development.
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http://dx.doi.org/10.1002/1873-3468.13812DOI Listing
July 2020

Anatomic abnormalities of hippocampal subfields in never-treated and antipsychotic-treated patients with long-term schizophrenia.

Eur Neuropsychopharmacol 2020 06 10;35:39-48. Epub 2020 May 10.

Huaxi MR Research Center (HMRRC), Department of Radiology, West China Hospital of Sichuan University, Chengdu, China. Electronic address:

Hippocampal volume deficits have been reported in chronically-treated schizophrenia patients, however, the longer-term effects of antipsychotic medications on hippocampal anatomy are unclear. This case-control study investigated volume differences in hippocampal subfields of never-treated and antipsychotic-treated patients with long-term schizophrenia. High spatial-resolution T1-weighted magnetic resonance images were collected from 29 never-treated and 40 antipsychotic-treated patients with long-term schizophrenia matched for illness duration (all ≥ 5 years), and 40 demographically-matched healthy controls. Hippocampal subfield volumes were measured using FreeSurfer v6.0, compared across groups and between hemispheres, and correlated with clinical features. Volume reductions were found in both patient groups compared to healthy controls in 8 of 26 hippocampal subfields (Cohen's d = 0.46 - 1.17, P = < .001 - .03), and more diffusely and obviously in never-treated than treated patients (Cohen's d = 0.50 - 0.90, P = < .001 - .04). Greater right-than-left volumes were seen in treated patients and healthy controls in 11 of 13 subfields (T = 2.30 - 7.29, P = < .001 - .03), but not in never-treated patients, in whom the volumes were reduced more on the right than on the left. Subfield volumes were negatively correlated with symptom severity and illness duration, and declined with age in never-treated patients. Findings indicate clinically-relevant and age-related volume reductions in hippocampal subfields of never-treated patients with long-term schizophrenia. Broader and greater subfield deficits in never-treated than treated patients, especially in the right hippocampus, suggest that long-term antipsychotic treatment may benefit hippocampal structures over the longer-term course of illness.
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http://dx.doi.org/10.1016/j.euroneuro.2020.03.020DOI Listing
June 2020

Analysis of a catastrophic commercial coach crash based on an improved accident causation model: cause classification and lessons learned.

Int J Occup Saf Ergon 2020 Jun 22:1-13. Epub 2020 Jun 22.

School of Transportation and Logistics Engineering, Shandong Jiaotong University, China.

This study aimed to perform an in-depth analysis of a catastrophic coach crash that occurred on the Chinese expressway, and thus draw useful lessons to avoid similar mistakes. Various causes were identified from the investigation report based on a proposed accident causation model, which provides a universal pathway for accident analysis from the individual level to the organizational level. Driver error in an emergency affected by fatigue and speeding led directly to the crash. Accordingly, drivers in coaches should be monitored effectively and their unsafe acts must be corrected in a timely manner to avoid the formation of unsafe habits. Based on individual flaws, weaknesses in the construction of the organizational safety management system and safety culture were further deduced and discussed. The work and rest system, as well as the dynamic monitoring system for drivers, should be perfected strictly according to the regulations. Additionally, external factors regarding deficiencies in the design and management of the expressway and the supervision of the transportation company also had great impact on this crash. In summary, more efforts should be taken regarding root causes at the organizational level, regardless of internal or external factors.
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http://dx.doi.org/10.1080/10803548.2020.1759314DOI Listing
June 2020

Expert consensus on the clinical application of enhanced external counterpulsation in elderly people (2019).

Aging Med (Milton) 2020 Mar 3;3(1):16-24. Epub 2020 Mar 3.

Department of Cardiovascular Medicine Research Center for Assisted Circulation Innovative Engineering Technologies The Eighth Affiliated Hospital of Sun Yat-sen University Shen-zhen city China.

Enhanced external counterpulsation (EECP) is a non-invasive assisted circulation technique and a rich pool of evidence has accumulated for its clinical application in the prevention and management of multiple comorbidities in the elderly population, including angina, heart failure, ischemic cerebrovascular diseases, neurodegenerative diseases, sleep disorder, diabetes and its complications, ischemic eye diseases, sudden hearing loss and erectile dysfunction, as well as various psychological and psychiatric conditions. When applying EECP to elderly patients, emphasis should be placed on issues such as safety assessment, risk management and protocol individualization, as well as the monitoring of efficacy during and after treatment.
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http://dx.doi.org/10.1002/agm2.12097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7099759PMC
March 2020

Trypsin activity governs increased susceptibility to pancreatitis in mice expressing human PRSS1R122H.

J Clin Invest 2020 01;130(1):189-202

Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida, USA.

Currently, an effective targeted therapy for pancreatitis is lacking. Hereditary pancreatitis (HP) is a heritable, autosomal-dominant disorder with recurrent acute pancreatitis (AP) progressing to chronic pancreatitis (CP) and a markedly increased risk of pancreatic cancer. In 1996, mutations in PRSS1 were linked to the development of HP. Here, we developed a mouse model by inserting a full-length human PRSS1R122H gene, the most commonly mutated gene in human HP, into mice. Expression of PRSS1R122H protein in the pancreas markedly increased stress signaling pathways and exacerbated AP. After the attack of AP, all PRSS1R122H mice had disease progression to CP, with similar histologic features as those observed in human HP. By comparing PRSS1R122H mice with PRSS1WT mice, as well as enzymatically inactivated Dead-PRSS1R122H mice, we unraveled that increased trypsin activity is the mechanism for R122H mutation to sensitize mice to the development of pancreatitis. We further discovered that trypsin inhibition, in combination with anticoagulation therapy, synergistically prevented progression to CP in PRSS1R122H mice. These animal models help us better understand the complex nature of this disease and provide powerful tools for developing and testing novel therapeutics for human pancreatitis.
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http://dx.doi.org/10.1172/JCI130172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6934224PMC
January 2020

Association of peripheral cytokine levels with cerebral structural abnormalities in schizophrenia.

Brain Res 2019 12 14;1724:146463. Epub 2019 Sep 14.

Department of Radiology, The Center for Medical Imaging, West China Hospital of Sichuan University, Chengdu, China; Huaxi MR Research Center (HMRRC), West China Hospital of Sichuan University, Chengdu, China. Electronic address:

A large body of evidence indicates that both the altered cytokines that mediate the immune-inflammatory process and abnormal gray matter are associated with schizophrenia. Whether peripheral cytokines are related to cerebral structural abnormality remains unclear. Therefore, we aimed to investigate the association of peripheral cytokine levels with gray matter abnormalities at the whole brain level in schizophrenia. Forty-four outpatients with schizophrenia and 44 controls were recruited. The serum levels of interleukin-1 beta (IL-1β), IL-2, IL-6, IL-8, interferon-gamma (IFN-γ), transforming growth factor-beta (TGF-β), and IL-10 were measured using a quantitative chemiluminescence assay. High-resolution T1 weighted images were acquired from all subjects and processed using FreeSurfer software to obtain the cortical thickness, surface area, and cortical and subcortical gray matter volumes. The cytokines and cerebral structures were compared between patients and controls using analysis of covariance (ANCOVA). The association between the cytokines and whole cerebral structures was performed using stepwise linear regression. Patients had higher levels of IL-2, IL-6, IL-8, and IL-10 than controls. In patients, the IL-6 level was significantly associated with the cortical thickness in the left pars opercularis, right pars triangularis, left superior temporal gyrus, and right middle temporal gyrus, which showed structural differences between the two groups. Altered cytokine levels may be associated with particular but not all cortical abnormalities in schizophrenia, especially IL-6, which was significantly associated with the abnormal cortical thickness of the bilateral Broca's area and temporal gyrus, which provided neuroimaging evidence to support the relationship between peripheral cytokines and the cerebral cortex in schizophrenia.
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http://dx.doi.org/10.1016/j.brainres.2019.146463DOI Listing
December 2019

A non-covalent inhibitor XMU-MP-3 overrides ibrutinib-resistant Btk mutation in B-cell malignancies.

Br J Pharmacol 2019 12 9;176(23):4491-4509. Epub 2019 Dec 9.

State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, State-Province Joint Engineering Laboratory of Targeted Drugs from Natural Products, School of Life Science, Xiamen University, Xiamen, China.

Background And Purpose: Bruton's tyrosine kinase (BTK) plays a key role in B-cell receptor signalling by regulating cell proliferation and survival in various B-cell malignancies. Covalent low-MW BTK kinase inhibitors have shown impressive clinical efficacy in B-cell malignancies. However, the mutant Btk poses a major challenge in the management of B-cell malignancies by disrupting the formation of the covalent bond between BTK and irreversible inhibitors, such as ibrutinib. The present studies were designed to develop novel BTK inhibitors targeting ibrutinib-resistant Btk mutation.

Experimental Approach: BTK-Ba/F3, BTK(C481S)-Ba/F3 cells, and human malignant B-cells JeKo-1, Ramos, and NALM-6 were used to evaluate cellular potency of BTK inhibitors. The in vitro pharmacological efficacy and compound selectivity were assayed via cell viability, colony formation, and BTK-mediated signalling. A tumour xenograft model with BTK-Ba/F3, Ramos and BTK(C481S)-Ba/F3 cells in Nu/nu BALB/c mice was used to assess in vivo efficacy of XMU-MP-3.

Key Results: XMU-MP-3 is one of a group of low MW compounds that are potent non-covalent BTK inhibitors. XMU-MP-3 inhibited both BTK and the acquired mutant BTKC481S, in vitro and in vivo. Further computational modelling, site-directed mutagenesis analysis, and structure-activity relationships studies indicated that XMU-MP-3 displayed a typical Type-II inhibitor binding mode.

Conclusion And Implications: XMU-MP-3 directly targets the BTK signalling pathway in B-cell lymphoma. These findings establish XMU-MP-3 as a novel inhibitor of BTK, which could serve as both a tool compound and a lead for further drug development in BTK relevant B-cell malignancies, especially those with the acquired ibrutinib-resistant C481S mutation.
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http://dx.doi.org/10.1111/bph.14809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6932946PMC
December 2019

Selective targeting of PARP-2 inhibits androgen receptor signaling and prostate cancer growth through disruption of FOXA1 function.

Proc Natl Acad Sci U S A 2019 07 2;116(29):14573-14582. Epub 2019 Jul 2.

Division of Urology, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;

Androgen receptor (AR) is a ligand-activated transcription factor and a key driver of prostate cancer (PCa) growth and progression. Understanding the factors influencing AR-mediated gene expression provides new opportunities for therapeutic intervention. Poly(ADP-ribose) Polymerase (PARP) is a family of enzymes, which posttranslationally modify a range of proteins and regulate many different cellular processes. PARP-1 and PARP-2 are two well-characterized PARP members, whose catalytic activity is induced by DNA-strand breaks and responsible for multiple DNA damage repair pathways. PARP inhibitors are promising therapeutic agents that show synthetic lethality against many types of cancer (including PCa) with homologous recombination (HR) DNA-repair deficiency. Here, we show that, beyond DNA damage repair function, PARP-2, but not PARP-1, is a critical component in AR transcriptional machinery through interacting with the pioneer factor FOXA1 and facilitating AR recruitment to genome-wide prostate-specific enhancer regions. Analyses of PARP-2 expression at both mRNA and protein levels show significantly higher expression of PARP-2 in primary PCa tumors than in benign prostate tissues, and even more so in castration-resistant prostate cancer (CRPC) tumors. Selective targeting of PARP-2 by genetic or pharmacological means blocks interaction between PARP-2 and FOXA1, which in turn attenuates AR-mediated gene expression and inhibits AR-positive PCa growth. Next-generation antiandrogens act through inhibiting androgen synthesis (abiraterone) or blocking ligand binding (enzalutamide). Selective targeting of PARP-2, however, may provide an alternative therapeutic approach for AR inhibition by disruption of FOXA1 function, which may be beneficial to patients, irrespective of their DNA-repair deficiency status.
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http://dx.doi.org/10.1073/pnas.1908547116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6642419PMC
July 2019

Brain Structural Alterations in Left-Behind Children: A Magnetic Resonance Imaging Study.

Front Neural Circuits 2019 8;13:33. Epub 2019 May 8.

Department of Radiology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.

Parental migration has caused millions of children left behind, especially in China and India. Left-behind children (LBC) have a high risk of mental disorders and may present negative life outcomes in the future. However, little is known whether there are cerebral structural alterations in LBC in relative to those with parents. This study is to explore the effect of parental migration on brain maturation by comparing gray matter volume (GMV) and fractional anisotropy (FA) of LBC with well-matched non-LBC. Thirty-eight LBC (21 boys, age = 9.60 ± 1.8 years) and 30 non-LBC (19 boys, age = 10.00 ± 1.95 years) were recruited and underwent brain scans in 3.0 T MR. Intelligence quotient and other factors including family income, guardians' educational level and separation time were also acquired. GMV and FA were measured for each participant and compared between groups using 2-sample -tests with atlas-based analysis. Compared to non-LBC, LBC exhibited greater GMV in emotional and cortico-striato-thalamo-cortical circuits, and altered FA in bilateral superior occipitofrontal fasciculi and right medial lemniscus ( < 0.05, Cohen's > 0.89, corrected for false-discovery rate). Other factors including family income, guardians' educational level and separation time were not associated with these brain changes. Our study provides empirical evidence of altered brain structure in LBC compared to non-LBC, responsible for emotion regulation and processing, which may account for mental disorders and negative life outcome of LBC. Our study suggests that absence of direct biological parental care may impact children's brain development. Therefore, public health efforts may be needed to provide additional academic and social/emotional supports to LBC when their parents migrate to seeking better economic circumstances, which has become increasingly common in developing countries.
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http://dx.doi.org/10.3389/fncir.2019.00033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6517480PMC
January 2020

Elevated intracellular trypsin exacerbates acute pancreatitis and chronic pancreatitis in mice.

Am J Physiol Gastrointest Liver Physiol 2019 06 3;316(6):G816-G825. Epub 2019 Apr 3.

Department of Cancer Biology, Mayo Clinic , Jacksonville, Florida.

Intra-acinar trypsinogen activation occurs in the earliest stages of pancreatitis and is believed to play important roles in pancreatitis pathogenesis. However, the exact role of intra-acinar trypsin activity in pancreatitis remains elusive. Here, we aimed to examine the specific effects of intra-acinar trypsin activity on the development of pancreatitis using a transgenic mouse model. This transgenic mouse model allowed for the conditional expression of a mutant trypsinogen that can be activated specifically inside pancreatic acinar cells. We found that expression of this active mutated trypsin had no significant effect on triggering spontaneous pancreatitis. Instead, several protective compensatory mechanisms, including SPINK1 and heat shock proteins, were upregulated. Notably, these transgenic mice developed much more severe acute pancreatitis, compared with control mice, when challenged with caerulein. Elevated tissue edema, serum amylase, inflammatory cell infiltration and acinar cell apoptosis were dramatically associated with increased trypsin activity. Furthermore, chronic pathological changes were observed in the pancreas of all transgenic mice, including inflammatory cell infiltration, parenchymal atrophy and cell loss, fibrosis, and fatty replacement. These changes were not observed in control mice treated with caerulein. The alterations in pancreata from transgenic mice mimicked the histological changes common to human chronic pancreatitis. Taken together, we provided in vivo evidence that increased intra-acinar activation of trypsinogen plays an important role in the initiation and progression of both acute and chronic pancreatitis. Trypsinogen is activated early in pancreatitis. However, the roles of trypsin in the development of pancreatitis have not been fully addressed. Using a genetic approach, we showed trypsin activity is critical for the severity of both acute and chronic pancreatitis.
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http://dx.doi.org/10.1152/ajpgi.00004.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6620583PMC
June 2019

Increased Peripheral Interleukin 10 Relate to White Matter Integrity in Schizophrenia.

Front Neurosci 2019 7;13:52. Epub 2019 Feb 7.

Huaxi MR Research Center, Department of Radiology, West China Hospital of Sichuan University, Chengdu, China.

Schizophrenia is characterized by the disruption of microstructural white matter (WM) integrity, while the pathogenesis remains unclear. Inflammation has been associated with the WM pathology in schizophrenia. Interleukin 10 (IL-10) has been proven to be related to schizophrenia in both animal and human models. The aim of this study was to explore whether peripheral IL-10 was associated with microstructural WM integrity in schizophrenia. A total of 47 patients with schizophrenia (SZ) and 49 healthy controls (HC) underwent diffusion tensor imaging and venous blood sampling. Tract-based spatial statistics was conducted to explore the differences in fractional anisotropy (FA), radial diffusivity (RD), mean diffusivity (MD), and axial diffusivity (AD) between patients and controls. A quantitative chemiluminescence assay was performed to measure peripheral IL-10 levels. General linear regression analysis using a stepwise method was applied to examine the relationship between peripheral IL-10 and diffusion measures. Compared with the HC, peripheral IL-10 levels were higher and a significant reduction of FA and AD, and increase of RD and MD were observed in SZ (corrected < 0.05). A regression analysis revealed that peripheral IL-10 was negatively correlated with FA in the right posterior thalamic radiation and left inferior fronto-occipital fasciculus, in SZ (β = -0.51, = 0.01; β = -0.47, = 0.02, respectively) but not in HC (β = -0.01, = 0.95; β = -0.003, = 0.98, respectively), and the differences in regression curves were significant ( = 2.50, = 0.01; = 2.37, = 0.02, respectively). IL-10 was negatively connected with MD in the right parietal arcuate fasciculus (β = -0.40, = 0.048) and body of the corpus callosum (β = -0.43, = 0.03) in SZ, while not in HC. The magnitude of correlation in the patient and control group was different ( = 2.48, = 0.01 and = 2.61, < 0.01, respectively). In addition, IL-10 was positively correlated with RD in the right parietal arcuate fasciculus in patients (β = 0.45, = 0.04) but not in HC (β = 0.26, = 0.94), but the correlation coefficients were not significant ( = 0.98, = 0.32). Our findings demonstrated that elevated peripheral IL-10 levels were associated with the disruption of microstructural WM integrity in schizophrenia, supporting the notion that inflammation plays a regulatory role in the pathology of microstructural WM and is associated with schizophrenia.
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http://dx.doi.org/10.3389/fnins.2019.00052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6374337PMC
February 2019
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